Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed.
To assess the ...prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS).
In the final study population (N=309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P=0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09-4.87; P=0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02-4.14; P=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05-2.07; P=0.025), but such effect was lost at multivariate analyses.
BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.
The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration ...can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.
Colorectal cancer (CRC) is an important cause of cancer-related death. Prediction of recurrence is an important issue in the treatment of disease, particularly for stage II patients. The level of ...telomere-specific reverse transcriptase (hTERT), the catalytic component of the telomerase complex, increases along with CRC progression, but its prognostic value is still unclear.
One hundred and thirty-seven CRC patients were studied for hTERT expression in tumour cells by real-time PCR. hTERT level was evaluated as a prognostic factor of overall survival (OS) in all patients and of disease recurrence in a subgroup of 50 stage II patients.
The median hTERT level was 93.8 copies (interquartile range 48-254). Patients with high hTERT levels (above the median) showed a significantly worse survival than those with low hTERT levels (below the median; log-rank test P<0.0001; hazard ratio (HR)=3.30 (95% confidence interval (CI) 1.98-5.52); P<0.0001). The negative prognostic value of high hTERT level is independent of the pathological stage and microsatellite instability (HR=2.09 (95% CI 1.20-3.64), P=0.009). Moreover, in stage II CRC, high hTERT levels identified patients with a higher risk of disease recurrence (HR=3.06 (95% CI 1.03-9.04), P=0.043) and death (HR=3.24 (95% CI 1.37-7.71), P=0.008).
hTERT level is an independent prognostic marker of OS in CRC patients. In addition, assessment of hTERT level could improve stratification of stage II CRC patients for the risk of disease recurrence.
Background
: Patients with recurrent or progressive low grade gliomas survive for a decade or more following diagnosis, and may be at a higher risk for treatment-related complications, such as ...cognitive impairment from radiotherapy.
Purpose
: The aim of the present study was to determine in patients with progressive or recurrent low grade gliomas, the response rate and toxicity incurred by a continued schedule of temozolomide chemotherapy administered before radiation therapy, and to explore correlations between response and survival with 1p/19q deletions and
MGMT
promoter methylation status.
Methods
: Progressive radio and chemotherapy naïve low grade glioma patients with O
6
-methyl-guanine-DNA-methyl-tranferase (
MGMT
) promoter status evaluation were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m
2
/daily for 21 days every 28 days for 12 cycles.
Results
: A total of 30 patients (median age 45 range: 24.2–68.6 years) with a median KPS of 90 (range 60–90) were accrued. The overall response rate was 30% (9 partial responses); 17 patients (56.7%) had disease stabilization.
Conclusion
: The prolonged temozolomide schedule considered in the present study is followed by a high response rate; toxicity is acceptable. Further randomized trials should therefore be conducted to confirm the efficacy of this regimen as first-line therapy in patients with progressive low grade glioma.
Activation of telomerase reverse transcriptase (hTERT) is essential for unlimited cell growth and plays a critical role in tumorigenesis. We investigated hTERT gene expression in 134 B-cell chronic ...lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression). Real-time PCR assays to quantify either all hTERT transcripts (AT) or only the full length (FL) transcript encoding the functional protein were developed. hTERT-AT levels strongly correlated with hTERT-FT levels (r=0.743, P<0.0001); both inversely correlated with the percentage of IgVH mutation (P<0.005) and were significantly higher in unmutated than in mutated cases (P=0.004 and P=0.001, respectively). The hTERT values which best discriminated between the unmutated and mutated IgVH cases were 150 and 40 copies for hTERT-AT and hTERT-FL, respectively. Using these cut-off values, there was a significant difference in the survival of patients with high or low hTERT levels (P<0.0001). Unmutated cases with low hTERT levels had an overall survival close to mutated cases with high hTERT levels. Thus, this work identifies hTERT-RNA level as a new prognostic marker in B-CLL, and may be used to identify previously unrecognized patient groups with the same IgVH mutation status and different disease outcomes.
