Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 4 Απριλίου 2018
Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review
Abstract
Purpose
The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and Methods
Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed. Results
Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials. Conclusion
The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.from Cancer via ola Kala on Inoreader https://ift.tt/2GAjsgQ
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ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma
Abstract
Background
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme – arginine deiminase – conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number
www.clinicaltrials (NCT 01287585)from Cancer via ola Kala on Inoreader https://ift.tt/2GSD9nw
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Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review
Abstract
Purpose
The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and Methods
Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed. Results
Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials. Conclusion
The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.https://ift.tt/2GAjsgQ
ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma
Abstract
Background
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme – arginine deiminase – conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number
www.clinicaltrials (NCT 01287585)https://ift.tt/2GSD9nw
Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance
Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the Type-I interferon, α- and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%-31%, median = 12%; interquartile range = 10-16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes are prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.
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Inositol trisphosphate receptor type 3-mediated enhancement of EGFR and MET co-targeting efficacy in non-small cell lung cancer detected by 18F-fluorothymidine
Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination. Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and post-treatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA. Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F ratio= 6.215, p=0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras. Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras.
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Risk assessment after neoadjuvant chemotherapy in luminal breast cancer using a clinico-molecular predictor
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathological tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen-receptor (ER)-positive/HER2-negative breast cancer (BC). We also compared the prognostic power of the mEPclin with that of the CPS-EG score. Experimental Design: 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cutoff values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS). Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse (HR=2.16 [95%CI 1.86-2.51]; p<0.001) and death (HR=2.28 [95% CI 1.90-2.75]; p<0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer disease-free and overall survival compared to those at low risk. In contrast to CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR=2.13 [1.73-2.63]; p<0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; p<0.001). Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies.
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Orthoxenografts of testicular germ cell tumors demonstrate genomic changes associated with cisplatin resistance and identify PDMP as a re-sensitizing agent
Purpose: To investigate the genetic basis of cisplatin resistance. Efficacy of cisplatin chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic/ acquired drug resistance of tumors. Experimental design: We produced 14 orthoxenograft transplanting human nonseminomatous (NSE) testicular germ cell tumors (TGCTs) to mice, keeping the primary tumor features (genotype, phenotype and sensitivity to cisplatin). Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in vivo. Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin refractory patients and poorer overall survival in metastatic TGCTs. We study the expression profile of the sixty genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Other four genes (GCS, ZNF883, CTR1 and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in C. elegans indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or down-regulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP re-sensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin. Conclusions: Orthoxenografts can be used preclinically to test the efficiency of drugs and also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance.
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Change in topoisomerase 1 (Top1) positive circulating tumor cells impacts overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTCs) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656/852 (77%) of patients was processed with ApoStream® to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers (Top1, Top2, Ki67, RAD51, ABCG2, H2AX, TUNEL) in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median 47-63 CTCs/ml; range 0-2020 CTCs/ml). Top1, Top2, and TUNEL expression was detected in 52%-90% of samples; no significant associations with OS were observed in pre-treatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared to those with higher positivity (14.1 months vs. 11.0 months, respectively, HR 0.7, P=0.02); this difference was not seen in TPC-treated patients (HR 1.12, P=0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR 0.57, P=0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.
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Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1–8. ©2018 AACR.
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Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance
Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the Type-I interferon, α- and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%-31%, median = 12%; interquartile range = 10-16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes are prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.
https://ift.tt/2qbVGSr
Inositol trisphosphate receptor type 3-mediated enhancement of EGFR and MET co-targeting efficacy in non-small cell lung cancer detected by 18F-fluorothymidine
Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination. Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and post-treatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA. Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F ratio= 6.215, p=0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras. Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras.
https://ift.tt/2GBXAlp
Risk assessment after neoadjuvant chemotherapy in luminal breast cancer using a clinico-molecular predictor
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathological tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen-receptor (ER)-positive/HER2-negative breast cancer (BC). We also compared the prognostic power of the mEPclin with that of the CPS-EG score. Experimental Design: 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cutoff values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS). Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse (HR=2.16 [95%CI 1.86-2.51]; p<0.001) and death (HR=2.28 [95% CI 1.90-2.75]; p<0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer disease-free and overall survival compared to those at low risk. In contrast to CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR=2.13 [1.73-2.63]; p<0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; p<0.001). Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies.
