New concept in neurovascular navigation: technical description and preclinical experience with the Bendit 17 and Bendit 21 microcatheters in a rabbit aneurysm model.

BACKGROUND: Endovascular treatment of intracranial vascular diseases, such as aneurysms, is often challenged by unfavorable vascular anatomy. The Bendit Steerable Microcatheter (Bendit Technologies, Tel Aviv, Israel) has bending and torqueing capabilities designed to improve navigation and stability during device delivery, with or without a guidewire. We describe our preclinical experience with the Bendit 17 and Bendit 21 microcatheters in a rabbit aneurysm model. METHODS: Bifurcation and side wall aneurysms were created surgically in six New Zealand rabbits. We attempted to navigate Bendit devices through the vasculature and enter the aneurysms without a guidewire. Various positions within the aneurysm were selectively explored. Angiographic imaging was used to visualize catheterization, navigation, vascular manipulations, and placement of coils, stents, and intrasaccular devices. RESULTS: We successfully navigated the Bendit microcatheters to all aneurysms without a guidewire. We successfully recanalized a nearly occluded carotid artery and navigated the Bendit through a braided stent. In contrast, we were unable to navigate a comparator device with a guidewire as effectively as the Bendit. Coils were introduced at different locations within the aneurysm and could be pushed, pulled, and repositioned with the Bendit tip. Finally, we used the Bendit to deliver intrasaccular devices designed for terminal aneurysms to treat side wall aneurysms. CONCLUSIONS: Bendit's bending and torqueing abilities, combined with its stability in the bent position, enable quick navigation and optimal deployment of devices. Clinical studies are necessary to determine whether these navigation advantages lead to more efficient treatment of intracranial and peripheral aneurysms.

Evaluation of a novel flow diverter, the DiVeRt system, in an animal model.

BACKGROUND: Using a surgical aneurysm model, this study assessed the performance of a new flow diverter (FD), the DiVeRt, and evaluated the angiographic and histologic features at different periods after stent deployment. METHODS: Fifteen New Zealand White rabbits were treated 3 days prior to intervention and until euthanization with dual antiplatelets. DiVeRt was implanted in bilateral carotid aneurysms (n=30) as well as in the aorta (n=15). The rate of technical success, assessment of aneurysm occlusion (measured by the O'Kelly-Marotta grading (OKM) scale), and stent patency were examined using angiography and histologic examinations in three groups at 1, 3, and 6 months follow-up (FU). In each FU group one control animal was included and treated with the XCalibur stent (n=3). RESULTS: Overall, DiVeRt placement was successful and without apparent intraprocedural complications. In total, four stents in the carotid artery were occluded and in-stent stenosis was registered in two carotid (7%) and one aortic (6%) vessels. Complete or near complete aneurysm occlusion (OKM scale D1 and C3) was seen in 100% in the 1-month FU group, 70% in the 2-month FU group, and 100% in the 3-month FU group. Histology showed loose, organizing fibrous tissue matrix within the sac and adequate neck endothelialization in all vessels. All branches covered by the DiVeRt remained patent. CONCLUSIONS: The DiVeRt system appears to be feasible and effective for the treatment of aneurysms with high rates of complete aneurysm occlusion, excellent vessel patency, and evidence of high biocompatibility. Occurrences of parent artery occlusion at follow-up did not result in clinical consequences.

Low Expression of miR-20a-5p Predicts Benefit to Bevacizumab in Metastatic Breast Cancer Patients Treated within the TANIA Phase III Trial.

BACKGROUND: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value. METHODS: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab. RESULTS: Low expression of miR-20a-5p (multivariate p = 0.035) and miR-21-5p (multivariate p = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37-0.89; p = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32-0.83; p = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, p = 0.119; OS: HR 1.01; p = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed. CONCLUSION: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.

Expression of the microRNA-200 Family, microRNA-205, and Markers of Epithelial-Mesenchymal Transition as Predictors for Endoscopic Submucosal Dissection over Esophagectomy in Esophageal Adenocarcinoma: A Single-Center Experience.

