Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.
The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.
Background and Purpose: <p>The immune checkpoint PD-1 and its receptor B7-H1 (PD-L1) are successful therapeutic targets in cancer but less is known about other B7 family members. Here, we determined the expression level of B7-H3 protein in non-small cell lung cancer (NSCLC) and evaluated its association with tumor infiltrating lymphocytes (TILs), PD-L1, B7-H4 and major clinico-pathological characteristics is in 3 NSCLC cohorts.</p> <p>Experimental design:</p> <p>We used multiplexed automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3, PD-L1, B7-H4 and TILs in 634 NSCLC cases with validated antibodies. Associations between the marker levels, major clinico-pathological variables and survival were analyzed.</p> <p>Results: </p> <p>Expression of B7-H3 protein was found in 80.4% (510/634) of the cases. High B7-H3 protein level (top 10 percentile) was associated with poor overall survival (p <0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage and histology. Co-expression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3, CD8 and CD20 positive TILs.</p> <p>Conclusion:</p> <p>B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High levels of B7-H3 protein has a negative prognostic impact in lung carcinomas. Co-expression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a non-redundant biological role of these targets.
Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy, and to predict the likelihood of local control as a function of dose and treatment fractions.<br /><br />Experimental Design: We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and 2 unpublished early stage patient cohorts, totaling 2701 patients.<br /><br />Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α (0.305 Gy-1; 95% CI: 0.120-0.365), the α/β ratio (2.80 Gy; 95% CI: 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI: 1.55-2.25). All fractionation groups are well-fitted by a single dose-response curve with a high 2 p-value, indicating consistency with the fitted model. The analysis was further validated with additional 23 patient cohorts (n=1628). The model indicates that hypofractionation regimes overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimes allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.<br /><br />Conclusions: The mechanistic tumor response modeling can accurately predict over-treatment or under-treatment for various treatment regimes.
Purpose: <p>Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes.</p> <br /><br />Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.<br /><br />Results: <p>Seventy-two patients (82%) had ≥ 1 ctDNA alteration(s); amongst these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% versus 61.5% (≤ 1 versus > 1 month between tests; P = 0.04)) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥ 1 ctDNA alteration(s); 72.3% (N=16/22) of the evaluable matched patients achieved stable disease ≥ 6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥ 1 alteration with ≥ 5% variant allele fraction (versus < 5%) had a significantly shorter median survival (P = 0.012).</p> <br /><br />Conclusions: <p>ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies.
Background: CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC in human breast cancer xenografts. This Phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). <p>Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a three-day run-in with reparixin oral tablets 3 times daily (t.i.d.), followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin tablets t.i.d. for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended Phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.</p> <p>Results: There were neither G4-5 adverse events nor serious adverse events related to study therapy, and no interactions between reparixin and paclitaxel to influence their respective PK profiles. A 30% response rate was recorded, with durable responses > 12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSC.</p> <p>Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally t.i.d., was selected for further study in a randomized Phase II trial. (NCT02370238)
Purpose: Many patients with BRAF V600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies. <br /><br />Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAF V600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAF V600E melanoma cell lines and its effect on drug sensitivity was evaluated.<br /><br />Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAF V600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of AGAP3-BRAF fusion in BRAF V600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAF V600E and AGAP3-BRAF only have a fitness advantage over parental BRAF V600E cells during active treatment with a BRAF inhibitor.<br /><br />Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma.
Background and Purpose: <p>The immune checkpoint PD-1 and its receptor B7-H1 (PD-L1) are successful therapeutic targets in cancer but less is known about other B7 family members. Here, we determined the expression level of B7-H3 protein in non-small cell lung cancer (NSCLC) and evaluated its association with tumor infiltrating lymphocytes (TILs), PD-L1, B7-H4 and major clinico-pathological characteristics is in 3 NSCLC cohorts.</p> <p>Experimental design:</p> <p>We used multiplexed automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3, PD-L1, B7-H4 and TILs in 634 NSCLC cases with validated antibodies. Associations between the marker levels, major clinico-pathological variables and survival were analyzed.</p> <p>Results: </p> <p>Expression of B7-H3 protein was found in 80.4% (510/634) of the cases. High B7-H3 protein level (top 10 percentile) was associated with poor overall survival (p <0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage and histology. Co-expression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3, CD8 and CD20 positive TILs.</p> <p>Conclusion:</p> <p>B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High levels of B7-H3 protein has a negative prognostic impact in lung carcinomas. Co-expression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a non-redundant biological role of these targets.
Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy, and to predict the likelihood of local control as a function of dose and treatment fractions.<br /><br />Experimental Design: We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and 2 unpublished early stage patient cohorts, totaling 2701 patients.<br /><br />Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α (0.305 Gy-1; 95% CI: 0.120-0.365), the α/β ratio (2.80 Gy; 95% CI: 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI: 1.55-2.25). All fractionation groups are well-fitted by a single dose-response curve with a high 2 p-value, indicating consistency with the fitted model. The analysis was further validated with additional 23 patient cohorts (n=1628). The model indicates that hypofractionation regimes overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimes allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.<br /><br />Conclusions: The mechanistic tumor response modeling can accurately predict over-treatment or under-treatment for various treatment regimes.
Purpose: <p>Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes.</p> <br /><br />Experimental Design: Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications.<br /><br />Results: <p>Seventy-two patients (82%) had ≥ 1 ctDNA alteration(s); amongst these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% versus 61.5% (≤ 1 versus > 1 month between tests; P = 0.04)) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥ 1 ctDNA alteration(s); 72.3% (N=16/22) of the evaluable matched patients achieved stable disease ≥ 6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥ 1 alteration with ≥ 5% variant allele fraction (versus < 5%) had a significantly shorter median survival (P = 0.012).</p> <br /><br />Conclusions: <p>ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies.