https://ift.tt/2q6pM9A
Orthoxenografts of testicular germ cell tumors demonstrate genomic changes associated with cisplatin resistance and identify PDMP as a re-sensitizing agent
Purpose: To investigate the genetic basis of cisplatin resistance. Efficacy of cisplatin chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic/ acquired drug resistance of tumors. Experimental design: We produced 14 orthoxenograft transplanting human nonseminomatous (NSE) testicular germ cell tumors (TGCTs) to mice, keeping the primary tumor features (genotype, phenotype and sensitivity to cisplatin). Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in vivo. Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin refractory patients and poorer overall survival in metastatic TGCTs. We study the expression profile of the sixty genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Other four genes (GCS, ZNF883, CTR1 and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in C. elegans indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or down-regulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP re-sensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin. Conclusions: Orthoxenografts can be used preclinically to test the efficiency of drugs and also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance.
https://ift.tt/2GznG8u
Change in topoisomerase 1 (Top1) positive circulating tumor cells impacts overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTCs) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656/852 (77%) of patients was processed with ApoStream® to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers (Top1, Top2, Ki67, RAD51, ABCG2, H2AX, TUNEL) in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median 47-63 CTCs/ml; range 0-2020 CTCs/ml). Top1, Top2, and TUNEL expression was detected in 52%-90% of samples; no significant associations with OS were observed in pre-treatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared to those with higher positivity (14.1 months vs. 11.0 months, respectively, HR 0.7, P=0.02); this difference was not seen in TPC-treated patients (HR 1.12, P=0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR 0.57, P=0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.
https://ift.tt/2q6pL5w
Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1–8. ©2018 AACR.
https://ift.tt/2GvJgia
Diagnosing cervical neoplasia in rural Brazil using a mobile van equipped with in vivo microscopy: A cluster-randomized community trial
Cervical cancer is a leading cause of death in underserved areas of Brazil. This prospective randomized trial involved 200 women in southern/central Brazil with abnormal Papanicolaou tests. Participants were randomized by geographic cluster and referred for diagnostic evaluation either at a mobile van upon its scheduled visit to their local community, or at a central hospital. Participants in both arms underwent colposcopy, in vivo microscopy, and cervical biopsies. We compared rates of diagnostic follow-up completion between study arms, and also evaluated the diagnostic performance of in vivo microscopy compared to colposcopy. There was a 23% absolute and 37% relative increase in diagnostic follow-up completion rates for patients referred to the mobile van (102/117, 87%) compared with the central hospital (53/83, 64%) (p=0.0001; risk ratio=1.37, 95%CI=1.14-1.63). In 229 cervical sites in 144 patients, colposcopic examination identified sites diagnosed as cervical intraepithelial neoplasia grade 2 or more severe (CIN2+; 85 sites) with a sensitivity of 94% (95%CI=87%-98%) and specificity of 50% (95%CI=42%-58%). In vivo microscopy with real-time automated image analysis identified CIN2+ with a sensitivity of 92% (95%CI=84%-97%) and specificity of 48% (95%CI=40%-56%). Women referred to the mobile van were more likely to complete their diagnostic follow-up compared to those referred to a central hospital, without compromise in clinical care. In vivo microscopy in a mobile van provides automated diagnostic imaging with sensitivity and specificity similar to colposcopy.
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A System-Level Approach to Improve the Uptake of Antiestrogen Preventive Therapy among Women with Atypical Hyperplasia and Lobular Cancer In Situ
Background: The low uptake of antiestrogen preventive therapy among women at high risk of developing breast cancer remains a challenge. We implemented a performance improvement program to increase the uptake of preventive therapy among women with atypical hyperplasia (AH) and lobular cancer in situ (LCIS).
Methods: A performance improvement program was implemented at the MD Anderson Cancer Center (Houston, TX), November 2015 to February 2017, for patients with a new (<6 months) or existing (≥6 months) diagnosis of AH/LCIS. The program consisted of an audit of eligible women who were recommended and prescribed preventive therapy and the provision of clinical performance feedback to providers. The baseline uptake of preventive therapy was estimated from patients enrolled in a high-risk breast cohort.
Results: Baseline uptake of preventive therapy was 44%. The program registered 408 patients with a new (n = 87) or existing diagnosis (n = 321) of AH/LCIS; mean age was 57 and 71% were non-Hispanic white. Ninety-eight percent of patients received a recommendation for preventive therapy. The overall prescribing of preventive therapy to patients with a new or existing diagnosis was 82% (monthly range, 40%–100%; Ptrend = 0.76) and 48% (monthly range, 27%–57%; Ptrend < 0.01), respectively. Adherence among patients with a new or existing diagnosis was 76% and 48% (P < 0.01) at 6 months, respectively.
