Basophil Activation Test Predicts Cetuximab Anaphylaxis Severity in Alpha-Gal IgE-Positive Patients.

Upon first exposure to cetuximab, hypersensitivity reactions can occur. We aimed to assess the utility of the basophil activation test (BAT) to alpha-gal and cetuximab for predicting severe reactions. We prospectively recruited 38 patients and evaluated sIgE to alpha-gal in all patients before the first application of cetuximab. In all alpha-gal-sensitized patients, we evaluated skin tests to meat extracts, gelatine, and cetuximab and performed BAT with alpha-gal and cetuximab. In 24% (9/38) of patients, sIgE to alpha-gal was >0.10 kUA/L, and 8/9 reacted to the cetuximab. Basophil activation tests with alpha-gal were positive in all sensitized patients and were higher in those with severe reactions (18.3% in grade 4 [n = 4] vs. 1.8% in grade 2 [n = 3] or no reaction [n = 1] at 3.3 ng/mL of alpha-gal; p = 0.03). All patients with severe grade 4 reactions had a positive CD63 BAT response to cetuximab compared to patients with moderate or no reaction, who all had negative BAT (57.7% vs. 0.9% at 500 µg/mL, 63.2% vs. 4.1% at 100 µg/mL, 58.2% vs. 2.7% at 10 µg/mL, and 32.1% vs. 3.3% at 1 µg/mL of cetuximab, respectively; p ≤ 0.001). In summary, before initiating cetuximab treatment, sIgE to alpha-gal should be assessed in all patients. To predict the severity of the reaction and to assess the risk of cetuximab-induced anaphylaxis, we should perform BATs with alpha-gal or more discriminative BATs with cetuximab.

Prognostic factors for overall survival and safety of trans-arterial chemoembolization (TACE) with irinotecan-loaded drug-eluting beads (DEBIRI) in patients with colorectal liver metastases.

BACKGROUND: Transarterial chemoembolisation with irinotecan-loaded drug-eluting beads (DEBIRI TACE) can be considered in patients with unresectable colorectal cancer liver metastases (CRLM) who progress after all approved standard therapies or in patients unsuitable for systemic therapy. PATIENTS AND METHODS: Between September 2010 and March 2020, thirty patients (22 men and 8 women; mean age 66.8 ± 13.2) were included in this retrospective study. DEBIRI TACE was conducted in 43% of patients unsuitable for systemic therapy as a first-line treatment and 57% as salvage therapy after the progression of systemic therapy. All the patients had liver-limited disease. In the case of unilobar disease, two treatments were performed at four-week intervals, and in the case of bilobar disease, four treatments were performed at two-week intervals. All patients were premedicated and monitored after the procedure. Adverse events were graded according to the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) classification system for complications. RESULTS: The median overall survival (OS) from the beginning of DEBIRI TACE in the salvage group was 17.4 months; in the group without prior systemic therapy, it was 21.6 months. The median overall survival of all patients was 17.4 months (95% confidence interval [CI]: 10.0-24.7 months), and progression-free survival (PFS) was 4.2 months (95% CI: 0.9-7.4 months). The one-year survival rate after the procedure was 61%, and the two-year rate was 25%. Univariate analysis showed better survival of patients with four or fewer liver metastases (p = 0.002). There were no treatment-related deaths or grade 4 and 5 adverse events. Nonserious adverse events (Grades 1 and 2) were present in 53% of patients, and Grade 3 adverse events were present in 6% of the patients. CONCLUSIONS: DEBIRI TACE is a well-tolerated treatment option for patients with liver metastases of colorectal cancer. Patients with four or fewer liver metastases correlated with better survival.

The Prognostic and Predictive Value of Human Gastrointestinal Microbiome and Exosomal mRNA Expression of PD-L1 and IFNγ for Immune Checkpoint Inhibitors Response in Metastatic Melanoma Patients: PROTOCOL TRIAL.

