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.

Long-term follow-up of complete remission in a patient with advanced hepatocellular carcinoma treated with sorafenib: a case report.

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer and can be caused by well-known risk factors, including infection with hepatitis B and C viruses, alcohol intake, and metabolic syndrome. The overall prognosis remains poor with a median survival of 1 year for symptomatic advanced-stage cases treated with systemic therapies. Case description: In July 2020, a 73-year-old male patient presented at our institution with mild abdominal pain and an attack of intense cold. After a radiological workup, the diagnosis of HCC located in the caudate lobe was established. The patient underwent atypical caudate lobe resection, and pathology confirmed the diagnosis of grade 3 HCC. Postoperative MRI showed a new metastasis in the 6th liver segment 1.3 cm in diameter, and a PVT progression which now affected the whole right lobe. The patient was started on sorafenib and demonstrated a complete response which still lasts for more than two years. Conclusion: We present a rare case of a patient who demonstrated a complete response to sorafenib treatment in advanced HCC with unfavorable prognostic factors.

Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy.

Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy.

Differences in Outcomes Between Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer Patients in Upper Middle-Income versus High-Income Countries: A Retrospective Study from 4 Oncology Centers.

BACKGROUND Therapeutic options for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (mBC) are developing rapidly. This study aimed to determine the differences in the survival outcomes of patients with HER2-positive mBC in relation to access to anti-HER therapy at 3 oncology centers in upper-middle-income countries (UMICs) and 1 oncology center in a high-income country (HIC). MATERIAL AND METHODS We retrospectively identified 42 patients from Croatia (HIC), 71 patients from Serbia (UMIC), and 57 from Bosnia and Herzegovina (UMIC) diagnosed with HER2-positive mBC who were treated between January 2015 and December 2020. The pathohistological features of the tumors were obtained from the pathological findings, which were made according to standard procedures for each center. Patients were treated depending on the availability of therapy, which differed for centers in different countries. We evaluated disease-free survival, progression-free survival, and overall survival (OS) based on the availability of first- and second-line anti-HER2 therapy in UMICs vs HIC. RESULTS OS in first-line therapy was better in patients treated with dual HER2 blockade than in patients treated without dual HER2 blockade, P<0.001. OS in second-line therapy was significantly better in patients treated with trastuzumab emtansine than in patients treated with other reported regimens, P=0.004. CONCLUSIONS Results of our study showed superior survival among patients who were treated with dual first-line HER2 therapy as well as second-line trastuzumab emtansine therapy than in those patients in other centers where these drugs were not available. Raising awareness about this could help improve the situation.

Correlation between psychological resilience and burnout syndrome in oncologists amid the Covid-19 pandemic.

PURPOSE: Oncologists are predisposed to developing burnout syndrome. Like other health care professionals worldwide, oncologists have endured additional, extreme challenges during the Covid-19 pandemic. Psychological resilience presents a potential protective mechanism against burnout. This cross-sectional study examines whether psychological resilience eased burnout syndrome among Croatian oncologists during the pandemic. METHODS: An anonymized self-reporting questionnaire was electronically distributed by the Croatian Society for Medical Oncology to 130 specialist and resident oncologists working in hospitals. Available for completion from September 6-24, 2021, the survey comprised demographic questions; the Oldenburg Burnout Inventory (OLBI), covering exhaustion and disengagement; and the Brief Resilience Scale (BRS). The response rate was 57.7%. RESULTS: Burnout was moderate or high for 86% of respondents, while 77% had moderate or high psychological resilience. Psychological resilience was significantly negatively correlated with the OLBI exhaustion subscale (r = - .54; p < 0.001) and the overall OLBI score (r = - .46; p < 0.001). Scheffe's post hoc test showed that oncologists with high resilience scored significantly lower on the overall OLBI (M = 2.89; SD = 0.487) compared to oncologists with low resilience (M = 2.52; SD = 0.493). CONCLUSION: The findings thus indicate that oncologists with high psychological resilience are at significantly lower risk of developing burnout syndrome. Accordingly, convenient measures to encourage psychological resilience in oncologists should be identified and implemented.

DPYD genotyping and predicting fluoropyrimidine toxicity: where do we stand?

Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.

The effectiveness of nab-paclitaxel plus gemcitabine and gemcitabine monotherapy in first-line metastatic pancreatic cancer treatment: A real-world evidence.