Background: CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC in human breast cancer xenografts. This Phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). <p>Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a three-day run-in with reparixin oral tablets 3 times daily (t.i.d.), followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin tablets t.i.d. for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended Phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy.</p> <p>Results: There were neither G4-5 adverse events nor serious adverse events related to study therapy, and no interactions between reparixin and paclitaxel to influence their respective PK profiles. A 30% response rate was recorded, with durable responses > 12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSC.</p> <p>Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally t.i.d., was selected for further study in a randomized Phase II trial. (NCT02370238)
Purpose: Many patients with BRAF V600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies. <br /><br />Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAF V600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAF V600E melanoma cell lines and its effect on drug sensitivity was evaluated.<br /><br />Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAF V600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of AGAP3-BRAF fusion in BRAF V600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAF V600E and AGAP3-BRAF only have a fitness advantage over parental BRAF V600E cells during active treatment with a BRAF inhibitor.<br /><br />Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma.
Metastasis to lymph nodes is a key determinant of thoracic esophageal squamous cell carcinoma (TE-SCC) prognosis. We sought to identify factors linked with cervical lymph node metastasis, which could be used to inform the decision of surgical and definitive radiotherapy.
http://ift.tt/2rWEazK
Gastrointestinal Stromal Tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDGFRA-wild type GIST, including mutant BRAF-driven tumors, have been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse GI tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents.
http://ift.tt/2qYkDlt
Gastrointestinal Stromal Tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDGFRA-wild type GIST, including mutant BRAF-driven tumors, have been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse GI tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents.
from Cancer via ola Kala on Inoreader http://ift.tt/2qYkDlt
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The relationship between lipid levels and risk of venous thrombosis is not well established. We aimed to assess the association between several lipids and risk of venous thrombosis using data from a population-based case–control study, and to evaluate the underlying mechanism, considering confounding by common risk factors and mediation via hemostatic factors and C-reactive protein. From the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study, 2234 patients with a first venous thrombosis and 2873 controls were included. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides, and apolipoproteins B and A1 were established in controls (<10th, 10th–25th, 25th–75th [reference], 75th–90th, >90th percentile). In age- and sex-adjusted models, decreasing levels of apolipoproteins B and A1 were dose-dependently associated with increased thrombosis risk, with odds ratios of 1.35 (95% confidence interval 1.12–1.62) and 1.50 (95% confidence interval 1.25–1.79) for the lowest category versus the reference category, respectively. The dose–response relation remained with further adjustment for body mass index, estrogen use, statin use, and diabetes. Although apolipoproteins B and A1 were associated with several hemostatic factors and C-reactive protein, none explained the increased risk in mediation analyses. The other lipids were not associated with venous thrombosis risk. In conclusion, decreasing levels of apolipoproteins B and A1 were associated with increased risk of venous thrombosis. Our findings are consistent with experimental data on the anticoagulant properties of apolipoproteins B and A1. These findings need to be confirmed and the underlying mechanism further investigated.
Hopefully devoted to Q: targeting glutamine addiction in cancer
British Journal of Cancer 116, 1375 (23 May 2017). doi:10.1038/bjc.2017.113
Authors: Emma R Still & Mariia O Yuneva
Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial
British Journal of Cancer 116, 1382 (23 May 2017). doi:10.1038/bjc.2017.111
Authors: Manuela Viviano, Rosa Catarino, Emilien Jeannot, Michel Boulvain, Manuela Undurraga Malinverno, Pierre Vassilakos & Patrick Petignat
Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer
British Journal of Cancer 116, 1462 (23 May 2017). doi:10.1038/bjc.2017.115
Authors: Michael Haas, Steffen Ormanns, Sibylle Baechmann, Anna Remold, Stephan Kruger, Christoph B Westphalen, Jens T Siveke, Patrick Wenzel, Anna Melissa Schlitter, Irene Esposito, Detlef Quietzsch, Michael R Clemens, Erika Kettner, Ruediger P Laubender, Andreas Jung, Thomas Kirchner, Stefan Boeck & Volker Heinemann
Long-term improvement of breast cancer survivors' quality of life by a 2-week group physical and educational intervention: 5-year update of the 'PACThe' trial
British Journal of Cancer 116, 1389 (23 May 2017). doi:10.1038/bjc.2017.112
Authors: Fabrice Kwiatkowski, Marie-Ange Mouret-Reynier, Martine Duclos, François Bridon, Thierry Hanh, Isabelle Van Praagh-Doreau, Armelle Travade, Marie-Paule Vasson, Sylvie Jouvency, Christian Roques & Yves-Jean Bignon
Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer
British Journal of Cancer 116, 1444 (23 May 2017). doi:10.1038/bjc.2017.108
Authors: J H Park, H van Wyk, C S D Roxburgh, P G Horgan, J Edwards & D C McMillan
Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators
British Journal of Cancer 116, 1394 (23 May 2017). doi:10.1038/bjc.2017.114
Authors: Delphine Héquet, Cyrille Huchon, Sandrine Baffert, Séverine Alran, Fabien Reyal, Thuy Nguyen, Alix Combes, Caroline Trichot, Karine Alves, Hélène Berseneff & Roman Rouzier
Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening
British Journal of Cancer 116, 1480 (23 May 2017). doi:10.1038/bjc.2017.107
Authors: M Román, M J Quintana, J Ferrer, M Sala & X Castells
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma
British Journal of Cancer 116, 1402 (23 May 2017). doi:10.1038/bjc.2017.119
Authors: Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Vivek Subbiah, Ralph Zinner & Nilofer S Azad
The prognostic value of dynamic contrast-enhanced MRI contrast agent transfer constant Ktrans in cervical cancer is explained by plasma flow rather than vessel permeability
British Journal of Cancer 116, 1436 (23 May 2017). doi:10.1038/bjc.2017.121
Authors: Ben R Dickie, Chris J Rose, Lucy E Kershaw, Stephanie B Withey, Bernadette M Carrington, Susan E Davidson, Gillian Hutchison & Catharine M L West
Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial
British Journal of Cancer 116, 1408 (23 May 2017). doi:10.1038/bjc.2017.117
Authors: Yasemin Hirst, Hanna Skrobanski, Robert S Kerrison, Lindsay C Kobayashi, Nicholas Counsell, Natasha Djedovic, Josephine Ruwende, Mark Stewart & Christian von Wagner
Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity
British Journal of Cancer 116, 1451 (23 May 2017). doi:10.1038/bjc.2017.110
Authors: Sofia Pruikkonen & Marko J Kallio
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity
British Journal of Cancer 116, 1415 (23 May 2017). doi:10.1038/bjc.2017.94
Authors: Didier Meulendijks, Linda M Henricks, Bart A W Jacobs, Abidin Aliev, Maarten J Deenen, Niels de Vries, Hilde Rosing, Erik van Werkhoven, Anthonius de Boer, Jos H Beijnen, Caroline M P W Mandigers, Marcel Soesan, Annemieke Cats & Jan H M Schellens
Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk
British Journal of Cancer 116, 1470 (23 May 2017). doi:10.1038/bjc.2017.104
Authors: Kathryn Hughes Barry, Lee E Moore, Joshua N Sampson, Stella Koutros, Liying Yan, Ann Meyer, Mahitha Reddy, Andrew J Oler, Michael B Cook, Joseph F Fraumeni Jr, Meredith Yeager, Laufey T Amundadottir & Sonja I Berndt
Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers
British Journal of Cancer 116, 1425 (23 May 2017). doi:10.1038/bjc.2017.116
Authors: Concetta Di Mauro, Roberta Rosa, Valentina D'Amato, Paola Ciciola, Alberto Servetto, Roberta Marciano, Roberta Clara Orsini, Luigi Formisano, Sandro De Falco, Valeria Cicatiello, Maurizio Di Bonito, Monica Cantile, Francesca Collina, Angela Chambery, Bianca Maria Veneziani, Sabino De Placido & Roberto Bianco
Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe
British Journal of Cancer 116, 1486 (23 May 2017). doi:10.1038/bjc.2017.106
Authors: Heinz Freisling, Melina Arnold, Isabelle Soerjomataram, Mark George O'Doherty, José Manuel Ordóñez-Mena, Christina Bamia, Ellen Kampman, Michael Leitzmann, Isabelle Romieu, Frank Kee, Konstantinos Tsilidis, Anne Tjønneland, Antonia Trichopoulou, Paolo Boffetta, Vassiliki Benetou, H B(as) Bueno-de-Mesquita, José María Huerta, Hermann Brenner, Tom Wilsgaard & Mazda Jenab
Hopefully devoted to Q: targeting glutamine addiction in cancer
British Journal of Cancer 116, 1375 (23 May 2017). doi:10.1038/bjc.2017.113
Authors: Emma R Still & Mariia O Yuneva
Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial
British Journal of Cancer 116, 1382 (23 May 2017). doi:10.1038/bjc.2017.111
Authors: Manuela Viviano, Rosa Catarino, Emilien Jeannot, Michel Boulvain, Manuela Undurraga Malinverno, Pierre Vassilakos & Patrick Petignat
Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer
British Journal of Cancer 116, 1462 (23 May 2017). doi:10.1038/bjc.2017.115
Authors: Michael Haas, Steffen Ormanns, Sibylle Baechmann, Anna Remold, Stephan Kruger, Christoph B Westphalen, Jens T Siveke, Patrick Wenzel, Anna Melissa Schlitter, Irene Esposito, Detlef Quietzsch, Michael R Clemens, Erika Kettner, Ruediger P Laubender, Andreas Jung, Thomas Kirchner, Stefan Boeck & Volker Heinemann
Long-term improvement of breast cancer survivors' quality of life by a 2-week group physical and educational intervention: 5-year update of the 'PACThe' trial
British Journal of Cancer 116, 1389 (23 May 2017). doi:10.1038/bjc.2017.112
Authors: Fabrice Kwiatkowski, Marie-Ange Mouret-Reynier, Martine Duclos, François Bridon, Thierry Hanh, Isabelle Van Praagh-Doreau, Armelle Travade, Marie-Paule Vasson, Sylvie Jouvency, Christian Roques & Yves-Jean Bignon
Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer
British Journal of Cancer 116, 1444 (23 May 2017). doi:10.1038/bjc.2017.108
Authors: J H Park, H van Wyk, C S D Roxburgh, P G Horgan, J Edwards & D C McMillan
Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators
British Journal of Cancer 116, 1394 (23 May 2017). doi:10.1038/bjc.2017.114
Authors: Delphine Héquet, Cyrille Huchon, Sandrine Baffert, Séverine Alran, Fabien Reyal, Thuy Nguyen, Alix Combes, Caroline Trichot, Karine Alves, Hélène Berseneff & Roman Rouzier
Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening
British Journal of Cancer 116, 1480 (23 May 2017). doi:10.1038/bjc.2017.107
Authors: M Román, M J Quintana, J Ferrer, M Sala & X Castells
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma
British Journal of Cancer 116, 1402 (23 May 2017). doi:10.1038/bjc.2017.119
Authors: Rachna T Shroff, Mark Yarchoan, Ashley O'Connor, Denise Gallagher, Marianna L Zahurak, Gary Rosner, Chimela Ohaji, Susan Sartorius-Mergenthaler, Vivek Subbiah, Ralph Zinner & Nilofer S Azad
The prognostic value of dynamic contrast-enhanced MRI contrast agent transfer constant Ktrans in cervical cancer is explained by plasma flow rather than vessel permeability
British Journal of Cancer 116, 1436 (23 May 2017). doi:10.1038/bjc.2017.121
Authors: Ben R Dickie, Chris J Rose, Lucy E Kershaw, Stephanie B Withey, Bernadette M Carrington, Susan E Davidson, Gillian Hutchison & Catharine M L West
Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial
British Journal of Cancer 116, 1408 (23 May 2017). doi:10.1038/bjc.2017.117
Authors: Yasemin Hirst, Hanna Skrobanski, Robert S Kerrison, Lindsay C Kobayashi, Nicholas Counsell, Natasha Djedovic, Josephine Ruwende, Mark Stewart & Christian von Wagner
Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity
British Journal of Cancer 116, 1451 (23 May 2017). doi:10.1038/bjc.2017.110