Conclusion: A system-level approach improved the uptake of preventive therapy. Identifying women at the time of diagnosis of AH/LCIS and offering a strong recommendation are key components for improving acceptance and adherence with preventive therapy. Cancer Prev Res; 1–7. ©2018 AACR.
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Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline
Source:Practical Radiation Oncology
Author(s): Benjamin Moeller, Ehsan H. Balagamwala, Aileen Chen, Kimberly M. Creach, Giuseppe Giaccone, Matthew Koshy, Sandra Zaky, George Rodrigues
PurposeTo revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer.Methods and materialsBased on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology–approved tools for grading evidence quality and recommendation strength.ResultsAlthough few randomized clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended.ConclusionsOptimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach.
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Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline
Source:Practical Radiation Oncology
Author(s): Benjamin Moeller, Ehsan H. Balagamwala, Aileen Chen, Kimberly M. Creach, Giuseppe Giaccone, Matthew Koshy, Sandra Zaky, George Rodrigues
PurposeTo revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer.Methods and materialsBased on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology–approved tools for grading evidence quality and recommendation strength.ResultsAlthough few randomized clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended.ConclusionsOptimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach.
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Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study
To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study.
https://ift.tt/2IqkoVF
Tumour lysis in newborn: spontaneous or secondary to antenatal steroids?
Malignancies are rare in the early neonatal period. Common congenital tumours include malignant teratoma and neuroblastomas. Tumour lysis syndrome is a serious condition usually seen after commencement of chemotherapy for a malignancy. Rare case reports of spontaneous tumour lysis have been reported though not in the newborn period. We report here an instance of tumour lysis syndrome in a newborn with congenital rhabdoid tumour, where the cause was either spontaneous or related to antenatal steroid exposure.
https://ift.tt/2IpjwQY
Surprising cause of a hoarse voice
Description
A 78-year-old woman presented to our otorhinolaryngology clinic with a 5-year history of gradually progressive, worsening dysphonia, associated with some recent weight loss. She denied any dysphagia, odynophagia, otalgia, dyspnoea or neck lumps. She had a significant cardiovascular history and was a non-smoker with no alcohol intake. Using the grade–roughness–breathiness–asthenicity–strain scale, the patient scored a 2/3 for grade and breathiness, 1/3 for roughness and 3/3 for strain. On examination, there was a large left-sided posterior pharyngeal wall swelling occluding most of the oropharynx (figure 1). It was firm, non-pulsatile and non-tender, with a normal overlying mucosal appearance. Flexible nasoendoscopy demonstrated that this swelling extended from the level of the soft palate to just below the level of the epiglottis, with laryngeal displacement to the right. However, there was no airway compression, and the patient had normal, mobile true vocal cords bilaterally. Videolaryngostroboscopy was not possible with...
https://ift.tt/2H8lF47
Corrigendum to “Reported Incidence and Survival of Fallopian Tube Carcinomas: A Population-Based Analysis From the North American Association of Central Cancer Registries”
Corrigendum to "Reported Incidence and Survival of Fallopian Tube Carcinomas: A Population-Based Analysis From the North American Association of Central Cancer Registries" by Britton Trabert et al. JNCI. J Natl Cancer Inst 2017; doi: https://ift.tt/2uKYudH.
https://ift.tt/2q51H2X
https://ift.tt/2q51H2X
Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number
Abstract
Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.
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Perspectives of patients with haematological cancer on how clinicians meet their information needs: “Managing” information versus “giving” it
Psycho-Oncology, EarlyView.
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Perspectives of patients with haematological cancer on how clinicians meet their information needs: “Managing” information versus “giving” it
Psycho-Oncology, EarlyView.
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Using in vivo fluorescence lifetime imaging to detect HER2-positive tumors
Abstract
Background
Assessment of the status of tumor biomarkers in individual patients would facilitate personalizing treatment strategy, and continuous monitoring of those biomarkers and their binding process to the therapeutic drugs would provide a means for early evaluation of the efficacy of therapeutic intervention. Fluorescent probes can accumulate inside the tumor region due to the leakiness of its vascularization and this can make it difficult to distinguish if the measured fluorescence intensity is from probes bound to target receptors or just accumulated unbound probes inside the tumor. In this paper, we have studied the fluorescence lifetime as a means to distinguish bound HER2 specific affibody probes to HER2 receptors.
Our imaging system is a time-resolved fluorescence system using a Ti-Sapphire femtosecond pulse laser as source and Time correlated Single photon Counting (TCSPC) system as detector for calculating the lifetime of the contrast agent. HER2-specific Affibody (His6-ZHER2:GS-Cys) (Affibody, Stockholm, Sweden) conjugated with a Dylight750 fluorescent probe (Thermo-Fisher-Scientific, Waltham, Massachusetts) was used as contrast agent and six human cancer cell lines, BT-474, SKOV-3, NCI-N87, MDA-MB-361, MCF-7, and MDA-MB-468, known to express different levels of HER2/neu, are used in athymic mice xenografts.