Pancreatic cancer is one of the most lethal malignancies with a rise in mortality rates. FOLFIRINOX and nab-paclitaxel plus gemcitabine demonstrated a survival benefit compared to gemcitabine alone. Both protocols are now considered the standard of first-line treatment with no significant difference between them, primarily based on observational studies. Although new therapeutic options have emerged recently, the prognosis remains poor. We conducted a retrospective single-center study on 139 patients treated for metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine monotherapy (Gem) or nab-paclitaxel + gemcitabine (Nab-P/Gem) in the first line. The aim of our study was to evaluate the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) as well as the influence of patient and disease characteristics on outcomes. Nab-P/Gem resulted in OS of 13.87 months compared to 8.5 months in patients receiving Gem. The same trend was achieved in PFS, 5.37 versus 2.80 months, respectively, but without reaching statistical significance. Furthermore, the 6-month survival in the Nab-P/Gem group was also higher, 78.1% versus 47.8%. In terms of survival, the group of elderly patients, patients of poorer performance, with higher metastatic burden and liver involvement, benefited the most from combination therapy. In our analysis ECOG performance status (p.s.), previous primary tumor surgery, and liver involvement were found to be independent prognostic factors. The addition of nab-paclitaxel to gemcitabine resulted in a significant improvement in the OS of patients with mPDAC. Subgroup analysis demonstrated that patients with some unfavorable prognostic factors benefited the most.

DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine-based protocols.

AIMS: Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs. METHODS: Consecutive FP-treated adult patients were genotyped for "standard" and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms). RESULTS: Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) [OR = 5.20 (95% CI 1.88-14.3), Bayesian OR = 5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) [OR = 1.88 (0.95-3.73), Bayesian OR = 1.90 (1.03-3.56)]. c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). CONCLUSION: DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.

Gastric cancer detection using the serum pepsinogen test method.

BACKGROUND: Gastric cancer (GC) is the eighth most common cause of cancer deaths in Croatia and one of the most common causes of cancer deaths worldwide. A reliable diagnostic tool for the early detection of GC is essential. OBJECTIVE: We previously suggested a pepsinogen test method to reduce the mortality from GC by allowing early detection. Here, we report an updated analysis from a prospective single-center clinical study to evaluate the sensitivity and specificity of the pepsinogen test method and to determine whether this test can be used as a part of routine laboratory assessment of high-risk patients. METHODS: We present mature data of the pepsinogen test method in the Croatian population after a median follow-up of 36 months. Statistical analyses were performed using a Mann-Whitney U test, multiple logistic regression, and receiver operating characteristics (ROC) to evaluate the predictive power of the assayed biomarkers. RESULTS: Of the 116 patients, 25 patients had GC and 91 demonstrated a nonmalignant pathology based on tissue biopsy. Cutoff values were pepsinogen I ⩽70 and pepsinogen I/II ratio ⩽3.0. Using ROC curve analysis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were determined to be 87.22%, 78.12%, 90.10%, 71.43%, and 92.86%, respectively, for the diagnosis of GC. The area under the curve was 0.700 (95% confidence interval 0.57-0.83). CONCLUSION: Pepsinogen tests are valuable for screening a population in need of further diagnosis and could help to avoid unnecessary invasive endoscopic procedures.

Frequency of Body Weight Loss is an Independent Prognostic Factor of First-Line Treatment Outcomes in Metastatic Colorectal Cancer.

One of the main features of wasting in cancer is an involuntary weight loss which is most pronounced in gastrointestinal tract tumors and leads to worse clinical outcomes. The aim of this study is to analyze the frequency of body weight loss (FBWL) as an additional prognostic factor in the treatment of patients with metastatic colorectal cancer (mCRC).In this observational, single-center study, data were retrieved for 236 patients treated for mCRC. FBWL was defined as a percent of change in weight divided by weeks of therapy. Patients were stratified into two groups according to the median of FBWL which equaled to the loss of 0.05%/week. Patients who lost >0.05%/week (N = 116) had shorter progression-free survival (PFS) in the first-line treatment, then the ones who lost <0.05%/week (N = 120); 28.3 vs 46.3 weeks, respectively. Cox regression model showed that FBWL and sidedness were significant predictors of PFS, while age, sex and ECOG were not. Significantly more patients with stable weight were also eligible for second-line treatment. In conclusion, stabilization of body weight is important and independent predictor of longer PFS in first-line therapy of patients with mCRC.

