Socio-emotional ability, temperament and coping strategies associated with different use of Internet in Internet addiction.

OBJECTIVE: The aim of the present study was to compare socio-emotional patterns, temperamental traits, and coping strategies, between a group of Internet addiction (IA) patients and a control group. PATIENTS AND METHODS: Twenty-five IA patients and twenty-six healthy matched subjects were tested on IA, temperament, coping strategies, alexithymia and attachment dimensions. Participants reported their prevalent Internet use (online pornography, social networks, online games). RESULTS: The IA patients using Internet for gaming online showed a greater attitude to novelty seeking and a lower tendency to use socio-emotional support and self-distraction compared to patients using Internet for social networking. Moreover, they showed a lower level of acceptance than patients using Internet for pornography. In the control group, the participants using Internet for online gaming showed higher levels of IA, emotional impairments and social alienation compared to social-networks and pornography users. CONCLUSIONS: Findings showed a higher psychological impairment in gaming online users compared to social networking and online pornography users.

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer.

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% γδ T cells on average, with the majority expressing Vδ1. Most Vδ1 and Vδ2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- Î³ which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant γδ T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.

Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Normal vs cancer thyroid stem cells: the road to transformation.

Recent investigations in thyroid carcinogenesis have led to the isolation and characterisation of a subpopulation of stem-like cells, responsible for tumour initiation, progression and metastasis. Nevertheless, the cellular origin of thyroid cancer stem cells (SCs) remains unknown and it is still necessary to define the process and the target population that sustain malignant transformation of tissue-resident SCs or the reprogramming of a more differentiated cell. Here, we will critically discuss new insights into thyroid SCs as a potential source of cancer formation in light of the available information on the oncogenic role of genetic modifications that occur during thyroid cancer development. Understanding the fine mechanisms that regulate tumour transformation may provide new ground for clinical intervention in terms of prevention, diagnosis and therapy.

The complex interplay of Depression, Inflammation and Omega-3: state of the art and progresses in research.

Many epidemiological and preclinical studies have proven the potential benefit and critical role of omega-3 PUFAs in the development and management of depressive disorders. Depression may be the consequence of a complex interplay between cell-mediated-immune activation and inflammation evolving in neuroprogression. Associations between n-3 PUFAs, inflammation, oxidative stress and the risk of depression have been demonstrated and clinical and animal supplementation studies have shown the potential of PUFAs to decrease neurodegeneration and inflammation. Future research should focus on the dynamic interactions between the different cell signaling networks and oxidative and nitrosative stress pathways that cause depression.

Clinical impact of the HGF/MET pathway activation in patients with advanced gastric cancer treated with palliative chemotherapy.

In gastric cancer, available clinical studies focusing on the activated hepatocyte growth factor (HGF)/MET pathway are limited to surgical and often heterogeneous series. MET copy number gain (CNG) and an activating truncation in the HGF promoter (deoxyadenosine tract element, DATE+) were studied in tumors of 95 patients with advanced gastric cancer treated with palliative chemotherapy. Associations with overall survival (OS) and the pattern of metastatic disease were studied. Median OS was 9.7 months in 80 MET CNG <5 copies cases (MET-), and 6.4 months in 15 MET CNG was ⩾5 copies cases (MET+) (P=0.001). MET+ status confirmed the adverse prognostic effect in the multivariate model. A significantly different distribution of MET+/DATE+ and MET-/DATE- cases was observed between patients with and without peritoneal carcinomatosis (PC). MET+ status confirms its adverse prognostic role in advanced gastric cancer patients. The activated MET/HGF axis seems to be associated with PC. These findings are relevant to the development of anti-MET/HGF compounds.

A second look at efficacy criteria for onychomycosis: clinical and mycological cure.

BACKGROUND: Approval of topical onychomycosis drugs by regulatory agencies may be negatively impacted by an overly stringent definition of complete cure, which includes nail clearing plus mycological cure. OBJECTIVES: In this position paper, we discuss interpretation of mycological outcome and clinical trial length. METHODS: We reviewed data from seven international onychomycosis trials that enrolled subjects with positive KOH and dermatophyte-positive culture at screening followed by 48 weeks of treatment. Further, we examined 94 KOH-positive/culture-negative week 52 follow-up samples for morphological hyphal damage. RESULTS: From 3054 samples collected at week 52 follow-up visits, 2360 were culture-negative. However, a significant percentage (78.7%) of these subungual samples (n = 1857) remained KOH-positive. From the subset of follow-up samples examined for morphological changes, we identified hyphal breakage or distortion in 56 direct smears (60%), which may indicate nonviability. CONCLUSIONS: Reassessment of the definition of onychomycosis cure is critical. For clinical trials of topical agents, length of treatment should be re-examined. Further, in our experience, a high rate of subungual debris samples remained direct smear-positive while converting to negative culture. Evidence of morphological hyphal damage suggests that late-visit microscopic results may be false-positives. Therefore, the absence of clinical signs following an adequate washout period, coupled with a negative culture, with or without negative microscopy, should be considered the definition of onychomycosis cure.

Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study.

BACKGROUND: Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. PATIENTS AND METHODS: This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. RESULTS: Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P=0.009) and produced a trend toward improved overall survival versus no zoledronic acid. CONCLUSION: This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

[Affective temperaments and psychopathological dimensions of personality in Bipolar Disorder]. / Temperamenti affettivi e dimensioni psicopatologiche di personalità nel Disturbo Bipolare.