Results
By comparing the lifetime of unbound contrast agent (at the contralateral site) to the fluorescence lifetime at the tumor site, our results show that the fluorescence lifetime decreases as HER2 specific Affibody probes bind to the tumor receptors. A decrease of ~15% (100ps) in tumor fluorescence lifetime was observed in tumors with mid to high HER2 expression. Smaller decreases were observed in tumors with low-level of HER2 receptors and no change was observed in the non-HER2-expressing tumors.
Conclusions
Using HER2-specific Affibody conjugated with the Dylight750 fluorescent probe as contrast agent, we demonstrated in live animals that change in fluorescence lifetime of the bound contrast agent can be used to assess the high to mid-level expression of HER2 expressing tumors in-vivo in only one measurement. The rationale is that the fluorescence lifetime of our specific probe is sensitive to affinity to, and specific interaction with, other molecules.
https://ift.tt/2Eh3177
Hallmarks in prostate cancer imaging with Ga68-PSMA-11-PET/CT with reference to detection limits and quantitative properties
Abstract
Background
Gallium-68-labeled prostate-specific antigen positron emission tomography/computed tomography imaging (Ga68-PSMA-11-PET/CT) has emerged as a potential gold standard for prostate cancer (PCa) diagnosis. However, the imaging limitations of this technique at the early state of PCa recurrence/metastatic spread are still not well characterized. The aim of this study was to determine the quantitative properties and the fundamental imaging limits of Ga68-PSMA-11-PET/CT in localizing small PCa cell deposits.
Methods
The human PCa LNCaP cells (PSMA expressing) were grown and collected as single cell suspension or as 3D-spheroids at different cell numbers and incubated with Ga68-PSMA-11. Thereafter, human HCT116 cells (PSMA negative) were added to a total cell number of 2 × 105 cells per tube. The tubes were then pelleted and the supernatant aspirated. A whole-body PET/CT scanner with a clinical routine protocol was used for imaging the pellets inside of a cylindrical water phantom with increasing amounts of background activity. The actual activity bound to the cells was also measured in an automatic gamma counter. Imaging detection limits and activity recovery coefficients as a function of LNCaP cell number were obtained. The effect of Ga68-PSMA-11 mass concentration on cell binding was also investigated in samples of LnCaP cells incubated with increasing concentrations of radioligand.
Results
A total of 1 × 104 LNCaP cells mixed in a pellet of 2 × 105 cells were required to reach a 50% detection probability with Ga68-PSMA-11-PET/CT without background. With a background level of 1 kBq/ml, between 4 × 105 and 1 × 106 cells are required. The radioligand equilibrium dissociation constant was 27.05 nM, indicating high binding affinity. Hence, the specific activity of the radioligand has a profound effect on image quantification.
Conclusions
Ga68-PSMA-11-PET detects a small number of LNCaP cells even when they are mixed in a population of non-PSMA expressing cells and in the presence of background. The obtained image detection limits and characteristic quantification properties of Ga68-PSMA-11-PET/CT are essential hallmarks for the individualization of patient management. The use of the standardized uptake value for Ga68-PSMA-11-PET/CT image quantification should be precluded.
https://ift.tt/2Gwigz2
Using in vivo fluorescence lifetime imaging to detect HER2-positive tumors
Abstract
Background
Assessment of the status of tumor biomarkers in individual patients would facilitate personalizing treatment strategy, and continuous monitoring of those biomarkers and their binding process to the therapeutic drugs would provide a means for early evaluation of the efficacy of therapeutic intervention. Fluorescent probes can accumulate inside the tumor region due to the leakiness of its vascularization and this can make it difficult to distinguish if the measured fluorescence intensity is from probes bound to target receptors or just accumulated unbound probes inside the tumor. In this paper, we have studied the fluorescence lifetime as a means to distinguish bound HER2 specific affibody probes to HER2 receptors.
Our imaging system is a time-resolved fluorescence system using a Ti-Sapphire femtosecond pulse laser as source and Time correlated Single photon Counting (TCSPC) system as detector for calculating the lifetime of the contrast agent. HER2-specific Affibody (His6-ZHER2:GS-Cys) (Affibody, Stockholm, Sweden) conjugated with a Dylight750 fluorescent probe (Thermo-Fisher-Scientific, Waltham, Massachusetts) was used as contrast agent and six human cancer cell lines, BT-474, SKOV-3, NCI-N87, MDA-MB-361, MCF-7, and MDA-MB-468, known to express different levels of HER2/neu, are used in athymic mice xenografts.