Endoscopic submucosal dissection (ESD) is an effective treatment of early esophageal adenocarcinomas (EACs). The decision of ESD over esophagectomy is based on clinical evaluation of tumor depth and invasion. On a molecular level, tumor invasion is strongly associated with epithelial-to-mesenchymal transition (EMT). Here, we investigated whether localized ESD-resected and surgically resected EAC samples displayed different expression profiles of EMT protein and microRNA markers and whether these different expression profiles were able to retrospectively discriminate localized and surgically resected samples. By doing this, we aimed to evaluate whether preoperative measurement of EMT marker expression might support the decision regarding ESD over surgery. The results showed that ESD-resected samples displayed an epithelial expression profile, i.e., high expression of epithelial protein markers, whereas surgically resected samples displayed high expression of mesenchymal markers. In addition, the anti-EMT microRNA-205 was significantly more expressed in ESD-resected samples, whereas we found no significant differences in the expression levels of microRNA-200 family members. Furthermore, in our retrospective approach, we have demonstrated that measurement of selected EMT markers and microRNA-205 has significant discrimination power to distinguish ESD-resected and surgically resected samples. We suggest that the assessment of EMT status of EAC samples on a molecular level may support clinical evaluation regarding the applicability of ESD.

Evaluation of circulating cell-free DNA as a molecular monitoring tool in patients with metastatic cancer.

The clinical decisions made when treating patients with metastatic cancer require knowledge of the current tumor extent and response to therapy. For the majority of solid tumors, a response assessment, which is based on imaging, is used to guide these decisions. However, measuring serum protein biomarkers (i.e. tumor markers) may be of additional use. Furthermore, tumor markers exhibit variable specificity and sensitivity and cannot therefore be solely relied upon when making decisions regarding cancer treatment. Therefore, there is a clinical requirement for the identification of specific, sensitive and quantitative biomarkers. In recent years, circulating cell-free DNA (cfDNA) and mutation-specific circulating cell-free tumor DNA (cftDNA) have been identified as novel potential biomarkers. In the current study, cfDNA and cftDNA were compared using imaging-based staging and current tumor markers in 15 patients with metastatic colorectal, pancreatic or breast cancer. These patients were treated at the Third Medical Department of Paracelsus Medical University Salzburg (Austria). The results of the current study demonstrated a statistically significant correlation between the concentration changes of cfDNA and cftDNA and response to treatment, which was assessed by imaging. A correlation was not indicated with current clinically used tumor markers, including carcinoembryonic antigen, carcinoma antigen 15-3 and carcinoma antigen 19-9. The present study also indicated a correlation between cfDNA and cftDNA and the tumor volume of metastatic lesions, which was not observed with the current clinically used tumor markers. In conclusion, cfDNA and cftDNA exhibit the potential to become novel biomarkers for the response assessment following cancer treatment, and may serve as a tool for the estimation of tumor volume. The current study further supports the increasingly important role of cfDNA and cftDNA as new monitoring tools for use during cancer therapy.

Overcoming negative predictions of microRNA expressions to gemcitabine response with FOLFIRINOX in advanced pancreatic cancer patients.

FOLFIRINOX is superior to gemcitabine in patients with pancreatic cancer, but this regimen is associated with toxicity and biomarkers for response are warranted. MicroRNAs can mediate drug resistance and could provide predictive information. Altered expressions of several microRNAs including miR-21-5p, miR-10b-5p and miR-34a-5p have been previously linked to a worse response to gemcitabine. We investigated the influence of expression levels in tumor tissue of those three microRNAs on outcome to FOLFIRINOX. Twenty-nine patients with sufficient formalin-fixed paraffin-embedded tumor tissue were identified. There was no significant association between high and low expression groups for these three microRNA. We conclude that polychemotherapy combination can overcome intrinsic negative prognostic factors.

BIRC3 Expression Predicts CLL Progression and Defines Treatment Sensitivity via Enhanced NF-κB Nuclear Translocation.

PURPOSE: Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-κB signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in patients with CLL. One of these molecules is BIRC3 (cIAP2), a central regulator of noncanonical NF-κB signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown.Experimental Design: We analyzed the role of BIRC3 mRNA expression in primary CLL samples in correlation to clinical datasets and used ex vivo assays to investigate functional consequences on the level of NF-κB signaling and downstream target gene regulation. For proof-of-principle experiments, we used genetically modified cell lines. RESULTS: We demonstrate that patients with CLL with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-κB target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-κB target gene activation, both anti- and proapoptotic Bcl-2 family members were upregulated in BIRC3low primary CLL cells, which was associated with higher sensitivity to venetoclax treatment in vitro. CONCLUSIONS: Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-κB target gene activation with therapeutic implications.

