Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Chemical aspects of hydrogen sulfide measurements in physiological samples.

BACKGROUND: Owing to recent discoveries of many hydrogen sulfide-mediated physiological processes, sulfide biology is in the focus of scientific research. However, the promiscuous chemical properties of sulfide pose complications for biological studies, which led to accumulation of controversial observations in the literature. SCOPE OF REVIEW: We intend to provide an overview of fundamental thermodynamic and kinetic features of sulfide redox- and coordination-chemical reactions and protonation equilibria in relation to its biological functions. In light of these chemical properties we review the strengths and limitations of the most commonly used sulfide detection methods and recently developed fluorescent probes. We also give a personal perspective on blood and tissue sulfide measurements based on proposed biomolecule-sulfide interactions and point out important chemical aspects of handling sulfide reagent solutions. MAJOR CONCLUSIONS: The diverse chemistries of sulfide detection methods resulted in orders of magnitude differences in measured physiological sulfide levels. Investigations that were aimed to dissect the underlying molecular reasons responsible for these controversies made the important recognition that there are large sulfide reserves in biological systems. These sulfide pools are tightly regulated in a dynamic manner and they are likely to play a major role in regulation of endogenous-sulfide-mediated biological functions and avoiding toxic side effects. GENERAL SIGNIFICANCE: Working with sulfide is challenging, because it requires considerable amounts of chemical knowledge to adequately handle reagent sulfide solutions and interpret biological observations. Therefore, we propose that a rigorous chemical approach could aid the reconciliation of the increasing number of controversies in sulfide biology. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.

A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients.

Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS). Methods: A new parameter, called "individual drug score" (IDS) was calculated by summing the "drug score"-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS. Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p <0.001). In multivariate analysis IDS proved to be an independent marker of TD and OS. The same analysis was performed in a separate group of 81 patients receiving AA+dexamethasone treatment. The previously observed relationships were observed again between IDS and TD or OS. After combining the AA+prednisolone and AA+dexamethasone groups, analysis of the IDS composition showed that patients in the high IDS group not only used more drugs (p <0.001), but their drugs also had a higher mean DS (p = 0.001). Conclusion: The more co-drugs with high DS, the longer the duration of AA treatment and OS, emphasizing the need for careful co-medication planning in patients with mCRPC treated with AA. It is recommended that, where possible, co-medication should be modified to minimize the number of drugs with negative DS and increase the number of drugs with high DS. Our new model can presumably be adapted to other drugs and other cancer types (or other diseases).

Impact of SHMT1 polymorphism on the clinical outcome of patients with metastatic colorectal cancer treated with first-line FOLFIRI+bevacizumab.

The impact of thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and serine hydroxymethyltransferase 1 (SHMT1) gene polymorphisms and that of dihydropyrimidine dehydrogenase (DPD) enzyme activity, serum total homocysteine level, and estimated serum creatinine clearance on first-line 5-fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI+bevacizumab) regimen efficacy in metastatic colorectal cancer patients was investigated. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed for TYMS 5'UTR variable number tandem repeat, TYMS 3'UTR ins/del, MTHFR C677T, and SHMT1 C1420T polymorphisms. The DPD activity of peripheral blood mononuclear cells was also determined. The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (P=0.034). Grade ≥2 hypertension was also an independent prognostic factor of longer progression-free survival and OS. Bevacizumab-related hypertension might be a predictive marker of treatment efficacy (P=0.0002 for OS) in the case of wild (CC) SHMT1 1420 genotypes only.

High Neutrophil-To-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammation Index (SII) Are Markers of Longer Survival After Metastasectomy of Patients With Liver-Only Metastasis of Rectal Cancer.