Results
By comparing the lifetime of unbound contrast agent (at the contralateral site) to the fluorescence lifetime at the tumor site, our results show that the fluorescence lifetime decreases as HER2 specific Affibody probes bind to the tumor receptors. A decrease of ~15% (100ps) in tumor fluorescence lifetime was observed in tumors with mid to high HER2 expression. Smaller decreases were observed in tumors with low-level of HER2 receptors and no change was observed in the non-HER2-expressing tumors.
Conclusions
Using HER2-specific Affibody conjugated with the Dylight750 fluorescent probe as contrast agent, we demonstrated in live animals that change in fluorescence lifetime of the bound contrast agent can be used to assess the high to mid-level expression of HER2 expressing tumors in-vivo in only one measurement. The rationale is that the fluorescence lifetime of our specific probe is sensitive to affinity to, and specific interaction with, other molecules.
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Hallmarks in prostate cancer imaging with Ga68-PSMA-11-PET/CT with reference to detection limits and quantitative properties
Abstract
Background
Gallium-68-labeled prostate-specific antigen positron emission tomography/computed tomography imaging (Ga68-PSMA-11-PET/CT) has emerged as a potential gold standard for prostate cancer (PCa) diagnosis. However, the imaging limitations of this technique at the early state of PCa recurrence/metastatic spread are still not well characterized. The aim of this study was to determine the quantitative properties and the fundamental imaging limits of Ga68-PSMA-11-PET/CT in localizing small PCa cell deposits.
Methods
The human PCa LNCaP cells (PSMA expressing) were grown and collected as single cell suspension or as 3D-spheroids at different cell numbers and incubated with Ga68-PSMA-11. Thereafter, human HCT116 cells (PSMA negative) were added to a total cell number of 2 × 105 cells per tube. The tubes were then pelleted and the supernatant aspirated. A whole-body PET/CT scanner with a clinical routine protocol was used for imaging the pellets inside of a cylindrical water phantom with increasing amounts of background activity. The actual activity bound to the cells was also measured in an automatic gamma counter. Imaging detection limits and activity recovery coefficients as a function of LNCaP cell number were obtained. The effect of Ga68-PSMA-11 mass concentration on cell binding was also investigated in samples of LnCaP cells incubated with increasing concentrations of radioligand.
Results
A total of 1 × 104 LNCaP cells mixed in a pellet of 2 × 105 cells were required to reach a 50% detection probability with Ga68-PSMA-11-PET/CT without background. With a background level of 1 kBq/ml, between 4 × 105 and 1 × 106 cells are required. The radioligand equilibrium dissociation constant was 27.05 nM, indicating high binding affinity. Hence, the specific activity of the radioligand has a profound effect on image quantification.
Conclusions
Ga68-PSMA-11-PET detects a small number of LNCaP cells even when they are mixed in a population of non-PSMA expressing cells and in the presence of background. The obtained image detection limits and characteristic quantification properties of Ga68-PSMA-11-PET/CT are essential hallmarks for the individualization of patient management. The use of the standardized uptake value for Ga68-PSMA-11-PET/CT image quantification should be precluded.
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Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy
Background: The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine have recently emerged as a potential novel treatment for medically refractory epilepsy. Blood-derived BCAAs can readily enter the brain, where they contribute to glutamate biosynthesis and may either suppress or trigger acute seizures. However, the effects of BCAAs on chronic (ie, spontaneous recurrent) seizures and epilepsy-associated neuron loss are incompletely understood. Materials and Methods: Sixteen rats with mesial temporal lobe epilepsy were randomized into 2 groups that could drink, ad libitum, either a 4% solution of BCAAs in water (n=8) or pure water (n=8). The frequency and relative percent of convulsive and nonconvulsive spontaneous seizures were monitored for a period of 21 days, and the brains were then harvested for immunohistochemical analysis. Results: Although the frequency of convulsive and nonconvulsive spontaneous recurrent seizures over a 3-week drinking/monitoring period were not different between the groups, there were differences in the relative percent of convulsive seizures in the first and third week of treatment. Moreover, the BCAA-treated rats had over 25% fewer neurons in the dentate hilus of the hippocampus compared with water-treated controls. Conclusions: Acute BCAA supplementation reduces seizure propagation, whereas chronic oral supplementation with BCAAs worsens seizure propagation and causes neuron loss in rodents with mesial temporal lobe epilepsy. These findings raise the question of whether such supplementation has a similar effect in humans. T.E. and R.D. are supported by grants from the National Institutes of Health (NIH): NINDS R01 NS070824. S.E.G. is supported by grants from the Foundation for Anesthesia Education and Research (FAER) and the NIH: T32 GM086287. This work was also made possible by a grant from the National Center for Advancing Translational Sciences (NCATS; UL1 TR000142), a component of the NIH and the NIH Roadmap for Medical Research. The authors have no conflicts of interest to disclose. Address correspondence to: Tore Eid, MD, PhD, Department of Laboratory Medicine, 330 Cedar St., P.O. Box 208035, Yale School of Medicine, New Haven, CT 06520 (e-mail: tore.eid@yale.edu). Received November 28, 2017 Accepted February 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved
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Lipid accumulation in human breast cancer cells injured by iron depletors
Current insights into the effects of iron deficiency in tumour cells are not commensurate with the importance of iron in cell metabolism. Studies have predominantly focused on the effects of oxygen or glucose ...