BACKGROUND: Mutation of IDH1 gene is a prognostic factor and a diagnostic hallmark of gliomas. Mutant IDH1 enzyme can convert alpha -KG into 2-Hydroxyglutarate(2HG); mutated gliomas have elevated ...amounts of intracellular 2HG. We analyzed 2HG concentration in plasma and urine in glioma patients(PTS) to identify a biomarker of IDH1 gene mutation METHODS: All PTS had a prior histological confirmation of glioma, a recent brain MRI (within 2 weeks) showing the neoplastic lesions. The exclusion criteria were any chemotherapy performed within 28 days prior, other neoplastic and metabolic diseases. Plasma and urine samples were taken from all PTS and 2HG concentrations determined by liquid chromatography tandem mass spectrometry; Mann-Whitney test was used to test for differences in metabolite concentrations. ROC curve was used to evaluate the cut off value of 2HG biomarker. RESULTS: 84 PTS were enrolled: 38 with IDH1 mutated and 46 IDH1 wild-type. Among PTS with mutant IDH1 we had 21 high-grade gliomas (HGG) and 17 low-grade gliomas (LGG); among PTS with IDH1 wild-type we had 35 HGG and 11 LGG. In all PTS we analyzed the mean 2HG concentration in plasma (P_2HG), in urine (U_2HG) and the ratio between P_2HG and U_2HG (R_2HG). We found an important significant difference in R_2HG between PTS with and without IDH1 mutation: 24.9 versus 15.3, respectively. The optimal cut-off value of R_2HG to identify glioma PTS with and without IDH1 mutation was 19 with sensitivity (S) 63%, specificity (SP) 76% and accuracy (A) 70%.; in only PTS with HGG the optimal cut-off value was 20 (S 76%, SP 89%, A 84%, PPV 80%, NPV 86%). No association between the grade or size of tumor and R_2HG were found. In 7 out of 7 HGG PTS, we found a correlation between R_2HG value and response to treatment. CONCLUSIONS: By analyzing the R_2HG derived from individual plasma and urine 2HG levels is possible discriminate glioma PTS with and without IDH1 mutation. A larger samples need to be analyzed to investigate this method to monitor treatment efficacy.
The reported incidence of hereditary colorectal cancers (CRCs) is widely variable. The principal aim of the study was to prospectively evaluate the incidence of familial CRCs in a region of northern ...Italy using a standardized method. Consecutive CRC patients were prospectively enrolled from October 2002 to December 2003. Patients underwent a structured family history, the microsatellite instability (MSI) test and a screen for
MUTYH
mutations. Following family history patients were classified as belonging to high, moderate and mild risk families. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins and investigation for
MLH1
/
MSH2
mutations, for
MLH1
promoter methylation and for the V600E hotspot
BRAF
mutation were performed in high MSI (MSI-H) cases. Of the 430 patients enrolled, 17 (4%) were high risk 4 hereditary non-polyposis colorectal cancer (HNPCC), 12 suspected HNPCC and 1 MUTYH-associated adenomatous polyposis coli (MAP), 53 moderate risk and 360 mild risk cases. The MSI test was performed on 393 tumours, and 46 (12%) of them showed MSI-H. In these patients, one
MLH1
pathogenetic mutations and two
MSH2
pathogenetic mutations were found. Thirty-two (70%) MSI-H cases demonstrated
MLH1
methylation and/or
BRAF
mutation: None of them showed
MLH1
/
MSH2
mutation. Two biallelic germline MUTYH mutations were found, one with clinical features of MAP. A strong family history of CRC was present in 4% of the enrolled cases; incidence of
MLH1
/
MSH2
or
MUTHY
mutations was 1.3% and of MSI-H phenotype was 12%.
MLH1
methylation and
BRAF
mutation can exclude 70% of MSI-H cases from gene sequencing.
Purpose
The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients >50 years with proximal colon cancer. The aim of the study ...was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51–60 years old than in early-onset rectal cancer.
Methods
Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in
MLH1
/
MSH2
were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51–60 years old and groups B, C and D, patients ≤50 years old, with rectal cancer, proximal and distal colon cancer, respectively.
Results
Out of 409 CRC patients evaluated, 48 (12%) showed tumors with MSI-H. No MSI-H tumors were found in distal and rectal tumors of patients at sixth decade of life. Group A included 27 patients, eight (29.7%) MSI-H cancers, four missense mutations in MLH1/MSH2; groups B, C and D included 26, 11 and 11 patients with two (7.7%), two (18%) and two (18%) MSI-H cancers, respectively. One missense mutation on
MSH2
in group B, one pathogenetic mutation on
MSH1
in group C and one pathogenetic mutation on
MSH2
in group D were found. Tumors of group A showed an increased probability to have MSI-H if compared to those of group B (OD = 4.907,
p
= 0.043).
Conclusions
The Bethesda criteria should be broadened to include patients 51–60 years old with proximal colon cancer.
The B-MYB proto-oncogene is a transcription factor belonging to the MYB family that is frequently overexpressed or amplified in different types of human malignancies. While it is suspected that B-MYB ...plays a role in human cancer, there is still no direct evidence of its causative role. Looking for mutations of the B-MYB gene in human cell lines and primary cancer samples, we frequently isolated two nonsynonymous B-MYB polymorphic variants (rs2070235 and rs11556379). Compared to the wild-type protein, the B-MYB isoforms display altered conformation, impaired regulation of target genes and decreased antiapoptotic activity, suggesting that they are hypomorphic variants of the major allele. Importantly, the B-MYB polymorphisms are common; rs2070235 and rs11556379 are found, depending on the ethnic background, in 10-50% of human subjects. We postulated that, if B-MYB activity is important for transformation, the presence of common, hypomorphic variants might modify cancer risk. Indeed, the B-MYB polymorphisms are underrepresented in 419 cancer patients compared to 230 controls (odds ratio 0.53; (95%) confidence interval 0.385-0.755; P=0.001). This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease.
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