BACKGROUND: Immunotherapy has been successful in treating advanced melanoma, but a large proportion of patients do not respond to the treatment with immune checkpoint inhibitors (ICIs). Preclinical and small cohort studies suggest gastrointestinal microbiome composition and exosomal mRNA expression of PD-L1 and IFNγ from the primary tumor, stool and body fluids as potential biomarkers for response. METHODS: Patients treated with immune checkpoint inhibitors as a first line treatment for metastatic melanoma are recruted to this prospective study. Stool samples are submitted before the start of treatment, at the 12th (+/-2) week and 28th (+/-2) week, and at the occurrence of event (suspected disease progression/hyperprogression, immune-related adverse event (irAE), deterioration). Peripheral venous blood samples are taken additionally at the same time points for cytologic and molecular tests. Histological material from the tumor tissue is obtained before the start of immunotherapy treatment. Primary objectives are to determine whether the human gastrointestinal microbiome (bacterial and viral) and the exosomal mRNA expression of PD-L1 and IFNγ and its dynamics predicts the response to treatment with PD-1 and CTLA-4 inhibitors and its association with the occurrence of irAE. The response is evaluated radiologically with imaging methods in accordance with the irRECIST criteria. CONCLUSIONS: This is the first study to combine and investigate multiple potential predictive and prognostic biomarkers and their dynamics in first line ICI in metastatic melanoma patients.

The five-year KRAS, NRAS and BRAF analysis results and treatment patterns in daily clinical practice in Slovenia in 1st line treatment of metastatic colorectal (mCRC) patients with RAS wild-type tumour (wtRAS) - a real- life data report 2013-2018.

BACKGROUND: We preformed a Phase IV non-interventional study to assess KRAS, NRAS and BRAF status in metastatic colorectal cancer (mCRC) patients suitable for 1st line treatment and to evaluate the decisions for 1st line treatment considering the treatment goals in the RAS wild type (wt) patients. The aim of our study was also to evaluate the influence of a waiting period for biomarkers analysis on the start of first-line treatment. PATIENTS AND METHODS: Patients with histologically confirmed mCRC adenocarcinoma suitable for first-line treatment fulfilling all inclusion criteria were included in the study. The KRAS, NRAS and BRAF analysis was performed from tissue samples of primary tumor site or metastatic site. All included patients have given consent to participate in the study by signing the informed consent form. RESULTS: From April 2013 to March 2018 at the Institute of Oncology Ljubljana 650 patients were included, 637 of them were treated with first- line systemic treatment according to RAS and BRAF status. Remaining 13 patients with mCRC did not receive systemic first-line treatment. The distribution of patients with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively, 89 % of the patients had wt NRAS tumours and 86.1% had wt BRAF tumours. The most frequently prescribed treatment was bevacizumab-based therapy (53.1%), either in combination with doublet chemotherapy or with mono-chemotherapy. EGFR inhibitors cetuximab and panitumumab were prescribed in wt RAS mCRC patients (30.9%). The waiting period for biomarkers analysis was two weeks. CONCLUSIONS: Our real-world data, single centre 5-year analysis showed that the distribution between wild type and mutated type tumors of the patients with mCRC was approximately the same, as worldwide, so the Slovenian population with mCRC has the same ratio distribution of KRAS, NRAS and BRAF wild and mutated genes. We concluded that a two-week waiting period for biomarkers analysis did not influence the first line treatment decision, so it was in the accordance with the worldwide treatment guidelines based on evidence-based medicine.

Biomarkers for Outcome in Metastatic Melanoma in First Line Treatment with Immune Checkpoint Inhibitors.

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.

Vismodegib in Locally Advanced Basal Cell Carcinoma in Slovenia.

BACKGROUND: Vismodegib is a first-in-class inhibitor of the hedgehog pathway for treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC. OBJECTIVES: The purpose of this study is to report outcomes of patients with laBCC, with basal cell carcinoma nevus syndrome (Gorlin Goltz syndrome [G-G Syn]) treated with vismodegib in routine clinical practice in Slovenia in 8.3-year period. METHODS: In this retrospective cohort study, we analyzed baseline characteristics, outcomes, and treatment-related adverse events from locally advanced BCC. The patients were divided into two cohorts: 39 laBCC or multiple BCC patients and 7 patients with G-G Syn who were treated with vismodegib from November 2012 till January 2021. RESULTS: During 100-month period, 46 patients were diagnosed with laBCC (26), multiple BCC (13), and G-G Syn (7), all inappropriate for surgery or radiotherapy. Baseline characteristics: median age was 72.8 years in laBCC + multiple BCC cohort and 47.4 years in G-G Syn cohort. The objective response rate was 80% in laBCC + multiple BCC and 86% in G-G Syn cohort. Disease control rate (DCR) was 95% in laBCC + multiple BCC and 100% in G-G Syn cohort. Median duration of treatment was 9.9 months (range: 1.5-43.1) in laBCC and multiple BCC cohort and 19.5 months (range: 3.6-94.1) in G-G Syn cohort. Majority of treatment-emergent adverse events (TEAEs) in laBCC or multiple BCC cohort were grade 1 or 2 (96%), only 4% of AEs were grade 3. Majority of TEAEs in G-G Syn cohort were also grade 1 or 2 (87%), 13% of AEs were grade 3. No grade 4 or 5 vismodegib-related AEs were reported. CONCLUSION: Vismodegib has shown meaningful efficacy with DCR from 95% to 100% in patients with laBCC, multiple BCC, and G-G Syn in Slovenia. TEAEs were successfully alleviated with multidisciplinary approach and early supportive care.