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Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis
Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis foll...
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MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma
By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) ...
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Mature and progenitor endothelial cells perform angiogenesis also under protease inhibition: the amoeboid angiogenesis
Controlling vascular growth is a challenging aim for the inhibition of tumor growth and metastasis. The amoeboid and mesenchymal types of invasiveness are two modes of migration interchangeable in cancer cells...
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Performing studies using the UK Clinical Practice Research Datalink: to link or not to link?
Abstract
The Clinical Practice Research Datalink (CPRD) is a repository of electronic medical records collected during routine primary care clinical practice in the UK, and is one of the most widely used sources of real-world data for healthcare research. Although CPRD provides access to comprehensive longitudinal patient records, the data does not fully capture diagnoses or outcomes occurring in secondary care and/or mortality. We provide here an overview of CPRD and the potential bias when using unlinked data in certain situations. Linkage of CPRD to other datasets can help to overcome these limitations. We discuss when to consider linkage to secondary care, disease-specific data sources or the official mortality data when conducting research using CPRD data.
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Does setup on rectal wall improve rectal cancer boost radiotherapy?
Rectal cancer patients that show a pathological complete response (pCR) after neo-adjuvant chemo-radiotherapy, have better prognosis. To increase pCR rates several studies escalate the tumor irradiation dose. ...
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Dosimetrical and radiobiological approach to manage the dosimetric shift in the transition of dose calculation algorithm in radiation oncology: how to improve high quality treatment and avoid unexpected outcomes?
For a given prescribed dose of radiotherapy, with the successive generations of dose calculation algorithms, more monitor units (MUs) are generally needed. This is due to the implementation of successive impro...
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Does setup on rectal wall improve rectal cancer boost radiotherapy?
Rectal cancer patients that show a pathological complete response (pCR) after neo-adjuvant chemo-radiotherapy, have better prognosis. To increase pCR rates several studies escalate the tumor irradiation dose. ...
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Dosimetrical and radiobiological approach to manage the dosimetric shift in the transition of dose calculation algorithm in radiation oncology: how to improve high quality treatment and avoid unexpected outcomes?
For a given prescribed dose of radiotherapy, with the successive generations of dose calculation algorithms, more monitor units (MUs) are generally needed. This is due to the implementation of successive impro...
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Cancer Immunotherapy Drug Simultaneously Targets Two Proteins that Block Immune Response
Two independent groups of researchers have fused a TGF-beta receptor to a monoclonal antibody that targets a checkpoint protein. The result is a single hybrid molecule called a Y-trap that blocks two pathways used by tumors to evade the immune system.
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Cancer Immunotherapy Drug Simultaneously Targets Two Proteins that Block Immune Response
Two independent groups of researchers have fused a TGF-beta receptor to a monoclonal antibody that targets a checkpoint protein. The result is a single hybrid molecule called a Y-trap that blocks two pathways used by tumors to evade the immune system.
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Cancers, Vol. 10, Pages 107: The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)
Cancers, Vol. 10, Pages 107: The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)
Cancers doi: 10.3390/cancers10040107
Authors: Ivonne A. Montes-Mojarro Julia Steinhilber Irina Bonzheim Leticia Quintanilla-Martinez Falko Fend
Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.
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Cancers, Vol. 10, Pages 107: The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)
Cancers, Vol. 10, Pages 107: The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)
Cancers doi: 10.3390/cancers10040107
Authors: Ivonne A. Montes-Mojarro Julia Steinhilber Irina Bonzheim Leticia Quintanilla-Martinez Falko Fend
Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.