Authors: Sofia Pruikkonen & Marko J Kallio
Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity
British Journal of Cancer 116, 1415 (23 May 2017). doi:10.1038/bjc.2017.94
Authors: Didier Meulendijks, Linda M Henricks, Bart A W Jacobs, Abidin Aliev, Maarten J Deenen, Niels de Vries, Hilde Rosing, Erik van Werkhoven, Anthonius de Boer, Jos H Beijnen, Caroline M P W Mandigers, Marcel Soesan, Annemieke Cats & Jan H M Schellens
Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk
British Journal of Cancer 116, 1470 (23 May 2017). doi:10.1038/bjc.2017.104
Authors: Kathryn Hughes Barry, Lee E Moore, Joshua N Sampson, Stella Koutros, Liying Yan, Ann Meyer, Mahitha Reddy, Andrew J Oler, Michael B Cook, Joseph F Fraumeni Jr, Meredith Yeager, Laufey T Amundadottir & Sonja I Berndt
Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers
British Journal of Cancer 116, 1425 (23 May 2017). doi:10.1038/bjc.2017.116
Authors: Concetta Di Mauro, Roberta Rosa, Valentina D'Amato, Paola Ciciola, Alberto Servetto, Roberta Marciano, Roberta Clara Orsini, Luigi Formisano, Sandro De Falco, Valeria Cicatiello, Maurizio Di Bonito, Monica Cantile, Francesca Collina, Angela Chambery, Bianca Maria Veneziani, Sabino De Placido & Roberto Bianco
Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe
British Journal of Cancer 116, 1486 (23 May 2017). doi:10.1038/bjc.2017.106
Authors: Heinz Freisling, Melina Arnold, Isabelle Soerjomataram, Mark George O'Doherty, José Manuel Ordóñez-Mena, Christina Bamia, Ellen Kampman, Michael Leitzmann, Isabelle Romieu, Frank Kee, Konstantinos Tsilidis, Anne Tjønneland, Antonia Trichopoulou, Paolo Boffetta, Vassiliki Benetou, H B(as) Bueno-de-Mesquita, José María Huerta, Hermann Brenner, Tom Wilsgaard & Mazda Jenab
Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years.
Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances. Concurrently, numerous genomic studies have enhanced understanding of disease pathogenesis. Advances in SDTs include topical resiquimod, a novel potent Toll-like receptor (TLR) agonist; consensus CTCL phototherapy guidelines; and use of low-dose radiation therapy. Novel systemic therapies for advanced disease of note include targeted antibody drug conjugates (brentuximab vedotin), immune checkpoint inhibitors, and allogeneic hematopoietic stem cell transplantation (HSCT).
Our "toolbox" to diagnose and treat the spectrum of MF/SS continues to expand. Further characterization of genomic data going forward will enable a rational approach to selecting and combining therapies to improve patient care.
Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years.
Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances. Concurrently, numerous genomic studies have enhanced understanding of disease pathogenesis. Advances in SDTs include topical resiquimod, a novel potent Toll-like receptor (TLR) agonist; consensus CTCL phototherapy guidelines; and use of low-dose radiation therapy. Novel systemic therapies for advanced disease of note include targeted antibody drug conjugates (brentuximab vedotin), immune checkpoint inhibitors, and allogeneic hematopoietic stem cell transplantation (HSCT).
Our "toolbox" to diagnose and treat the spectrum of MF/SS continues to expand. Further characterization of genomic data going forward will enable a rational approach to selecting and combining therapies to improve patient care.
Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereas XPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype in XPC Ala499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.
Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereas XPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype in XPC Ala499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.
BK polyomavirus-associated nephropathy is an important cause of post-transplantation renal failure. We present two cases of BK polyomavirus-associated nephropathy who were submitted to contrasting strategies o...
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3-Iodothyronamine (T1AM) is an endogenous metabolite of thyroid hormone with noticeable metabolic and neurological effects. Alteration of feeding behaviour by this compound was different at various doses in experimental models and it is not clear whether this effect is partially accounted by changes in neuropeptide secretion. In this study, we attempted to find out whether chronic low dose 3-iodothyronamine treatment could modulate some food intake regulatory neuropeptides such as leptin, ghrelin, and galanin in mice brain. Eighteen male mice were divided randomly into control (n = 8) and treatment (n = 10) groups. The experimental procedure was applied for 7 days during which treatment group received T1AM (i.p) whereas the control group received DMSO and normal saline. The brain was analyzed for leptin, ghrelin, and galanin concentrations. There were significant differences in leptin concentration (1.75 ± 0.05 versus 2.9 ± 0.07 ng/ml) and ghrelin concentration (8.4 ± 0.35 versus 5 ± 0.08 ng/ml) between control and treatment groups (P < 0.05). There was no significant difference in galanin concentration (745.87 ± 34.91 ng/l) in control group compared with the treatment group (698.05 ± 66.88 ng/l). Interestingly, the treatment group mice lost weight (~1 g) whereas non-significant increase in weight mean was seen in control group before (day 1) and after the procedure (day 8). Clearly, further works in this area will be required to delineate the central role of T1AM, but based on our findings described here, we propose that some of peripheral metabolic effects of this compound may be accomplished by brain peptide regulation.
Blockade of the programmed cell death protein 1 (PD1) pathway is clinically effective against human cancers. Although multiple types of malignancies have been shown to respond to PD1 agents, only a small percentage of patients typically benefit from this treatment. In addition, PD1 therapy often causes serious immune-related adverse events. A recent study demonstrated that local, intra-tumoral, administration of modified oncolytic myxoma virus which expresses a truncated version of the PD1 protein resulted in both increased efficacy and reduced toxicity in a clinically relevant melanoma model.