DNA Methylation Signatures Predicting Bevacizumab Efficacy in Metastatic Breast Cancer.

Background: Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Methods: Genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in archival FFPE specimens of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (learning set). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (Δß>0.15 or Δß<-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients (optimization set) and in 15 patients treated with chemotherapy alone (control set) using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the optimization set but not in the control set using Spearman rank correlation, Cox regression, and logrank test. Results: Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the optimization set, but not in the control set. Using information from the optimization set, the panel was reduced to a 9-gene signature, which could divide patients from the learning set into 2 clusters, thereby predicting response with an OR of 40 (p<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of predicted responders with longer PFS in the learning and optimization set even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Conclusion: Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab.

Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian Study Group of Medical Tumour Therapy study group.

BACKGROUND: Tumour heterogeneity and clonal evolution within a cancer patient are deemed responsible for relapse in malignancies and present challenges to the principles of targeted therapy, for which treatment modality is often decided based on the molecular pathology of the primary tumour. Nevertheless, the clonal architecture in distant relapse of head and neck cancer is fairly unknown. PATIENTS AND METHODS: For this project, we analysed a cohort of 386 patients within the Austrian Registry of head and neck cancer. We identified 26 patients with material from the primary tumour, the distant metastasis after curative first-line treatment and a germline sample for analysis of clonal evolution. After pathological analyses, these samples were analysed using a targeted massively parallel sequencing (MPS) panel of 257 genes known to be recurrently mutated in head and neck cancer plus a genome-wide SNP-set. RESULTS: Despite histological diagnosis of distant metastasis, no corresponding mutation in the supposed metastases was found in two of 23 (8.6%) evaluable patients suggesting a primary tumour of the lung instead of a distant metastasis of head and neck cancer. We observed a branched pattern of evolution in 31.6% of the analysed patients. This pattern was associated with a shorter time to distant metastasis, compared with a pattern of punctuated evolution. Structural genomic changes over time were also present in 7 of 12 (60%) evaluable patients with metachronous metastases. CONCLUSION: Targeted MPS demonstrated substantial heterogeneity at the time of diagnosis and a complex pattern of evolution during disease progression in head and neck cancer. Copy number analyses revealed additional changes that were not detected by mutational analyses. Mutational and structural changes contribute to tumour heterogeneity at diagnosis and progression.

Sidedness and TP53 mutations impact OS in anti-EGFR but not anti-VEGF treated mCRC - an analysis of the KRAS registry of the AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie).

BACKGROUND: In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance. METHODS: With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013. RESULTS: Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18.1 months [95%-CI: 14.3-40.7] versus 32.3 months [95%-CI: 25.5-38.6]; HR: 1.63 [95%-CI: 1.13-2.84]; p = 0.013). The choice of the biological agent in front-line therapy had a statistically significant impact on median OS in patients with right-sided tumours (anti-epidermal growth factor receptor (EGFR): 10.6 months [95%-CI: 5.2-NA]; anti-vascular endothelial growth factor (VEGF): 26.2 months [95%-CI: 17.9-NA]; HR: 2.69 [95%-CI: 1.30-12.28]; p = 0.015) but not in patients with left-sided tumours (anti-EGFR: 37.0 months [95%-CI: 20.2-56.6]; anti-VEGF: 32.3 months [95%-CI: 23.6-41.1]; HR: 0.97 [95%-CI: 0.56-1.66]; p = 0.905). When evaluating molecular characteristics of tumour samples, we found a clinically meaningful trend towards an inferior OS in TP53 mutant mCRC treated with anti-EGFR based therapy compared to anti-VEGF based therapy (17.1 months [95%-CI: 8.7-NA] versus 38.3 months [95%-CI: 23.6-48.0], HR = 1.95 [95%-CI: 0.95-5.88]; p = 0.066), which was not significantly dependent on sidedness. This was not the case in patients with TP53 wild-type tumours. Therefore we evaluated the combined impact of sidedness and TP53 mutation status in the anti-EGFR treated cohort and patients with left-sided/TP53 wild-type mCRC showed the longest median OS (38.9 months) of all groups (right-sided/TP53 mutant: 12.1 months; right-sided/TP53 wild-type: 8.9 months; left-sided/TP53 mutant: 18.4 months; p = 0.020). CONCLUSIONS: TP53 mutation and right-sidedness are associated with shorter OS in patients treated with anti-EGFR based therapy but not with anti-VEGF based therapy. The confirmation of the predictive value of TP53 mutation status in a larger cohort is warranted.