Background: The literature data regarding colon cancer patients with liver-only metastases (CLM) show that NLR determined before metastasectomy is a prognostic marker of shorter relapse-free survival (RFS), but no results has been reported to date for rectal cancer patients with liver-only metastases (RLM). This study aimed to investigate the NLR and SII in CLM and RLM. Methods: Relapse-free (RFS) and overall survival (OS) were evaluated in 67 CLM and 103 RLM patients with a median follow-up of 46.5 and 59.8 months, respectively. Pre- and/or postoperative chemotherapy ± targeted treatment was applied in 96% and 87% of CLM and RLM patients, respectively. The cut-off level for hematologic parameters were determined by receiver operating characteristic (ROC) analysis. Univariate analysis was performed by Kaplan-Meier method and log rank test. For multivariate analysis Cox regression was applied. Results: In univariate analysis low NLR (cut-off 2) and SII (535) were predictors of longer RFS in case of CLM (p < 0.01). In contrast, for RLM high NLR (2.42) and SII (792) were predictors of longer RFS (p < 0.001). For RLM both NLR and SII proved to be independent markers of RFS (HR 0.66 (95% CI 0.52-0.84) and 0.73 (0.57-0.91), respectively) and OS (0.76 (0.58-0.99) and 0.66 (0.5-0.87), respectively). Only NLR (1.44 (1.04-1.99)) was independent marker of RFS for CLM. The preoperative treatment has not influenced the role of NLR or SII. Conclusion: In contrast to CLM, in RLM the high NLR or SII determined before metastasectomy proved to be independent prognostic factors of longer RFS and OS.

Corrigendum: High Neutrophil-to-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammation Index (SII) are Markers of Longer Survival After Metastasectomy of Patients With Liver-Only Metastasis of Rectal Cancer.

[This corrects the article DOI: 10.3389/pore.2022.1610315.].

[Fertility preservation in testicular cancer patients]. / Heretumoros betegek termékenyítoképességének vizsgálata.

Germ cell tumors of the testicle account for 1% of all tumors. Testicular cancer (TC) is the most common malignancy in men aged 15-35 years. Patients with TC have an excellent survival rate but often have not yet attempted to father children, and fertility is one of the main concerns of survivors, therefore it is important to preserve it. The most commonly used method is sperm banking. Retrospective analysis of the Hungarian data showed that in case of testicular cancer spermatogenesis is more impaired in the more advanced disease. No correlation was found among the histological types and the proportion of azoo- and oligozoospermia. The parameters of testicular cancer and non-Hodgkin lymphoma patients were worse compared to the normal population. Sperm cryopreservation prior to initiating life-saving cancer treatment offers men the best chance to father children and should be offered to all men with testicular cancer before chemotherapy, since cytostatic therapy may lead to infertility.

Pathologic Complete Response Rates After Neoadjuvant Pertuzumab and Trastuzumab with Chemotherapy in Early Stage HER2-Positive Breast Cancer - Increasing Rates of Breast Conserving Surgery: A Real-World Experience.

Purpose: The neoadjuvant use of pertuzumab and trastuzumab with chemotherapy improves the pathologic complete response (pCR) in early HER2+ breast cancer. The aim of this study was to determine the pCR rate obtained with dual HER2 blockade in routine clinical practice. The secondary and tertiary objective was to investigate the impact of neoadjuvant systemic therapy (NST) on performing breast-conserving surgery and survival data. Methods: This was a multicentre, retrospective, observational study in patients with stage II and III HER2+ early breast cancer who received pertuzumab and trastuzumab-based NST. Data were collected from patients' medical records. Results: Eighty-two patients were included in the study treated in 8 cancer centers in Hungary between March 2015 and January 2020. The study included women with a median age of 50.3 years. The majority of the patients (95%) received a sequence of anthracycline-based chemotherapy followed by docetaxel. pCR was achieved in 54% of the cases. As a result of NST a significant increase of conservative breast surgeries (33% vs. 3.6% planned, p = 0.0001) was observed. Ki67 expression and neutrophil-to-lymphocyte ratio (NLR) significantly predicted pCR. None of the variables were independent predictors of DFS. Conclusion: The pCR rate achieved in our study demonstrates the reproducibility of trial data in a real-world population. The rate of breast-conserving surgery was significantly increased.

SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer.

BACKGROUND: Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated. METHODS: The SHMT1 and MTHFR genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated. RESULTS: There was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for SHMT1 TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for MTHFR CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene-dosage effect was observed for SHMT1 with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the SHMT1 T allele/MTHFR CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by SHMT1 polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of SHMT1 1420CC genotypes. CONCLUSIONS: A protective effect of SHMT1 1420T allele or SHMT1 1420 T allele/MTHFR 677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of SHMT1 1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in SHMT1 1420 wild-type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why SHMT1 and MTHFR polymorphisms are associated only with rectal and not colon cancer risk.