High-grade gliomas are aggressive and intensely glycolytic tumors. In the present study, we evaluated the mitochondrial respiratory function of glioma cells (T98G and U-87MG) and fresh human glioblastoma (GBM) tissue. To this end, measurements of oxygen consumption rate (OCR) were performed under various experimental conditions. The OCR of T98G and U-87MG cells was well coupled to ADP phosphorylation based on the ratio of ATP produced per oxygen consumed of ~2.5. In agreement, the basal OCR of GBM tissue was also partially associated with ADP phosphorylation. The basal respiration of intact T98G and U-87MG cells was not limited by the supply of endogenous substrates, as indicated by the increased OCR in response to a protonophore. These cells also displayed a high affinity for oxygen, as evidenced by the values of the partial pressure of oxygen when respiration is half maximal (p 50). In permeabilized glioma cells, ADP-stimulated OCR was only approximately 50% of that obtained in the presence of protonophore, revealing a significant limitation in oxidative phosphorylation (OXPHOS) relative to the activity of the electron transport system (ETS). This characteristic was maintained when the cells were grown under low glucose conditions. Flux control coefficient analyses demonstrated that the impaired OXPHOS was associated with the function of both mitochondrial ATP synthase and the adenine nucleotide translocator, but not the phosphate carrier. Altogether, these data indicate that the availability and metabolism of respiratory substrates and mitochondrial ETS are preserved in T98G and U-87MG glioma cells even though these cells possess a relatively restrained OXPHOS capability.
The goal of this study was to investigate the impact of patient-, disease-, and treatment-related variables upon neurocognitive outcomes in pediatric patients with craniopharyngioma prior to treatment with proton therapy or observation after radical resection. For all participants (N = 104), relevant clinical and demographic variables were attained and neurocognitive evaluations completed prior to irradiation or planned observation. One-sample t-tests were conducted to compare performance to published normative data. Linear models were used to investigate predictors of performance on measures where performance was below normative expectations. Participants showed poorer performance in comparison to the normative group across neurocognitive domains including executive functions (e.g., working memory; Wechsler Digit Span Backward p = 0.03), learning and memory (e.g., California Verbal Learning Test [CVLT] Total T p = 0.00), and fine-motor coordination (e.g., Grooved Pegboard Dominant Hand p = 0.00). Poor performance across areas was predicted by presurgical hypothalamic involvement (e.g., Behavior Rating Inventory of Executive Function Working Memory Index Grade 2 β = −7.68, p = 0.03; CVLT Total T Grade 2 β = 7.94, p = 0.04; Grade 3 β = −9.80, p = 0.00), extent of surgery (e.g., CVLT Total T Resection β = −7.77, p = 0.04; Grooved Pegboard Dominant Hand β = −1.58, p = 0.04), and vision status (e.g., CVLT Total T Reduced vision without impairment β = −10.01, p = 0.02; Grooved Pegboard Dominant Hand Bilateral field defect β = −1.45, p = 0.01; Reduced vision without impairment β = −2.30, p = 0.00). This study demonstrated that patients with craniopharyngioma show weaker neurocognitive performance in comparison to the normative population resulting from tumor, events leading to diagnosis, and early surgical intervention. Systematic investigation of neurocognitive performance before treatment with radiation therapy is essential to evaluating the potential risks and benefits of newer methods of radiation therapy including proton therapy.
Fatigue is the most prevalent and disabling symptom in cancer patients. Yet, scientific literature on this topic is scarce and reports disparate results. This study systematically reviews how fatigue is assessed in patients with low-grade glioma and evaluates its prevalence in LGG patients. A systematic literature search was performed in PubMed, Embase and PsychINFO for articles reporting on fatigue in patients with LGG. Two reviewers independently extracted data from selected articles. Inclusion criteria were: (1) patients with suspected or confirmed LGG; (2) fatigue was assessed as primary or secondary outcome measure; (3) age≥ 18 years; (4) full-length article written in English or Dutch. In total, 19 articles were selected, including 971 patients. Seven self-assessment instruments were identified. Prevalence rates ranged from 39 to 77%. Fatigue was found to be a common side effect of treatment. The prevalence rates ranged from 20 to 76% when fatigue was reported as a mild or moderate side effect and fatigue was prevalent in 4% when reported as a severe side effect. Fatigue is a common problem in LGG patients that warrants more therapeutic and scientific attention. Gaining deeper insight in the underlying mechanisms of fatigue is essential in targeting therapy to individual patients.
Blockade of the programmed cell death protein 1 (PD1) pathway is clinically effective against human cancers. Although multiple types of malignancies have been shown to respond to PD1 agents, only a small percentage of patients typically benefit from this treatment. In addition, PD1 therapy often causes serious immune-related adverse events. A recent study demonstrated that local, intra-tumoral, administration of modified oncolytic myxoma virus which expresses a truncated version of the PD1 protein resulted in both increased efficacy and reduced toxicity in a clinically relevant melanoma model.
To evaluate the prognostic impact of maximum standardized uptake value (SUVmax) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing pretreatment [F-18] fluoro-d-glucose-positron emission tomography/computed tomography (FDG PET/CT) imaging.
Fifty-eight patients undergoing FDG PET/CT before radical treatment with definitive radiotherapy (±concomitant chemotherapy) or surgery + postoperative (chemo)radiation were analyzed. The effects of clinicopathological factors (age, gender, tumor location, stage, Karnofsky Performance Status (KPS), and treatment strategy) including primary tumor SUVmax and nodal SUVmax on overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) were evaluated. Kaplan–Meier survival curves were generated and compared with the log-rank test.
