[Show abstract][Hide abstract] ABSTRACT: Introduction
In Finland, a total of 98 glioma patients, 59 with malignant glioma recurrence after surgery and 39 who had undergone surgery for newly diagnosed glioblastoma, were treated with L-BPA-F-mediated BNCT in 1999 to 2011. Normal-brain-toblood (N/B) and tumor-to-blood (T/B) 10B concentration ratios of 1 and 3.5, respectively, were assumed in dose calculations. A correlation between the calculated tumor doses and survival was not found, suggesting an incorrect estimation of the dose. In this study, the T/B and tumor-to-normal-brain (T/N) ratios are estimated using a closed 3-compartment pharmacokinetic model based on the measured blood 10B concentrations.
Patients and Methods
Published average rate constants obtained from 8F-BPA-PET studies, and validated for a slow intravenous L-BPA-F infusion, were applied to predict the tumor and the normal brain 10B uptake based on the 3-compartment model and the measured blood 10B levels. Altogether 22 patients with recurrent glioma, treated within a clinical trial, were evaluated using their individual measured blood 10B concentration curves. The patients received a 290 to 450 mg/kg dose of L-BPA-F administered as a 2-hour intravenous infusion. Neutron irradiation was initiated 46 to 144 minutes after the end of infusion. The 10B concentrations of peripheral venous blood samples collected at 20-minute intervals were analyzed with inductively ICP-AES. The first blood sample was taken immediately before the initiation of the L-BPA F-infusion (the baseline sample), and the last one immediately after the completion of neutron irradiation.
Results and conclusions
According to the 3-compartment model, the T/B ratios reached their peaks of 2.3 to 3.1 at the time of the last blood sample taken after irradiation, consequently being lower during irradiation. The model predicts differing pharmacokinetics for the brain tissue and the blood, which results in distinct T/N and T/B concentration ratio curves. The highest T/N ratio of 1.9 to 2.0 was obtained at the end of the L-BPA-F infusion, and the ratio decreased thereafter gradually to 1.5 to 1.6. Instead of examining the T/N ratio, the ratio of tumor-to-combination of 1/3 blood + 2/3 the normal brain tissue T/(1/3B+2/3N) has been proposed to be examined, as the vascular endothelium may be the main target of BNCT damage.
The highest T/(1/3B+2/3N) of 1.8 to 2.0 were observed 70 to 130 minutes after end of the L-BPA F-infusions, which was the time range within which all patients received neutron irradiation. The model suggests that the treated patients received a lower tumor dose than previously predicted due to considerably lower 10B levels in the tumor. The patient doses will be re-evaluated according to the 10B levels estimated here.
16th International Congress on Neutron Capture Therapy, Helsinki; 06/2014
[Show abstract][Hide abstract] ABSTRACT: We have previously shown the prognostic importance of tumor infiltrating lymphocytes (TILs) in newly-diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+).
A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-non-amplified. Those with HER2+ disease (n=232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92·6%) available slides. The primary endpoint of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models.
Confirming our previous findings in TNBC (n=134), each 10% increase in TILs located in the stroma was significantly associated with decreased distant recurrence in TNBC; for DDFS hazard-ratio adjusted for clinic-pathological factors: 0·77; 95%CI 0·61-0·98,P=0·02. In HER2+ BC (n=209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS Pinteraction=0·025).
Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. This data confirms our previous data and further support that TILs should be considered a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host anti-tumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.