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Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review.
Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review.
Cancer Biol Ther. 2018 Apr 03;:1-19
Authors: Zhang Y, Wang X, Liu Y, Sun C, Shi W, Huang H
Abstract
CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is associated with poor survival compared with CD5-negative DLBCL. The clinical characteristics of CD5+ DLBCL are different from both CD5-negative DLBCL and other CD5+ B cell lymphomas. There is currently no promising chemotherapy for CD5+ DLBCL. Herein, we report a 49-year-old Asian male with refractory CD5+ DLBCL. He complained of aggravated abdominal pain and weight loss. Computed tomography scan revealed abdominal masses, widespread lymphadenopathy, splenomegaly, and intussusception of the ileocecal junction with bowel wall thickening. Core needle aspiration biopsy of an abdominal mass was performed and immunohistochemistry revealed DLBCL of nongerminal center type. In this report, the dose-intensified R-Hyper CVAD (A) regimen as salvage therapy was introduced but failed to result in substantial improvement over the initially standard R-CHOP regimen. Next, the R-GDP regimen was administered as second-line treatment, but only resulted in a partial response. However, the addition of lenalidomide to R-GDP (R2-GDP) resulted in complete remission. The clinical features, pathogenesis, and possible mechanism of action of lenalidomide in CD5+ DLBCL have been described in the literature. The results of the present case report and literature searches indicate that CD5+ DLBCL may share a common pathway with activated B-cell like (ABC) DLBCL as determined by gene expression profiling. Lenalidomide is expected to induce favorable responses in patients with CD5+ DLBCL.
PMID: 29611764 [PubMed - as supplied by publisher]
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(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC.
(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC.
Cancer Biol Ther. 2018 Apr 03;:1-28
Authors: Yang X, Zhu J, Wu J, Huang N, Cui Z, Luo Y, Sun F, Pan Q, Li Y, Yang Q
Abstract
(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (-)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (-)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients.
PMID: 29611762 [PubMed - as supplied by publisher]
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Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review.
Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review.
Cancer Biol Ther. 2018 Apr 03;:1-19
Authors: Zhang Y, Wang X, Liu Y, Sun C, Shi W, Huang H
Abstract
CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is associated with poor survival compared with CD5-negative DLBCL. The clinical characteristics of CD5+ DLBCL are different from both CD5-negative DLBCL and other CD5+ B cell lymphomas. There is currently no promising chemotherapy for CD5+ DLBCL. Herein, we report a 49-year-old Asian male with refractory CD5+ DLBCL. He complained of aggravated abdominal pain and weight loss. Computed tomography scan revealed abdominal masses, widespread lymphadenopathy, splenomegaly, and intussusception of the ileocecal junction with bowel wall thickening. Core needle aspiration biopsy of an abdominal mass was performed and immunohistochemistry revealed DLBCL of nongerminal center type. In this report, the dose-intensified R-Hyper CVAD (A) regimen as salvage therapy was introduced but failed to result in substantial improvement over the initially standard R-CHOP regimen. Next, the R-GDP regimen was administered as second-line treatment, but only resulted in a partial response. However, the addition of lenalidomide to R-GDP (R2-GDP) resulted in complete remission. The clinical features, pathogenesis, and possible mechanism of action of lenalidomide in CD5+ DLBCL have been described in the literature. The results of the present case report and literature searches indicate that CD5+ DLBCL may share a common pathway with activated B-cell like (ABC) DLBCL as determined by gene expression profiling. Lenalidomide is expected to induce favorable responses in patients with CD5+ DLBCL.
PMID: 29611764 [PubMed - as supplied by publisher]
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(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC.
(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC.
Cancer Biol Ther. 2018 Apr 03;:1-28
Authors: Yang X, Zhu J, Wu J, Huang N, Cui Z, Luo Y, Sun F, Pan Q, Li Y, Yang Q
Abstract
(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (-)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (-)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients.
PMID: 29611762 [PubMed - as supplied by publisher]
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Cancers, Vol. 10, Pages 106: Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma
Cancers, Vol. 10, Pages 106: Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma
Cancers doi: 10.3390/cancers10040106
Authors: Shaina Chor Mei Huang Sai Wah Tsao Chi Man Tsang
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies.
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Cancers, Vol. 10, Pages 106: Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma
Cancers, Vol. 10, Pages 106: Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma
Cancers doi: 10.3390/cancers10040106
Authors: Shaina Chor Mei Huang Sai Wah Tsao Chi Man Tsang
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies.
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Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome
Abstract
Introduction
The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients.