Median follow-up for the whole population was 31 months (range 2.3–53.5). Two-year OS, LRC, DFS and DMFS, for the entire cohort were 62.1, 78.3, 55.2 and 67.2%, respectively. Median pretreatment SUVmax for the primary tumor and lymph nodes was 11.85 and 5.4, respectively. According to univariate analysis, patients with KPS < 80% (p < 0.001), AJCC stage IVa or IVb vs III (p = 0.037) and patients undergoing radiotherapy vs surgery (p = 0.042) were significantly associated with worse OS. Patients with KPS < 80% (p = 0.003) or age ≥65 years (p = 0.007) had worse LRC. The KPS < 80% was the only factor associated with decreased DFS (p = 0.001). SUVmax of the primary tumor or the lymph nodes were not associated with OS, DFS or LRC. The KPS < 80% (p = 0.002), tumor location (p = 0.047) and AJCC stage (p = 0.025) were associated with worse cancer-specific survival (CSS). According to Cox regression analysis, on multivariate analysis KPS < 80% was the only independent parameter determining worse OS, DFS, CSS. Regarding LRC only patients with IK < 80% (p = 0.01) and ≥65 years (p = 0.01) remained statistically significant. Nodal SUVmax was the only factor associated with decreased DMFS. Patients with a nodal SUVmax > 5.4 presented an increased risk for distant metastases (HR, 3.3; 95% CI 1.17–9.25; p = 0.023).
The pretreatment nodal SUVmax in patients with locally advanced HNSCC is prognostic for DMFS. However, according to our results primary tumor SUVmax and nodal SUVmax were not significantly related to OS, DFS or LRC. Patients presenting KPS < 80% had worse OS, DFS, CSS and LRC.
To evaluate the prognostic impact of maximum standardized uptake value (SUVmax) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing pretreatment [F-18] fluoro-d-glucose-positron emission tomography/computed tomography (FDG PET/CT) imaging.
Fifty-eight patients undergoing FDG PET/CT before radical treatment with definitive radiotherapy (±concomitant chemotherapy) or surgery + postoperative (chemo)radiation were analyzed. The effects of clinicopathological factors (age, gender, tumor location, stage, Karnofsky Performance Status (KPS), and treatment strategy) including primary tumor SUVmax and nodal SUVmax on overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) were evaluated. Kaplan–Meier survival curves were generated and compared with the log-rank test.
Median follow-up for the whole population was 31 months (range 2.3–53.5). Two-year OS, LRC, DFS and DMFS, for the entire cohort were 62.1, 78.3, 55.2 and 67.2%, respectively. Median pretreatment SUVmax for the primary tumor and lymph nodes was 11.85 and 5.4, respectively. According to univariate analysis, patients with KPS < 80% (p < 0.001), AJCC stage IVa or IVb vs III (p = 0.037) and patients undergoing radiotherapy vs surgery (p = 0.042) were significantly associated with worse OS. Patients with KPS < 80% (p = 0.003) or age ≥65 years (p = 0.007) had worse LRC. The KPS < 80% was the only factor associated with decreased DFS (p = 0.001). SUVmax of the primary tumor or the lymph nodes were not associated with OS, DFS or LRC. The KPS < 80% (p = 0.002), tumor location (p = 0.047) and AJCC stage (p = 0.025) were associated with worse cancer-specific survival (CSS). According to Cox regression analysis, on multivariate analysis KPS < 80% was the only independent parameter determining worse OS, DFS, CSS. Regarding LRC only patients with IK < 80% (p = 0.01) and ≥65 years (p = 0.01) remained statistically significant. Nodal SUVmax was the only factor associated with decreased DMFS. Patients with a nodal SUVmax > 5.4 presented an increased risk for distant metastases (HR, 3.3; 95% CI 1.17–9.25; p = 0.023).
The pretreatment nodal SUVmax in patients with locally advanced HNSCC is prognostic for DMFS. However, according to our results primary tumor SUVmax and nodal SUVmax were not significantly related to OS, DFS or LRC. Patients presenting KPS < 80% had worse OS, DFS, CSS and LRC.
High-grade gliomas are aggressive and intensely glycolytic tumors. In the present study, we evaluated the mitochondrial respiratory function of glioma cells (T98G and U-87MG) and fresh human glioblastoma (GBM) tissue. To this end, measurements of oxygen consumption rate (OCR) were performed under various experimental conditions. The OCR of T98G and U-87MG cells was well coupled to ADP phosphorylation based on the ratio of ATP produced per oxygen consumed of ~2.5. In agreement, the basal OCR of GBM tissue was also partially associated with ADP phosphorylation. The basal respiration of intact T98G and U-87MG cells was not limited by the supply of endogenous substrates, as indicated by the increased OCR in response to a protonophore. These cells also displayed a high affinity for oxygen, as evidenced by the values of the partial pressure of oxygen when respiration is half maximal (p 50). In permeabilized glioma cells, ADP-stimulated OCR was only approximately 50% of that obtained in the presence of protonophore, revealing a significant limitation in oxidative phosphorylation (OXPHOS) relative to the activity of the electron transport system (ETS). This characteristic was maintained when the cells were grown under low glucose conditions. Flux control coefficient analyses demonstrated that the impaired OXPHOS was associated with the function of both mitochondrial ATP synthase and the adenine nucleotide translocator, but not the phosphate carrier. Altogether, these data indicate that the availability and metabolism of respiratory substrates and mitochondrial ETS are preserved in T98G and U-87MG glioma cells even though these cells possess a relatively restrained OXPHOS capability.