[Show abstract][Hide abstract] ABSTRACT: Background:Prokineticin-1 (PROK1) and prokineticin-2 (PROK2) are chemokine-like proteins that may influence cancer growth by regulating host defence and angiogenesis. Their significance in viral infection-associated cancer is incompletely understood. We studied prokineticins in Merkel cell carcinoma (MCC), a skin cancer linked with Merkel cell polyomavirus (MCPyV) infection.Methods:Carcinoma cell expression of PROK1 and PROK2 and their receptors (PROKR1 and PROKR2) was investigated with immunohistochemistry, and tumour PROK1 and PROK2 mRNA content with quantitative PCR from 98 MCCs. Subsets of tumour infiltrating leukocytes were identified using immunohistochemistry.Results:Merkel cell polyomavirus-positive MCCs had higher than the median PROK2 mRNA content, whereas MCPyV-negative MCCs contained frequently PROK1 mRNA. Cancers with high tumour PROK2 mRNA content had high counts of tumour infiltrating macrophages (CD68+ and CD163+ cells). Patients with higher than the median PROK2 mRNA content had 44.9% 5-year survival compared with 23.5% among those with a smaller content (hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.34-0.84; P=0.005), whereas the presence of PROK1 mRNA in tumour was associated with unfavourable survival (P=0.052).Conclusions:The results suggest that prokineticins are associated with MCPyV infection and participate in regulation of the immune response in MCC, and may influence outcome of MCC patients.British Journal of Cancer advance online publication, 4 February 2014; doi:10.1038/bjc.2014.20 www.bjcancer.com.
British Journal of Cancer 02/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4months (95% confidence interval [CI], 4.6-8.0months) and median overall survival (OS) 13.5months (95% CI, 10.0-21.0months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.
European journal of cancer (Oxford, England: 1990) 11/2012; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conventional chemotherapy is the mainstay of adjuvant systemic treatment for most patients with early triple-negative breast cancer (TNBC). At present, comparisons between adjuvant chemotherapy regimens are retrospective in nature, and so the optimal drugs or drug combinations have not been established for patients with early TNBC. In retrospective subgroup analyses, taxanes are more effective than 5-fluorouracil in combination with cyclophosphamide and doxorubicin. Classical CMF (cyclophosphamide, methotrexate and 5-fluorouracil) has shown efficacy, whereas few data on the role of anthracyclines are available. An unplanned subgroup analysis of one randomised study suggests that capecitabine adds efficacy to a taxane-anthracycline regimen, but this observation requires confirmation. High-dose adjuvant chemotherapy is considered experimental. Ongoing trials are comparing standard adjuvant regimens with regimens that integrate an anti-angiogenic agent, a platin or maintenance capecitabine. Inhibitors of DNA repair or specific tyrosine kinases have not yet been addressed in the adjuvant setting. In the absence of data from prospective trials that focus on adjuvant therapy of early TNBC, several regimens, such as a taxane and an anthracycline-containing regimen or classical CMF may be considered reasonable choices.
[Show abstract][Hide abstract] ABSTRACT: Background The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. Materials and methods A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. Results Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. Conclusions Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.
Annals of Oncology 07/2012; 23(11):2776-81. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use.DesignNested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records.ResultsThe largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking).Conclusions
Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.
[Show abstract][Hide abstract] ABSTRACT: In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics.
Breast (Edinburgh, Scotland) 02/2012; 21(1):20-6. · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Protein phosphatase 2A (PP2A) is a critical human tumor-suppressor complex. A recently characterized PP2A inhibitor protein, namely cancerous inhibitor of PP2A (CIP2A), has been found to be overexpressed at a high frequency in most of the human cancer types. However, our understanding of gene expression programs regulated by CIP2A is almost absent. Moreover, clinical relevance of the CIP2A-regulated transcriptome has not been addressed thus far. Here, we report a high-confidence transcriptional signature regulated by CIP2A. Bioinformatic pathway analysis of the CIP2A signature revealed that CIP2A regulates several MYC-dependent and MYC-independent gene programs. With regard to MYC-independent signaling, JNK2 expression and transwell migration were inhibited by CIP2A depletion, whereas MYC depletion did not affect either of these phenotypes. Instead, depletion of either CIP2A or MYC inhibited cancer cell colony growth with statistically indistinguishable efficiency. Moreover, CIP2A depletion was shown to regulate the expression of several established MYC target genes, out of which most were MYC-repressed genes. CIP2A small-interfering RNA-elicited inhibition of colony growth or activation of MYC-repressed genes was reversed at large by concomitant PP2A inhibition. Finally, the CIP2A signature was shown to cluster with basal-type and human epidermal growth factor receptor (HER)2-positive (HER2+) breast cancer signatures. Accordingly, CIP2A protein expression was significantly associated with basal-like (P=0.0014) and HER2+ (P<0.0001) breast cancers. CIP2A expression also associated with MYC gene amplification (P<0.001). Taken together, identification of CIP2A-driven transcriptional signature, and especially novel MYC-independent signaling programs regulated by CIP2A, provides important resource for understanding CIP2A's role as a clinically relevant human oncoprotein. With regard to MYC, these results both validate CIP2A's role in regulating MYC-mediated gene expression and provide a plausible novel explanation for the high MYC activity in basal-like and HER2+ breast cancers.