Choroidal thickening with serous retinal detachment in BRAF/MEK inhibitor-induced uveitis: A case report.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma. In addition to systemic side effects, several usually mild ocular adverse effects have been reported. We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment, thickened choroid, and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase (BRAF) mutant metastatic cutaneous melanoma. CASE SUMMARY: A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes. Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber, mild vitritis, bullous multiple serous retinal detachments, and chorioretinal folds in both eyes. Treatment with dabrafenib and trametinib was suspended, and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule. One and a half months after the disease onset, ocular morphological and functional improvement was noted. Due to the metastatic melanoma dissemination, BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared, which later subsided after receiving oral corticosteroids. CONCLUSION: Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis. Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients. Furthermore, appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.

Adverse events during immunotherapy in Slovenian patients with metastatic melanoma reveal a positive correlation with better treatment outcomes.

BACKGROUND: Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy. PATIENTS AND METHODS: A retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups. RESULTS: Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort. CONCLUSIONS: Patients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.

Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab - real-world experience.

Background Based on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question remains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials. Patients and methods This observational retrospective cohort study included 138 consecutive metastatic treatment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019. Results The estimated median overall survival (OS) was 25.1 months (95% CI, 14.6-35.6) and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.9-15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3-4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment. Conclusions Our real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients.

Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients.

Background Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not predictive for response rate of systemic therapy. KRAS mutations in codons 12 and 13 were first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all patients with wild-type KRAS (wtKRAS) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway, such as other mutations in RAS gene, mutations in P13K and PTEN expression. Patients and methods In the prospective study prognostic and predictive impact of histological parameters of primary tumour, KRAS and BRAF mutations on overall survival (OS) and objective response (OR) rate of metastatic CRC (mCRC) patients treated with 1st line systemic therapy were analysed. We additionally retrospectively analysed other mutations in RAS genes and their impact on survival and time to progression. Results From November 2010 to December 2012, we enrolled 154 patients in the study, 95 men and 59 women. Mutations in KRAS gene and V600E BRAF gene were found in 42% and in 3% of patients, respectively. Median OS of the patients with T1, T2 and T3 tumour was 65.4 months (95% CI, 55.7-75.6) while in patients with T4 tumour, lymphangiosis, vascular and perineural invasion it has not been reached yet. Median OS of the patients with G1, G2 and G3 of tumour differentiation was 65.6 (95% CI, 53.7-77.5) and 25.3 months (95% CI, 16.6-34.1), respectively. Median OS of the patients with stage N0, N1 and N2 was 65.6 (95% CI, 56.4-74.8) and 58.0 months (95% CI, 21.9-94.2), respectively. Median OS of wtKRAS and mutated KRAS patients was 56.5 (95% CI, 48.2-64.9) and 58 months (95% CI, 52.6-63.4), respectively. Median OS of mutated codon 12 and codon 13 patients was 57 (95% CI, 50.9-64.4) and 44 months (95% CI, 40.1-48.4), respectively. Median OS of wtBRAF and of mutated BRAF patients was 59.2 (95% CI, 52.5-65.9) and 27.6 months (95% CI, 12.6-42.5), respectively. wtKRAS significantly affected the response to the first systemic therapy (p = 0.028), while other parameters did not affected it, p= 0.07. In 14 patients (17%), additional mutations in NRAS gene, codon 61 and codon 146 were found. Median OS of wtNRAS, codon 61 and 146 patients was 67.1 months (50.3-67.6) while median OS of mutated NRAS patients has not been reached yet (p = 0.072). Median time to progression of wtNRAS, codon 61 and 146 patients was 11.7 months (10.4-14.5) while median time to progression of mutated NRAS patients was 7.9 months (6.1-11.0), (p = 0.025). Conclusions Mutated BRAF, N2 and G3 of primary tumour were poor prognostic factors for OS in mCRC patients. wtKRAS significantly affected the response to the first line systemic therapy. Histological parameters included in the analysis and mutated BRAF did not affect significantly the efficacy of 1st line systemic therapy in mCRC patients.