Unlocking Access to Broad Molecular Profiling: Benefits, Barriers, and Policy Solutions.

OBJECTIVES: "Personalized healthcare" is generating new approaches to disease management by considering inter-individual variability in genes, environment, and lifestyle. Technologies such as comprehensive genomic profiling (CGP) are drivers of this shift. Here, we address the significant hurdles to the equitable implementation of CGP into routine clinical practice. METHODS: This article draws on published evidence on the value of genomic profiling, as well as interviews with nine academic and clinical experts from six different countries to validate findings and test policy proposals for reforms. RESULTS: The potential benefits of CGP extend beyond direct patient outcomes, to healthcare systems with societal and economic impacts. Among key barriers impeding integration into routine clinical practice are the lack of infrastructure to ensure reliable clinical testing and the limited understanding of genomics among healthcare personnel. In addition, the absence of health economic evidence supporting broader use of CGP is creating concerns for payers regarding the systemic benefits and affordability of this technology. CONCLUSION: Policy proposals that aim to improve equitable patient access to CGP will need to consider new funding models, health technology assessment processes that capture both patient and systemic benefits, and appropriate regulatory standards to determine the quality of genomic profiling tests.

Precision Oncology in Metastatic Uterine Cancer; Croatian First-Year Experience of the Comprehensive Genomic Profiling in Everyday Clinical Practice.

Comprehensive genomic profiling (CGP) is gradually becoming an inevitable part of the everyday oncology clinical practice. The interpretation and optimal implementation of the results is one of the hot topics of modern-day oncology. According to the recent findings, uterine cancer harbors a high level of gene alterations but is still insufficiently explored. The primary goal of this project was to assess the proportion of patients with targetable mutations. Also, the aim was to define and emphasize potential opportunities as well as the problems we have faced in the first year of testing on the national level. We performed a multicentric, retrospective, nested cross-sectional analysis on the total population of Croatian patients with advanced/metastatic uterine cancer where the tumor CGP was performed during 2020. CGP of the tumor tissue of 32 patients revealed clinically relevant genomic alterations (CRGA) in 27 patients (84%) with a median of 3 (IQR 1-4) CRGA per patient. The most common CRGAs were those of phosphatide-inositol-3 kinases (PIK3) in 22 patients (69%), with 13/22 (59%) of those patients harboring PIK3CA mutation. The next most common CGRAs were ARID1A and PTEN mutations in 13 (41%) and 11 (34%) patients, respectively. Microsatellite status was determined as stable in 21 patients (66%) and highly unstable in 10 patients (31%). A high tumor mutational burden (≥10Muts/Mb) was reported in 12 patients (38%). CGP analysis reported some kind of targeted therapy for 28 patients (88%). CGP determined clinically relevant genomic alterations in the significant majority of patients with metastatic uterine cancer, defining it as a rich ground for further positioning and development of precision oncology.

Impact of the coronavirus disease pandemic on cancer care in Croatia: a multicentre cross-sectional study.

PURPOSE: The coronavirus disease (COVID-19) pandemic has greatly affected the oncology community worldwide. Lockdowns, an epidemiological measure, have made it difficult for oncologists to provide care. In this study, we analysed the impact of the COVID-19 pandemic on Croatian cancer care. METHODS: This was a multicentre cross-sectional observational study of 422 patients who received systemic oncology therapy during the pandemic. The patients completed a survey to capture their views on the impact of the COVID-19 pandemic on their cancer care. Univariate descriptive and bivariate analyses were performed to analyse the relationship between the patients' perspective on the impact of the COVID-19 pandemic on cancer care and the quality of Croatian cancer care and their clinical and sociodemographic data. RESULTS: Discontinuation or change in cancer treatment during the COVID-19 pandemic was observed in 10.2% of cases. Most did not change their place of treatment owing to the lockdown (97.6%). 14.7% of the patients felt that the quality of cancer care received had changed during the pandemic. CONCLUSIONS: In the first few months of the pandemic, Croatia had a favourable epidemiological situation. However, 25% of patients with cancer reported that the pandemic affected cancer treatment and the quality of cancer care.