OBJECTIVES: The first objective of our study is the evaluation of correlation between affective temperaments and psychopathological dimensions in a clinical sample of patients with Bipolar Disorder and the individualization of possible differences within the three diagnostic subtypes (bipolar I, II and cyclothymia). The second one is to observe whether any specific temperament may influence the number of hospitalizations or the age of the bipolar depression onset. MATERIALS AND METHODS: At the Bipolar Disorder Unit of Policlinico Gemelli (Rome, Italy) a group of 60 patients with Bipolar Disorder (BD) has been enrolled. All patients have been submitted to the TEMPS-A for the evaluation of affective temperament and TCI-R for the evaluation of psychopathological dimensions of personality. RESULTS: BD I group showed 5 significant correlations from moderate (r=0.40) to high degree (r=0.60). SD dimension of TCI shows 3 significant correlations with TEMPS-A dimensions: it is inversely correlated with Cyclothymia (r= -0.57; p<0.01), Irritability (r=0.60; p<0.01) and Anxiety (r=-.45; p<0.05). BDII group showed 5 significant correlations. Irritability dimension of TEMPS-A presented the highest number of correlations with TCI dimensions: it was inversely correlated to SD (r= -.65; p<0.01) and directly correlated with HA (r=0.48; p<0.05) and ST (r=-0.49; p<0.05). In the comparison of diagnostic groups with regards to temperamental dimensions, only Hyperthymia and Irritability dimensions were significative. CONCLUSIONS: Many works have evaluated temperament through the use of these two tools (TEMPS-A and TCI-R) but few have analysed correlation between them and none has focused attention on patients with bipolar disorder diagnosis only.

[Diagnosis of deficit and attention/hyperactivity disorders (ADHD) in patients with bipolar or unipolar depression: an experimental study]. / Diagnosi pregressa di Disturbo da Defi cit d'Attenzione/Iperattività (ADHD) in pazienti con Depressione Bipolare e Unipolare: uno studio sperimentale.

INTRODUCTION: The present research study starts up from the current scientific and academic interest concerning Deficit and Attention/Hyperactivity Disorders, which in this period seems to have an "epidemic" diffusion. Some authors have proved how the Deficit and Attention/Hyperactivity Disorder may predispose to the development of other psychopathological attitude in adulthood. A recent study has underlined a common comorbidity between ADHD in childhood and Bipolar Disorder. The aim of the present was to verify the existence of an ADHD diagnosis in patients with depression (Unipolar and Bipolar) and to verify if such syndrome overstays in the present psychopathological picture. Moreover there has been even the intention to investigate on a difference in ADHD symptomatology in patients with Bipolar and Unipolar Depression. MATERIALS AND METHODS: The study has been conducted on a sample of 67 patients with depression diagnosis (35 patients with bipolar depression diagnosis, 32 patients with depression unipolar diagnosis) enrolled at the Bipolar Disorders Unit of the Clinical Psychiatry and Drug Dependence Institute of the Policlinico Universitario A. Gemelli in Rome. The evaluation has been performed through the supply of the following psychometric tests: Neo Personality Inventory (Mole-pi-R), Brown Attention Deficit Disorder Scale (Brown ADD-Scale), Adult ADHD Self-Report Staircases (ASRS-v1.1), Criteria of the Deficit and Attention / Hyperactivity Disorder for childhood according to the DSM-IV-Tr. RESULTS: The achieved results point out that 42% of the sample has satisfied the ADHD Criterions during their childhood according to the DSM-IV-Tr and that symptomatology seems to remain in the present psychopathological picture. As to polarity of depression it has emerged that patients with Bipolar Depression diagnosis have satisfied with a greater frequency the ADHD criteria during their childhood than patients with Unipolar Depression. CONCLUSIONS: Our results seem to confirm the hypothesis that patients with bipolar depression diagnosis have more Deficit and Attention / Hyperactivity Disorders comorbidity diagnosis than others.

"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

BACKGROUND: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). METHODS: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. RESULTS: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). CONCLUSIONS: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses.

[An observational study evaluating comorbidity between bipolar disorder and personality disorders]. / Comorbilità fra Disturbo Bipolare e Disturbi di Personalità: uno studio osservazionale.

OBJECTIVES: In literature there are a few studies evaluating comorbidity between bipolar disorder (type I, II and cyclothymic ) and personality disorders. Aim of the current study is to deepen the existing comorbidity between Axis II and the three subtypes of bipolar disorder. MATERIALS AND METHODS: At the Psychiatry Day Hospital of Gemelli Polyclinic seventy patients with a diagnosis of bipolar disorder (type I, II and cyclothymic ) were enrolled. Axis I diagnosis was defined by the SCID-I. Axis II diagnosis was made by the SCID-II. RESULTS: Of seventy patients in euthymic state, thirty-nine patients (55.7%) show comorbidity with Axis II. The different clusters are such represented: two patients (5.1%) are part of cluster A, twenty-four patients (61.5%) of cluster B, nine patients (23%) of cluster C, and four patients (10.4%) have Not Otherwise Specified personality disorder. On the whole thirty-nine patients whereof twenty-four (61.5%) with bipolar disorder type I, six (15.3%) with bipolar disorder type II and nine patients (23.0%) with cyclothymic disorder show comorbidity for a Axis II disorder. It must be observed that, in our sample, the comorbidity between cyclothymic and personality disorder is significant. CONCLUSIONS: In our sample more than half of the patients (55.7%) show a comorbidity for a Axis II disorder. Most of the patients present a Cluster B personality disorder and even cyclothymic patients in 23% of cases have comorbidity with Axis II disorders.

Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan.

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer.

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites > or =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.

Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer.

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20-40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16-2.77; P=0.008), haemoglobin 50 ng ml(-1) (HR, 1.86; 95% CI, 1.21-2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16-2.53; P=0.006), and time-to-progression under first-line chemotherapy

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy.

We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5'-untranslated region (5'-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6+/6-) in the TS 3'-UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5'-UTR VNTR+G/C nucleotide change showed significant association with tumour response (P=0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.