Nuclear magnetic resonance metabolic fingerprint of bevacizumab in mutant IDH1 glioma cells.

Background Malignant gliomas are rapidly growing tumours that extensively invade the brain and have bad prognosis. Our study was performed to assess the metabolic effects of bevacizumab on the glioma cells carrying the IDH1 mutation, a mutation, associated with better prognosis and treatment outcome. Bevacizumab is known to inhibit tumour growth by neutralizing the biological activity of vascular endothelial growth factor (VEGF). However, the direct effects of bevacizumab on tumour cells metabolism remain poorly known. Materials and methods The immunoassay and MTT assay were used to assess the concentration of secreted VEGF and cell viability after bevacizumab exposure. Metabolomic studies on cells were performed using high resolution magic angle spinning spectroscopy (HRMAS). Results mIDH1-U87 cells secreted VEGF (13 ng/mL). Regardless, bevacizumab had no cytotoxic effect, even after a 72h exposure and with doses as high as 1 mg/mL. Yet, HRMAS analysis showed a significant effect of bevacizumab (0.1 mg/mL) on the metabolic phenotype of mIDH1-U87 cells with elevation of 2-hydroxyglutarate and changes in glutamine group metabolites (alanine, glutamate, glycine) and lipids (polyunsaturated fatty acids [PUFA], glycerophosphocholine, and phosphocholine). Conclusions In mIDH1-U87 cells, changes in glutamine group metabolites and lipids were identified as metabolic markers of bevacizumab treatment. These data support the possibility of a functional tricarboxylic acid cycle that runs in reductive manner, as a probable mechanism of action of bevacizumab in IDH1 mutated gliomas and propose a new target pathway for effective treatment of malignant gliomas.

Malignant gliomas: old and new systemic treatment approaches.

BACKGROUND: Malignant (high-grade) gliomas are rapidly progressive brain tumours with very high morbidity and mortality. Until recently, treatment options for patients with malignant gliomas were limited and mainly the same for all subtypes of malignant gliomas. The treatment included surgery and radiotherapy. Chemotherapy used as an adjuvant treatment or at recurrence had a marginal role. CONCLUSIONS: Nowadays, the treatment of malignant gliomas requires a multidisciplinary approach. The treatment includes surgery, radiotherapy and chemotherapy. The chosen approach is more complex and individually adjusted. By that, the effect on the survival and quality of life is notable higher.

Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience.

BACKGROUND: Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients' register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories. RESULTS: Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1(st) line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1(st) line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7-16.2) and 11.3 (95% CI, 10.2-12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4-28.9) and 27.4 (95% CI, 22.7-31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively. CONCLUSIONS: In routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer.

The cost of systemic therapy for metastatic colorectal carcinoma in Slovenia: discrepancy analysis between cost and reimbursement.

BACKGROUND: The aim of the study was to estimate the direct medical costs of metastatic colorectal cancer (mCRC) treated at the Institute of Oncology Ljubljana and to question the healthcare payment system in Slovenia. METHODS: Using an internal patient database, the costs of mCRC patients were estimated in 2009 by examining (1) mCRC direct medical related costs, and (2) the cost difference between payment received by Slovenian health insurance and actual mCRC costs. Costs were analysed in the treatment phase of the disease by assessing the direct medical costs of hospital treatment with systemic therapy together with hospital treatment of side effects, without assessing radiotherapy or surgical treatment. Follow-up costs, indirect medical costs, and nonmedical costs were not included. RESULTS: A total of 209 mCRC patients met all eligibility criteria. The direct medical costs of mCRC hospitalization with systemic therapy in Slovenia for 2009 were estimated as the cost of medications (cost of systemic therapy + cost of drugs for premedication) + labor cost (the cost of carrying out systemic treatment) + cost of lab tests + cost of imaging tests + KRAS testing cost + cost of hospital treatment due to side effects of mCRC treatment, and amounted to €3,914,697. The difference between the cost paid by health insurance and actual costs, estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009, was €1,900,757.80. CONCLUSIONS: The costs paid to the Institute of Oncology Ljubljana by health insurance for treating mCRC with systemic therapy do not match the actual cost of treatment. In fact, the difference between the payment and the actual cost estimated as direct medical costs of hospitalization of mCRC patients treated with systemic therapy at the Institute of Oncology Ljubljana in 2009 was €1,900,757.80. The model Australian Refined Diagnosis Related Groups (AR-DRG) for cost assessment in oncology being currently used is probably one of the reasons for the discrepancy between pay-outs and actual costs. We propose new method for more precise cost assessment in oncology.