Neutrophil-to-lymphocyte ratio in primary mediastinal germ cell tumors: A retrospective analysis of >20 years single institution experience.

OBJECTIVES: To obtain information on outcome stratified by histology, extent and primary treatment patients' data with primary malignant mediastinal germ cell tumors treated between 1998 and 2018 were retrospectively analyzed. METHODS: The primary treatment for localized malignant mediastinal germ cell tumors was neoadjuvant bleomycin + etoposid + cisplatin (BEP) ± surgery (n = 22); or surgery ± adjuvant BEP (n = 16). For disseminated disease (n = 21) first line BEP ± second line chemotherapy were administered. For nonseminomas (NS) the NLR at start of BEP was analyzed in relation to disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). RESULTS: After neoadjuvant treatment the 5-year DFS was 100% for seminomas (S), and 63.4% for NS. The 5-year OS was 100% for S, and 76.9% for NS. The 5-year DFS and OS after surgery ± BEP for S was 72.9% and 100%, for NS was 75% and 87.5%, respectively. The 5-year PFS and OS of metastatic patients for S was 60% and 80%, while the median PFS and OS of NS were 5.7 and 11.1 months, respectively. Objective response (P = 0.006) and low NLR (P = 0.043) were independent prognostic markers of longer OS. CONCLUSIONS: We confirmed the good outcome of BEP-treated S, while NS had poorer prognosis. Previously published prognostic models for NS were validated. Based on NLR and response a new prognostic model was developed.

GSTM1 null and GSTT1 null: predictors of cisplatin-caused acute ototoxicity measured by DPOAEs.

Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3-16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4-16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23-4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies. KEY MESSAGES: The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients. GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected). The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null. GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity. A high-risk group may be selected for new, individualized otoprotective treatment.

Predictive Markers of First Line Pazopanib Treatment in Kidney Cancer.

Real-world evidence from clinical practices is fundamental for understanding the efficacy and tolerability of medicinal products. Patients with renal cell cancer were studied to gain data not represented by analyses conducted on highly selected patients participating in clinical trials. Our goal was to retrospectively collect data from patients with advanced renal tumours treated with pazopanib (PZ) to investigate the efficacy, frequency of side effects, and searching for predictive markers. Eighty-one patients who had received PZ therapy as first-line treatment were retrospectively evaluated. Overall survival (OS), progression-free survival (PFS) were assessed as endpoints. Median PFS and OS were 11.8 months (95% CI: 8.8-22.4); and 30.2 months (95% CI: 20.3-41.7) respectively. Severe side effects were only encountered in 11 (14%) patients. The presence of liver metastasis shortened the median PFS (5.5 vs. 14.8 months, p = 0.003). Median PFS for patients with or without side effects was 25.6 vs. 7.3 months, respectively (p = 0.0001). Patients younger than 65 years had a median OS of 41.7 months vs. 25.2 months for those over 65 years of age (p = 0.008). According to our results absence of liver metastases, younger age (<65 years) and presence of side effects proved to be independent predictive markers of better PFS and OS.

Outcome of Restarted Sunitinib Treatment in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Trial and Combined Case Reports from Literature.

In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3 months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient' choice (24%). Median duration of interruption was 7 (range 3-41) months. The OR of baseline and restarted treatment was 63% and 39%, respectively. After a median follow-up of 76 (95% CI 65-79) months the median PFS of baseline and restarted treatment was 21 (18-27) and 14 (10-18) months, respectively. The median OS was 61 (56-80) months. In multivariate analysis the lack of OR of restated treatment was an independent predictor of shorter PFS of restarted Su. According to our findings and also on combined case studies from literature restarted Su can be effective in selected cases of patients who progressed during treatment holiday.

Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study.