Is it too expensive to fight cancer? Analysis of incremental costs and benefits of the Croatian National Plan Against Cancer.

This cost-effectiveness study analyses the expected impacts of activities proposed by the Croatian National Plan Against Cancer (NPAC) on cancer incidence and survival rates, as related to their respective costs. We evaluated the impact of the NPAC on two main outcomes, namely, reduced incidence and the improved survival of cancer patients, expressed as life years gained (LYGs), which enabled the calculation of incremental cost-effectiveness ratios (ICERs) in the form of cost per LYG. In the analysis of costs, we considered both the direct costs of NPAC activities as well as the wider indirect societal costs of cancer, thus permitting the calculation of the ICER both from the narrower national health insurer's perspective (accounting only for the direct costs) and the wider societal perspective (accounting both for the direct and indirect costs). We estimated that on average, for all patients benefiting from the implementation of the NPAC in Croatia, an additional LYG would be yielded at the additional cost of €1.021 (societal perspective). The NPAC can, for some sites, even be considered a dominant intervention due to the negative cost/LYG ratio, meaning that it generates additional LYGs while at the same time, reducing total societal costs. Taking a narrower health insurer's perspective (i.e., accounting only for the direct costs), the NPAC produces an additional LYG at an additional cost of €1.408. Both cost per LYG estimates can be considered cost-effective investment options.

The First Wave of the COVID-19 Pandemic and Its Impact on the Level of Distress in Patients with Breast Cancer, a Multicentric Study.

BACKGROUND: Information on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), later termed coronavirus disease (COVID-19), first emerged by the end of 2019. As the pandemic spread, cancer patients were immediately recognized as a high-risk population with regard to COVID-19 infection. Moreover, epidemiological measures, like social distancing and lockdowns, additionally burdened patients with cancer. Even outside pandemic breast cancer patients are prone to psychological distress with prevalence ranging approximately 20-40%. This multicentric study aimed to examine the impact of COVID-19 pandemic on the level of distress among breast cancer patients in Croatia while the first wave of COVID-19 pandemic. SUBJECTS AND METHODS: Fife hundred forty-five breast cancer patients were offered to participate in the study. A total of two hundred and one patient, with disease stages ranging I-IV, completed the questionnaire. The questionnaire consisted of disease and socio-demographic characteristics followed by the Distress Thermometer and a problem list. The cut off value of 4 was used to define the high level of distress within Distress Thermometer. RESULTS: High distress level was reported in 54.2% of patients. The most significant problems reported by the participants of our study affected emotions, causing worry, sadness, depression, fear, and nervousness. Additionally, specific practical problems emerged (e.g., child care, housing, and work/school), most probably partly due to the lockdowns and social distancing. Interestingly enough, none of the socio-demographic or disease characteristics were linked to the level of distress. CONCLUSIONS: During first wave of COVID-19 pandemic more than half of breast cancer patients, undergoing active oncologic treatment, experienced a high level of distress. Therefore, distress driven by the COVID-19 pandemic should be promptly addressed and additional psychological and social support, targeting specific practical and emotional problems, should be provided for those patients. All the more so as global COVID-19 pandemic far exceeded the duration of the first wave.

Prognostic value of circulating Bcl-2 and anti-p53 antibodies in patients with breast cancer: A long term follow-up (17.5 years).

BACKGROUND: Apoptosis inhibition is a major tumorigenic factor. Bcl-2 dysregulation and TP53 mutation status, which may correlate with autoantibody generation, contribute to impaired apoptosis. OBJECTIVE: This study aimed to investigate the prognostic value of circulating Bcl-2 and anti-p53 antibodies (p53Abs) in a 17.5-year follow-up of breast cancer patients. We also analyzed the correlations of Bcl-2 and p53Abs with various clinicopathological parameters in order to assess their impact on tumor aggressiveness. METHODS: Serum Bcl-2 and p53Abs levels were analyzed by the enzyme-linked immunosorbent assay (ELISA) in 82 patients with invasive breast cancer and twenty individuals without malignancy. RESULTS: Serum Bcl-2 and p53Abs levels in breast cancer patients were significantly higher than those in controls. Patients with high levels of Bcl-2 (cut-off 200 U/ml) had a poorer prognosis (17.5-year survival) than those with lower Bcl-2 values. In combined analysis the subgroup of patients with elevated p53Abs (cut-off 15 U/ml) and elevated Bcl-2 (cut-offs 124 U/ml and 200 U/ml) had the worse prognosis in 17.5-year survival. In correlation analysis p53Abs and Bcl-2 were associated with unfavorable clinicopathological parameters. CONCLUSIONS: Our results suggest that breast cancer patients with high serum levels of p53Abs and Bcl-2 present an especially unfavorable group in a long follow-up.