The goal of this study was to investigate the impact of patient-, disease-, and treatment-related variables upon neurocognitive outcomes in pediatric patients with craniopharyngioma prior to treatment with proton therapy or observation after radical resection. For all participants (N = 104), relevant clinical and demographic variables were attained and neurocognitive evaluations completed prior to irradiation or planned observation. One-sample t-tests were conducted to compare performance to published normative data. Linear models were used to investigate predictors of performance on measures where performance was below normative expectations. Participants showed poorer performance in comparison to the normative group across neurocognitive domains including executive functions (e.g., working memory; Wechsler Digit Span Backward p = 0.03), learning and memory (e.g., California Verbal Learning Test [CVLT] Total T p = 0.00), and fine-motor coordination (e.g., Grooved Pegboard Dominant Hand p = 0.00). Poor performance across areas was predicted by presurgical hypothalamic involvement (e.g., Behavior Rating Inventory of Executive Function Working Memory Index Grade 2 β = −7.68, p = 0.03; CVLT Total T Grade 2 β = 7.94, p = 0.04; Grade 3 β = −9.80, p = 0.00), extent of surgery (e.g., CVLT Total T Resection β = −7.77, p = 0.04; Grooved Pegboard Dominant Hand β = −1.58, p = 0.04), and vision status (e.g., CVLT Total T Reduced vision without impairment β = −10.01, p = 0.02; Grooved Pegboard Dominant Hand Bilateral field defect β = −1.45, p = 0.01; Reduced vision without impairment β = −2.30, p = 0.00). This study demonstrated that patients with craniopharyngioma show weaker neurocognitive performance in comparison to the normative population resulting from tumor, events leading to diagnosis, and early surgical intervention. Systematic investigation of neurocognitive performance before treatment with radiation therapy is essential to evaluating the potential risks and benefits of newer methods of radiation therapy including proton therapy.
Fatigue is the most prevalent and disabling symptom in cancer patients. Yet, scientific literature on this topic is scarce and reports disparate results. This study systematically reviews how fatigue is assessed in patients with low-grade glioma and evaluates its prevalence in LGG patients. A systematic literature search was performed in PubMed, Embase and PsychINFO for articles reporting on fatigue in patients with LGG. Two reviewers independently extracted data from selected articles. Inclusion criteria were: (1) patients with suspected or confirmed LGG; (2) fatigue was assessed as primary or secondary outcome measure; (3) age≥ 18 years; (4) full-length article written in English or Dutch. In total, 19 articles were selected, including 971 patients. Seven self-assessment instruments were identified. Prevalence rates ranged from 39 to 77%. Fatigue was found to be a common side effect of treatment. The prevalence rates ranged from 20 to 76% when fatigue was reported as a mild or moderate side effect and fatigue was prevalent in 4% when reported as a severe side effect. Fatigue is a common problem in LGG patients that warrants more therapeutic and scientific attention. Gaining deeper insight in the underlying mechanisms of fatigue is essential in targeting therapy to individual patients.
High-grade gliomas are aggressive and intensely glycolytic tumors. In the present study, we evaluated the mitochondrial respiratory function of glioma cells (T98G and U-87MG) and fresh human glioblastoma (GBM) tissue. To this end, measurements of oxygen consumption rate (OCR) were performed under various experimental conditions. The OCR of T98G and U-87MG cells was well coupled to ADP phosphorylation based on the ratio of ATP produced per oxygen consumed of ~2.5. In agreement, the basal OCR of GBM tissue was also partially associated with ADP phosphorylation. The basal respiration of intact T98G and U-87MG cells was not limited by the supply of endogenous substrates, as indicated by the increased OCR in response to a protonophore. These cells also displayed a high affinity for oxygen, as evidenced by the values of the partial pressure of oxygen when respiration is half maximal (p 50). In permeabilized glioma cells, ADP-stimulated OCR was only approximately 50% of that obtained in the presence of protonophore, revealing a significant limitation in oxidative phosphorylation (OXPHOS) relative to the activity of the electron transport system (ETS). This characteristic was maintained when the cells were grown under low glucose conditions. Flux control coefficient analyses demonstrated that the impaired OXPHOS was associated with the function of both mitochondrial ATP synthase and the adenine nucleotide translocator, but not the phosphate carrier. Altogether, these data indicate that the availability and metabolism of respiratory substrates and mitochondrial ETS are preserved in T98G and U-87MG glioma cells even though these cells possess a relatively restrained OXPHOS capability.
The goal of this study was to investigate the impact of patient-, disease-, and treatment-related variables upon neurocognitive outcomes in pediatric patients with craniopharyngioma prior to treatment with proton therapy or observation after radical resection. For all participants (N = 104), relevant clinical and demographic variables were attained and neurocognitive evaluations completed prior to irradiation or planned observation. One-sample t-tests were conducted to compare performance to published normative data. Linear models were used to investigate predictors of performance on measures where performance was below normative expectations. Participants showed poorer performance in comparison to the normative group across neurocognitive domains including executive functions (e.g., working memory; Wechsler Digit Span Backward p = 0.03), learning and memory (e.g., California Verbal Learning Test [CVLT] Total T p = 0.00), and fine-motor coordination (e.g., Grooved Pegboard Dominant Hand p = 0.00). Poor performance across areas was predicted by presurgical hypothalamic involvement (e.g., Behavior Rating Inventory of Executive Function Working Memory Index Grade 2 β = −7.68, p = 0.03; CVLT Total T Grade 2 β = 7.94, p = 0.04; Grade 3 β = −9.80, p = 0.00), extent of surgery (e.g., CVLT Total T Resection β = −7.77, p = 0.04; Grooved Pegboard Dominant Hand β = −1.58, p = 0.04), and vision status (e.g., CVLT Total T Reduced vision without impairment β = −10.01, p = 0.02; Grooved Pegboard Dominant Hand Bilateral field defect β = −1.45, p = 0.01; Reduced vision without impairment β = −2.30, p = 0.00). This study demonstrated that patients with craniopharyngioma show weaker neurocognitive performance in comparison to the normative population resulting from tumor, events leading to diagnosis, and early surgical intervention. Systematic investigation of neurocognitive performance before treatment with radiation therapy is essential to evaluating the potential risks and benefits of newer methods of radiation therapy including proton therapy.