BACKGROUND: Sunitinib is still one of the standard therapies in metastatic renal cell carcinoma (mRCC). Despite the benefit of sunitinib resistance will develop in the majority of patients. Most of them receive multiple sequential therapies during the course of disease. OBJECTIVES: To retrospectively investigate the efficacy and safety of rechallenged sunitinib in third or later line settings. PATIENTS AND METHODS: Twenty-one mRCC patients were identified who received rechallenged sunitinib between March 2010 and April 2018. Patients received sunitinib in first or second line, then other tyrosine kinase and/or mTOR inhibitors were applied, then sunitinib was rechallenged. Patients' characteristics, tolerability, treatment modalities, and treatment outcomes were recorded. The primary end-point was progression-free survival (PFS) of rechallenged sunitinib. RESULTS: Median age of patients was 62 years at the start of sunitinib rechallenge. Sixty-seven percent of patients were male. All patients had prior nephrectomy. Upon rechallenge 4 patients achieved partial response and 12 stable disease. The median PFS of first sunitinib treatment was 22 (95% CI 17-26) months and for rechallenged sunitinib 14 (95% CI 6-20) months. No increased severity of prior toxicity or new adverse events was reported during rechallenged sunitinib. The median overall survival (OS) from the start of first sunitinib was 67 (95% CI 46-76) months. Multivariate Cox regression analysis revealed that younger age (< 57 years) at start of first sunitinib (HR = 0.24; 95% CI 0.07-0.79; p = 0.019) and longer (> 2 years) first sunitinib treatment (HR = 0.28; 95% CI 0.09-0.93; p = 0.038) were independent markers of longer OS. CONCLUSION: Sunitinib rechallenge is a feasible and tolerable option with clinical benefit in selected mRCC patients.

Effects of the lactase 13910 C/T and calcium-sensor receptor A986S G/T gene polymorphisms on the incidence and recurrence of colorectal cancer in Hungarian population.

BACKGROUND: Epidemiological studies suggested the chemopreventive role of higher calcium intake in colorectal carcinogenesis. We examined genetic polymorphisms that might influence calcium metabolism: lactase (LCT) gene 13910 C/T polymorphism causing lactose intolerance and calcium-sensing receptor (CaSR) gene A986S polymorphism as a responsible factor for the altered cellular calcium sensation. METHODS: 538 Hungarian subjects were studied: 278 patients with colorectal cancer and 260 healthy controls. Median follow-up was 17 months. After genotyping, the relationship between LCT 13910 C/T and CaSR A986S polymorphisms as well as tumor incidence/progression was investigated. RESULTS: in patient with colorectal cancer, a significantly higher LCT CC frequency was associated with increased distant disease recurrence (OR = 4.04; 95% CI = 1.71-9.58; p = 0.006). The disease free survival calculated from distant recurrence was reduced for those with LCT CC genotype (log rank test p = 0.008). In case of CaSR A986S polymorphism, the homozygous SS genotype was more frequent in patients than in controls (OR = 4.01; 95% CI = 1.33-12.07; p = 0.014). The number of LCT C and CaSR S risk alleles were correlated with tumor incidence (p = 0.035). The CCSS genotype combination was found only in patients with CRC (p = 0.033). CONCLUSION: LCT 13910 C/T and CaSR A986S polymorphisms may have an impact on the progression and/or incidence of CRC.

Abiraterone acetate + prednisolone treatment beyond prostate specific antigen and radiographic progression in metastatic castration-resistant prostate cancer patients.

OBJECTIVES: To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP. METHODS: At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals. RESULTS: The median OS was significantly longer (P<0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly. CONCLUSIONS: In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration-resistant prostate cancer.

Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer.

Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m2/week, loading dose: 400 mg/m2), gemcitabine (1000 mg/m2 on day 1 and 8), and capecitabine (1300 mg/m2/day on days 1-14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24-40) and 54 (43-67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance status, previous stent implantation, thrombocyte count at the start of therapy, early neutropenia and skin rash statistically significantly influenced the ORR, PFS and/or OS. In multivariate Cox regression analysis only normal thrombocyte count at treatment start and early acneiform rash were independent markers of longer survival. In patients showing early skin rash compared to the others the median PFS was 39 vs. 13 weeks and the median OS was 67 vs. 26 weeks, respectively. It is suggested that early skin rash can be used as a biomarker to select patients who would benefit from the treatment with cetuximab plus chemotherapy.