Leukocytoclastic vasculitis associated with sorafenib treatment for hepatocellular carcinoma.

Small-vessel vasculitis is an uncommon diagnosis associated with many causes, including certain medication. Characteristic findings are immune complex deposition, vessel wall damage, and erythrocyte extravasation. We present a case of a 77-year-old man with advanced hepatocellular carcinoma who was treated with sorafenib. Twenty days post introduction to sorafenib, the patient experienced high fever and painful purpura on the lower limbs. The results of the skin biopsy confirmed the diagnosis. More extensive diagnostics was undertaken, which excluded other possible causes of vasculitis and infectious disease. Following a full recovery, after the steroid treatment was completed, sorafenib has been continued until the progression of the carcinoma. This is the second described case of hepatocellular carcinoma associated with sorafenib treatment and leukocytoclastic vasculitis. Sorafenib is a potential cause of vasculitis, and clinicians should bear in mind to differentiate it from hand-foot skin reaction, which is a common side effect of multikinase inhibitors. The result of our assessment is important considering that vasculitis requires more specific diagnostic procedures, treatment, and often drug discontinuation.

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

Vemurafenib prolongs survival in patients with BRAFV600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAFV600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers.

Hepatocellular Carcinoma Surveillance-Experience from Croatian Referral Centre for Chronic Liver Diseases.

PURPOSE: For patients at high-risk of developing hepatocellular carcinoma (HCC), biannual ultrasound surveillance has long been recommended, in order to detect the tumor in the early, potentially curative stages. However, globally reported HCC surveillance rates vary greatly, ranging from as low as 1.7 to as high as 80%. Our aim was to assess the utilization of surveillance with biannual ultrasound in high-risk Croatian patients and to identify the factors that impact the implementation of the recommended protocol. METHODS: This retrospective study included 145 newly diagnosed HCC patients in the period from January 2010 to September 2015. We identified low-risk and high-risk patients. The latter were further subdivided into the regular biannual ultrasound surveillance group and the non-surveillance group. The groups were compared according to demographic characteristics and BCLC stage at the time of HCC diagnosis. RESULTS: Among 145 patients, 80 patients were classified as high-risk according to EASL criteria. During the relevant period, 28.7% underwent regular surveillance, while 71.25% did not. Younger patients were more likely to undergo surveillance (OR 0.935 CI 0.874-0.999; p = 0.05). The patients who underwent regular surveillance had a higher chance of being diagnosed at a curative stage (BCLC 0 or A) (OR 3.701 CI 1.279-10.710; p < 0.05).Gender was not a predictor of participation in the regular surveillance protocol. Among the high-risk patients who did not undergo regular surveillance, 56.1% were not aware of the chronic liver disease prior to the HCC diagnosis. CONCLUSION: HCC surveillance is still underutilized in high-risk Croatian patients despite its obvious benefits possibly due to the untimely diagnosis of the chronic liver disease.

[CLINICAL GUIDELINES FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH INVASIVE BREAST CANCER--CROATIAN ONCOLOGY SOCIETY]. / KLINICKE UPUTE HRVATSKOGA ONKOLOSKOG DRUSTVA ZA DIJAGNOZU, LIJECENJE I PRACENJE BOLESNICA/KA OBOLJELIH OD INVAZIVNOG RAKA DOJKE.

Breast cancer is the most common cancer in women. It can be diagnosed in early stage through screening, early detection and educational programs, and when diagnosed early it can be efficiently treated. Treatment modalities include surgery, chemotherapy, radiotherapy, hormonal therapy and targeted biologic therapy, according to the stage of the disease and patient condition. Treatment decisions should be made after multidisciplinary team discussion. Due to the significance of this disease it is important to define and implement standardized approach for diagnostic, treatment and monitoring algorithm as well. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and monitoring of patients with breast cancer in the Republic of Croatia.