[Show abstract][Hide abstract] ABSTRACT: PROX1 is a specific target of the β-catenin/TCF pathway in the intestinal epithelium. It acts as a regulator of progression from a benign to a highly dysplastic phenotype in colorectal tumours. However, the clinical significance of PROX1 expression is not known.
We studied the prognostic value of immunohistochemical expression of PROX1 in a series of 517 patients with colorectal cancer (CRC).
The majority of the tumour samples expressed PROX1 (91%, 471 out of 517). High PROX1 expression was associated with a poor grade of tumour differentiation (P<0.0001). In the subgroup of patients with colon cancer, high PROX1 expression was associated with unfavourable colorectal cancer-specific survival (CCSS) as compared with low PROX1 expression (CCSS 47% vs 62%; P=0.045; RR 1.47). The association between high PROX1 and poor outcome was further strengthened in female colon cancer patients (CCSS 38% vs 63%; P=0.007; RR 2.02). Nonetheless, in multivariate survival analysis PROX1 expression was not retained as an independent prognostic factor.
High PROX1 expression is associated with a poor grade of tumour differentiation, and, in colon cancer patients, also with less favourable patient outcome. Our results strengthen the previous preclinical observations that PROX1 has a role in tumour progression in CRC.
British Journal of Cancer 10/2011; 105(9):1346-51. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events.
We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected.
We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA.
A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.
Annals of Oncology 10/2011; 23(5):1335-40. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant glioma is the most common brain tumor with 16,000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc and nuclear factor-κB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis.
[Show abstract][Hide abstract] ABSTRACT: Approval of imatinib for adjuvant treatment of gastrointestinal stromal tumours (GIST) raised discussion about accuracy of prognostic factors in GIST and the clinical significance of the available risk stratification criteria.
We studied the influence of a new modification of the NIH Consensus Criteria (the Joensuu risk criteria), NCCN-AFIP criteria, and several clinicopathological factors, including tumour rupture, on relapse-free survival (RFS) in a prospectively collected tumour registry series consisting of 640 consecutive patients with primary, resectable, CD117-immunopositive GIST. The median follow-up time after tumour resection was 39 months. None of the patients received adjuvant imatinib.
The median RFS time after surgery was 50 months. In univariable analyses, high Joensuu risk group, tumour mitotic count >5/50 HPF, size >5 cm, non-gastric location, tumour rupture (7% of cases; P = 0.0014) and male gender had adverse influence on RFS. In a multivariable analysis mitotic count >5/50HPF, tumour size >5 cm and non-gastric location were independent adverse prognostic factors. Forty, 151, 86 and 348 patients were assigned according to the Joensuu criteria to very low, low, intermediate and high risk groups and had 5-year RFS of 94%, 94%, 86% and 29%, respectively.
The Joensuu criteria, which include 4 prognostic factors (tumour size, site, mitotic count and rupture) and 3 categories for the mitotic count, were found to be a reliable tool for assessing prognosis of operable GIST. The Joensuu criteria identified particularly well high risk patients, who are likely the proper candidates for adjuvant therapy.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 07/2011; 37(10):890-6. · 2.56 Impact Factor