Increase of hypophyseal hormone levels in male head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) develops in at least 80% of cases in men with a history of smoking and heavy alcohol consumption, still it is only diagnosed in a small proportion of alcoholics. Endocrine milieu is an important factor in carcinogenesis and prognosis of several cancer types. The aim of our study was to investigate sex steroid and hypophyseal hormone status of male HNSCC patients in comparison to healthy volunteers and to patients with alcoholic liver disease, to determine possible hormonal alterations characteristic of cancer. Liver function (GGT level), and serum levels of gonadotropic hormones (FSH, LH, prolactin), sex steroids (estradiol, progesterone, testosterone) and sex hormone-binding globulin (SHBG) were compared in 130 male HNSCC patients, 54 patients with alcoholic liver disease but no known cancer, and 56 healthy controls. We found abnormal values of liver function in both HNSCC patients and alcoholics compared to healthy controls, suggesting the presence of alcoholic liver disease in the former group as well. On the other hand, a significant elevation in the level of DHEA, FSH and LH was observed in cancer patients exclusively. As a conclusion, abnormal alterations in sex steroid hormone levels can frequently be found in HNSCC patients, which may be caused in part by the alcoholic liver damage accompanying the disease. The significant increase in FSH and LH serum levels, observed only in the cancer patients, indicates that these hormones may play a role in the development and/or progression of HNSCC.

[Pharmacogenetic studies on the prediction of efficacy and toxicity of fluoropyrimidine-based adjuvant therapy in colorectal cancer]. / Farmakogenetikai vizsgálatok a fluoropirimidint tartalmazó adjuváns kezelés hatékonyságának és toxicitásának elôrejelzésére colorectalis daganatokban.

The cytotoxic effect of 5-fluorouracil (5-FU) is mediated by the inhibition of thymidylate synthase (TS), however, at the same time 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). Efficacy of 5-FU may therefore depend on the TS and DPD activity and on pharmacogenetic factors influencing these enzymes. Our aims were (1) to determine the distribution of DPD activity, the frequency of DPD deficiency and the DPD (IVS14+1G>A) mutation in the peripheral blood mononuclear cells of colorectal cancer (CRC) patients, and study the relationship between DPD deficiency and toxicity of 5-FU; (2) to investigate the influence of TS polymorphisms and DPD activity on the survival of CRC patients receiving 5-FU-based adjuvant therapy. The frequency of DPD deficiency was determined by radiochemical methods in the peripheral blood mononuclear cells (PBMCs) of 764 CRC patients treated with 5-FU. The relationship between the TS polymorphisms, DPD activity and the disease-free and overall survival was studied in 166 CRC patients receiving 5-FU-based adjuvant therapy. TS polymorphisms were determined in the DNA samples separated from the PBMCs, by PCR-PAGE and PCR-RFLP-PAGE (restriction fragment length polymorphism) methods. Low DPD values (<10 pmol/min/106 PBMCs) were demonstrated in 160/764 patients (20.9%), and of those DPD deficiency (<5 pmol/min/106 PBMCs) was verified in 38 patients (4.9%). In the latter group severe (>Gr 3) toxicity was found in 87%. The prevalence of the DPD IVS14+1G>A mutation among the 38 DPD-deficient patients was 7.8% (3/38) and was accompanied by severe Gr 4 toxic symptoms (neutropenia, mucositis, diarrhea). TS polymorphisms showed a relationship with the survival of CRC patients. It is important to mention that by combining the 3-3 genotypes of 5'-TSER and 3'-TSUTR polymorphisms the obtained 8 genotype combinations showed significantly different Kaplan-Meier survival curves. The evaluation of these curves with Cox regression analysis resulted in two prognostically different groups: "A" good prognosis (RR<1) and "B" bad prognosis (RR>1). The disease-free- and overall survival of these two groups were significantly different. DPD activity also showed correlation with the survival; patients with DPD activity <10 pmol/min/106 PBMCs showed significantly longer disease-free and overall survival. The determination of DPD activity proved to be a more valuable parameter in the evaluation of serious 5-FU-related toxicity compared to the IVS14+1G>A mutation analysis. According to the Cox multivariate analysis the combination of germline TS polymorphisms and DPD activity is/an independent prognostic marker of survival in CRC patients treated with adjuvant 5-FU therapy.