Bevacizumab and irinotecan in recurrent malignant glioma, a single institution experience.

BACKGROUND: Treatment options of recurrent malignant gliomas are very limited and with a poor survival benefit. The results from phase II trials suggest that the combination of bevacizumab and irinotecan is beneficial. PATIENTS AND METHODS: The medical documentation of 19 adult patients with recurrent malignant gliomas was retrospectively reviewed. All patients received bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) or 125 mg/m(2)) every two weeks. Patient clinical characteristics, drug toxicities, response rate, progression free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Between August 2008 and November 2011, 19 patients with recurrent malignant gliomas (median age 44.7, male 73.7%, WHO performance status 0-2) were treated with bevacizumab/irinotecan regimen. Thirteen patients had glioblastoma, 5 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. With exception of one patient, all patients had initially a standard therapy with primary resection followed by postoperative chemoradiotherapy. Radiological response was confirmed after 3 months in 9 patients (1 complete response, 8 partial responses), seven patients had stable disease and three patients have progressed. The median PFS was 6.8 months (95% confidence interval [CI]: 5.3-8.3) with six-month PFS rate 52.6%. The median OS was 7.7 months (95% CI: 6.6-8.7), while six-month and twelve-month survival rates were 68.4% and 31.6%, respectively. There were 16 cases of hematopoietic toxicity grade (G) 1-2. Non-hematopoietic toxicity was present in 14 cases, all G1-2, except for one patient with proteinuria G3. No grade 4 toxicities, no thromboembolic event and no intracranial hemorrhage were observed. CONCLUSIONS: In recurrent malignant gliomas combination of bevacizumab and irinotecan might be an active regimen with acceptable toxicity.

Metabolic impact of anti-angiogenic agents on U87 glioma cells.

BACKGROUND: Glioma cells not only secrete high levels of vascular endothelial growth factor (VEGF) but also express VEGF receptors (VEGFR), supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev) or VEGFR Tyrosine Kinase Inhibitor (TKI), is poorly known. MATERIAL AND METHODS: U87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS). RESULTS: U87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells. CONCLUSION: Although both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS) might be a valuable marker to assess drug cytotoxicity.

Eleven years of experience with AIDS-related lymphomas at the Institute of Oncology Ljubljana.

Neoplastic diseases are currently recognized in more than 40% of HIV sero-positive patients, with AIDS-related lymphomas (ARL) being most common. A survey of the ARLs in patients attending our institute from 1998 to 2009 is given along with the clinical and pathological manifestations, treatment and outcomes. We conducted a retrospective chart review of patients treated for ARL between 1998 and 2009 at the Institute of Oncology Ljubljana. Patients were identified from the lymphoma database of our institute. Eight patients with ARL were diagnosed and treated at our Institute according to the then protocol for HIV sero-negative lymphoma patients. Seven patients received HAART. Six patients received prophylaxis for opportunistic infections and febrile neutropenia (FN), and 6 of them had at least one episode of FN. Seven patients are still alive and in complete remission 7-142 months after the diagnosis of ARL. One of the patients died of progressive lymphoma. The low incidence of ARL in the HIV-infected population, early stages at the presentation and the good response to treatment are not in accordance with the data from the literature. Whether this goes on account of the HAART treatment, prophylaxis for opportunistic infections and FN or a better follow-up of these patients remains to be answered. Also, the group is very small to make any definitive conclusions.

Digital ischemic events related to gemcitabine: Report of two cases and a systematic review.

BACKGROUND: 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. CASE REPORT: 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. CONCLUSIONS: 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.