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones.

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites.

For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan(®) Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)(®) microarrays from Agilent(®) was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.

Independent Prognostic Value of Serum Markers in Diffuse Large B-Cell Lymphoma in the Era of the NCCN-IPI.

BACKGROUND: Several serum parameters have been evaluated for adding prognostic value to clinical scoring systems in diffuse large B-cell lymphoma (DLBCL), but none of the reports used multivariate testing of more than one parameter at a time. The goal of this study was to validate widely available serum parameters for their independent prognostic impact in the era of the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score to determine which were the most useful. PATIENTS AND METHODS: This retrospective bicenter analysis includes 515 unselected patients with DLBCL who were treated with rituximab and anthracycline-based chemoimmunotherapy between 2004 and January 2014. RESULTS: Anemia, high C-reactive protein, and high bilirubin levels had an independent prognostic value for survival in multivariate analyses in addition to the NCCN-IPI, whereas neutrophil-to-lymphocyte ratio, high gamma-glutamyl transferase levels, and platelets-to-lymphocyte ratio did not. CONCLUSIONS: In our cohort, we describe the most promising markers to improve the NCCN-IPI. Anemia and high C-reactive protein levels retain their power in multivariate testing even in the era of the NCCN-IPI. The negative role of high bilirubin levels may be associated as a marker of liver function. Further studies are warranted to incorporate these markers into prognostic models and define their role opposite novel molecular markers.

Anti-Hu Antibody Associated Paraneoplastic Cerebellar Degeneration in Head and Neck Cancer.

BACKGROUND: Paraneoplastic syndromes are most frequently associated with small cell lung carcinoma, hematologic and gynecologic malignancies while reports in head and neck cancer are rare. CASE PRESENTATION: We present the case of a 60-year old female patient who developed paraneoplastic cerebellar degeneration upon locoregional recurrence of a poorly differentiated spindle cell carcinoma of the nasal cavity and paranasal sinus. The neurological symptoms, especially ataxia, stabilized after resection of tumor recurrence and concomitant chemoradiotherapy whereas anti-Hu-antibodies remained positive. Despite the unfavorable prognosis of paraneoplastic neurological disorders associated with onconeural antibodies, the patient achieved long-standing stabilization of neurological symptoms. CONCLUSION: We report the first patient with anti-Hu antibodies and paraneoplastic cerebellar degeneration associated with a spindle cell carcinoma of the head and neck. We recommend that evaluation of neurological symptoms in patients with this tumor entity should also include paraneoplastic syndromes as differential diagnoses and suggest early extensive screening for onconeural antibodies.

CYP39A1 polymorphism is associated with toxicity during intensive induction chemotherapy in patients with advanced head and neck cancer.

BACKGROUND: Induction chemotherapy incorporating docetaxel, cisplatin and 5- fluorouracil before radiotherapy may improve the outcome of patients with advanced head and neck cancer. Nevertheless, the addition of docetaxel increases hematological toxicity and infectious complications. Therefore, genetic markers predicting toxicity and efficacy of this treatment regimen may help to identify patients, who would have the most benefit from this intensive treatment. METHODS: A cohort of 78 patients with advanced head and neck cancer treated with induction chemotherapy was assessed for clinical outcome and toxicity during treatment with curative intention. Genetic polymorphisms primary associated with treatment efficacy (ERCC2-rs13181, rs1799793, ERCC1-rs3212986, rs11615, XRCC1-rs25487) or with docetaxel caused toxicity (CYP39A1-rs7761731, SLCO1B3-rs11045585) were evaluated in all patients. The results of these analyses were correlated with the clinical outcome of the patients (loco regional control, progression free survival, overall survival) and treatment related toxicity during induction chemotherapy. RESULTS: Median progression free survival and overall survival was 20 and 31 months in an intention to treat analysis, respectively. Overall response rate to induction chemotherapy was high with 78.1 % of all patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. Genotype A of the CYP39A1 rs7761731 polymorphism was associated with a higher incidence of leucopenia and infections or death during induction chemotherapy. CONCLUSIONS: Intensive induction chemotherapy results in a high response rate in the majority of patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. The CYP39A1 polymorphism rs7761731 may help to identify patients at high risk for treatment related toxicity.

Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial.

BACKGROUND: Trastuzumab, one important treatment option for HER2-positive metastatic breast cancer (MBC) is limited by its cardiotoxic potential. Lapatinib and pegylated liposomal doxorubicin (PLD) represent a cardiosparing alternative that can cross the blood brain barrier. This is important, because one third of breast cancer patients develop brain metastases. PATIENTS AND METHODS: We included 24 patients with HER2-positive MBC progressing under trastuzumab. They received 1,250 mg lapatinib daily until progression plus PLD (40 mg/m(2)) every 4 weeks for maximal 6 cycles. The primary end-point was the overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), 1-year PFS and 1-year OS rates. RESULTS: ORR was 54%. Median PFS was 5.8 and median OS 23.3 months. The one-year PFS rate was 27% and 1-year OS rate 76%. CONCLUSION: Lapatinib-plus-PLD is active and safe in HER2-positive MBC, especially suitable for patients with cardiological risk or brain metastases.

Treatment of aggressive B-cell lymphoma in elderly patients: influence of single nucleotide polymorphisms affecting pharmacodynamics of chemotherapeutics.

Clinical and/or biological risk factors are needed to identify elderly patients with aggressive B-cell lymphoma able to receive full-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) treatment. We present a retrospective analysis of 83 patients≥75 years of age (range: 75-97) who were diagnosed with aggressive B cell lymphoma between 2004 and 2011 in our clinic. R-CHOP-like therapy was administered in 82% of these patients resulting in a median overall survival of 54 months. A median cumulative dose of 226 mg/m2 doxorubicin and a median of six cycles were applied in these patients. Two genotypes of the CBR3 and MLH1 genes affecting the metabolism of cytostatics identified a subgroup with a favorable prognosis (median overall survival not reached vs. 30 months, p=0.01). A treatment strategy aiming at full-dose R-CHOP was feasible and resulted in an encouraging treatment outcome in patients≥75 years. Pharmacogenetic parameters, if independently validated, may be helpful in elderly patients.

A modified scoring of the NCCN-IPI is more accurate in the elderly and is improved by albumin and ß2 -microglobulin.

The International Prognostic Index (IPI) has been used for decades in diffuse large B-cell lymphoma (DLBCL). A retrospective cancer registry analysis in North America showed significantly improved results when an enhanced IPI, the National Comprehensive Cancer Network (NCCN)-IPI was applied. This novel score puts more weight on age and high levels of lactate dehydrogenase (LDH). Nevertheless, it remains unclear if these results can be extrapolated to the general population. This retrospective bi-centre analysis included 499 unselected DLBCL patients who were treated with rituximab and anthracycline-based chemoimmunotherapy between 2004 and 2013. In our cohort, the NCCN-IPI was more accurate in identifying patients at low or high risk, despite older age, and more patients with increased LDH. Nevertheless, a modified scoring of the risk factors was required to more accurately identify elderly patients with a very favourable diagnosis, suggesting an impaired value of the original NCCN-IPI in the elderly. Serum ß2 -microglobulin and albumin were retained as independent prognostic factors for survival in a multivariate analysis. Our data confirm, for the first time, the superior prognostic power of the NCCN-IPI in an unselected, middle-European cohort. We furthermore propose a modified NCCN-IPI for more accurate prognostication in the elderly. Albumin and ß2 -microglobulin levels are likely to add significant information to the NCCN-IPI.

Liver toxicity during temozolomide chemotherapy caused by Chinese herbs.

BACKGROUND: Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. CASE PRESENTATION: We report the case of severe liver toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no liver toxicity was observed. CONCLUSIONS: We conclude that the observed toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.