Methods
We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups.
Results
Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037).
Conclusion
Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.
https://ift.tt/2Gxfo4W
Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome
Abstract
Introduction
The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients.
Methods
We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups.
Results
Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV ≥ 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037).
Conclusion
Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.
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The predictors and oncological outcomes of repeat surgery for recurrence after hepatectomy for colorectal liver metastases
Abstract
Purpose
Although recurrence after hepatectomy for colorectal liver metastases (CRLM) is common, the optimal treatment strategy remains unclear. The aims of this study were to clarify the impact of repeat surgery and identify the predictive factors for repeat surgery.
Methods
Among the 170 patients who underwent potentially curative surgery for CRLM, 113 developed recurrence. The predictive factors for the performance of repeat surgery were identified and a predictive model was constructed.
Results
The patterns of recurrence were as follows; single site [n = 100 (liver, n = 61; lung, n = 22; other, n = 17)], multiple site (n = 13). Repeat surgery was performed in 54 patients (47.8%) including re-hepatectomy (n = 25), radiofrequency ablation (n = 12), and resection of the extrahepatic recurrent disease (n = 17), and their overall survival (OS) was significantly better than that of those who could not (5-year OS 60.7 vs 19.5%, P < 0.0001). A multivariate analysis revealed that a primary N-negative status [relative risk (RR) 2.93, P = 0.017], indocyanine retention rate at 15 min ≤ 10% before hepatectomy (RR 2.49, P = 0.04), and carcinoembryonic antigen ≤ 5 ng/mL before hepatectomy (RR 2.96, P = 0.017) independently predicted the performance of repeat surgery. For patients who did not present any factors, the probability of repeat surgery was 19.6%. The addition of each subsequent factor increased the probability to 41.9, 67.8, and 84.0% (for 1, 2, and 3 factors, respectively).
Conclusions
Repeat surgery for not only intrahepatic but also extrahepatic recurrence is crucial for prolonging the survival of CRLM patients. The proposed model may help to predict the possibility of repeat surgery and provide optimal individualized treatment.
https://ift.tt/2GQGfIK
The predictors and oncological outcomes of repeat surgery for recurrence after hepatectomy for colorectal liver metastases
Abstract
Purpose
Although recurrence after hepatectomy for colorectal liver metastases (CRLM) is common, the optimal treatment strategy remains unclear. The aims of this study were to clarify the impact of repeat surgery and identify the predictive factors for repeat surgery.
Methods
Among the 170 patients who underwent potentially curative surgery for CRLM, 113 developed recurrence. The predictive factors for the performance of repeat surgery were identified and a predictive model was constructed.
Results
The patterns of recurrence were as follows; single site [n = 100 (liver, n = 61; lung, n = 22; other, n = 17)], multiple site (n = 13). Repeat surgery was performed in 54 patients (47.8%) including re-hepatectomy (n = 25), radiofrequency ablation (n = 12), and resection of the extrahepatic recurrent disease (n = 17), and their overall survival (OS) was significantly better than that of those who could not (5-year OS 60.7 vs 19.5%, P < 0.0001). A multivariate analysis revealed that a primary N-negative status [relative risk (RR) 2.93, P = 0.017], indocyanine retention rate at 15 min ≤ 10% before hepatectomy (RR 2.49, P = 0.04), and carcinoembryonic antigen ≤ 5 ng/mL before hepatectomy (RR 2.96, P = 0.017) independently predicted the performance of repeat surgery. For patients who did not present any factors, the probability of repeat surgery was 19.6%. The addition of each subsequent factor increased the probability to 41.9, 67.8, and 84.0% (for 1, 2, and 3 factors, respectively).
Conclusions
Repeat surgery for not only intrahepatic but also extrahepatic recurrence is crucial for prolonging the survival of CRLM patients. The proposed model may help to predict the possibility of repeat surgery and provide optimal individualized treatment.
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Cancers, Vol. 10, Pages 105: Inhibiting TRK Proteins in Clinical Cancer Therapy
Cancers, Vol. 10, Pages 105: Inhibiting TRK Proteins in Clinical Cancer Therapy
Cancers doi: 10.3390/cancers10040105
Authors: Allison M. Lange Hui-Wen Lo
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.
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Cancers, Vol. 10, Pages 105: Inhibiting TRK Proteins in Clinical Cancer Therapy
Cancers, Vol. 10, Pages 105: Inhibiting TRK Proteins in Clinical Cancer Therapy
Cancers doi: 10.3390/cancers10040105
Authors: Allison M. Lange Hui-Wen Lo
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.
https://ift.tt/2uJDPXo
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