Fatigue is the most prevalent and disabling symptom in cancer patients. Yet, scientific literature on this topic is scarce and reports disparate results. This study systematically reviews how fatigue is assessed in patients with low-grade glioma and evaluates its prevalence in LGG patients. A systematic literature search was performed in PubMed, Embase and PsychINFO for articles reporting on fatigue in patients with LGG. Two reviewers independently extracted data from selected articles. Inclusion criteria were: (1) patients with suspected or confirmed LGG; (2) fatigue was assessed as primary or secondary outcome measure; (3) age≥ 18 years; (4) full-length article written in English or Dutch. In total, 19 articles were selected, including 971 patients. Seven self-assessment instruments were identified. Prevalence rates ranged from 39 to 77%. Fatigue was found to be a common side effect of treatment. The prevalence rates ranged from 20 to 76% when fatigue was reported as a mild or moderate side effect and fatigue was prevalent in 4% when reported as a severe side effect. Fatigue is a common problem in LGG patients that warrants more therapeutic and scientific attention. Gaining deeper insight in the underlying mechanisms of fatigue is essential in targeting therapy to individual patients.
Micropulse laser treatment is an alternative to the conventional continuous-wave laser for the treatment of retinal or macular diseases. In contrast to the conventional laser, the therapeutic effect of the subthreshold micropulse laser is not accompanied by thermal retinal damage. This fact is of particular importance when a treatment near the fovea is required. Micropulse treatment is applied in indications such as central serous chorioretinopathy (CSC), diabetic macular edema (DME), or macular edema due to retinal vein occlusion (RVO). This review outlines and discusses the published literature of subthreshold micropulse laser treatment for CSC, DME, and macular edema after RVO.
Nalmefene is the first drug to be approved for reducing alcohol consumption in alcohol use disorder (AUD) patients at high drinking risk. In real-world settings, there is a high prevalence of concurrent psychiatric disorders in AUD subjects, with associated increased morbidity and worse prognosis. This study evaluated the use of nalmefene in AUD patients with stabilized psychiatric comorbidity previously treated unsuccessfully for alcohol dependence, and assessed craving reduction and safety.
Sixty-five AUD outpatients treated with as-needed 18 mg nalmefene for 24 weeks were included. Primary outcome measures were: changes in heavy drinking days (HDDs) and total alcohol consumption (TAC, g/day). Secondary outcome measures were: changes in drinking risk level and craving (obsessive–compulsive drinking scale and visual analogue scale for craving).
Forty-two AUD subjects (64.6%) had one or more stabilized psychiatric comorbidity. There was a significant reduction in HDDs, TAC and craving measures (p < 0.001), with no differences between subjects with and without psychiatric comorbidity. Nalmefene was safe and well tolerated in all patients.
As-needed nalmefene reduced drinking and craving in AUD subjects with and without psychiatric comorbidity. These findings suggest that nalmefene is a valid therapeutic option in real-world clinical settings, where comorbid conditions are common, and has the potential to engage AUD patients who may otherwise not have sought help.
Lundbeck Italia S.P.A.
Micropulse laser treatment is an alternative to the conventional continuous-wave laser for the treatment of retinal or macular diseases. In contrast to the conventional laser, the therapeutic effect of the subthreshold micropulse laser is not accompanied by thermal retinal damage. This fact is of particular importance when a treatment near the fovea is required. Micropulse treatment is applied in indications such as central serous chorioretinopathy (CSC), diabetic macular edema (DME), or macular edema due to retinal vein occlusion (RVO). This review outlines and discusses the published literature of subthreshold micropulse laser treatment for CSC, DME, and macular edema after RVO.
Nalmefene is the first drug to be approved for reducing alcohol consumption in alcohol use disorder (AUD) patients at high drinking risk. In real-world settings, there is a high prevalence of concurrent psychiatric disorders in AUD subjects, with associated increased morbidity and worse prognosis. This study evaluated the use of nalmefene in AUD patients with stabilized psychiatric comorbidity previously treated unsuccessfully for alcohol dependence, and assessed craving reduction and safety.
Sixty-five AUD outpatients treated with as-needed 18 mg nalmefene for 24 weeks were included. Primary outcome measures were: changes in heavy drinking days (HDDs) and total alcohol consumption (TAC, g/day). Secondary outcome measures were: changes in drinking risk level and craving (obsessive–compulsive drinking scale and visual analogue scale for craving).
Forty-two AUD subjects (64.6%) had one or more stabilized psychiatric comorbidity. There was a significant reduction in HDDs, TAC and craving measures (p < 0.001), with no differences between subjects with and without psychiatric comorbidity. Nalmefene was safe and well tolerated in all patients.
As-needed nalmefene reduced drinking and craving in AUD subjects with and without psychiatric comorbidity. These findings suggest that nalmefene is a valid therapeutic option in real-world clinical settings, where comorbid conditions are common, and has the potential to engage AUD patients who may otherwise not have sought help.
Lundbeck Italia S.P.A.
A recent revision in thyroid tumor nomenclature has resulted in a change from a malignant diagnosis (noninvasive follicular variant of papillary thyroid carcinoma) to one that is nonmalignant (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]). The objective of the current study was to evaluate the impact of this change on the performance of the Afirma gene expression classifier (GEC).
The authors retrospectively analyzed consecutive thyroid fine-needle aspiration specimens with indeterminate diagnoses on which GEC was performed. Surgical pathology material was reviewed with the reclassification of nodules into NIFTP.
GEC testing was performed on 384 fine-needle aspiration specimens diagnosed as atypia of undetermined significance (AUS) (304 cases) and suspicious for a follicular neoplasm (SFN) (80 cases) and yielded a suspicious result in 152 of the AUS cases (50%) and 50 of the SFN cases (63%). Thyroidectomy was performed on 177 patients. After reclassifying NIFTP, the positive predictive value of GEC decreased from 42% (95% confidence interval [95% CI], 39%-45%) to 24% (95% CI, 22%-26%) in the AUS group and from 23% (95% CI, 19%-27%) to 13% (95% CI, 9%-18%) in the SFN group. Total thyroidectomy was performed more frequently than a partial thyroidectomy in patients with AUS with a suspicious GEC result compared with pre-GEC controls (68% vs 49%; P = .037).
Reclassification of NIFTP significantly decreases the positive predictive value of GEC in indeterminate thyroid nodules. Nevertheless, the majority of patients with indeterminate thyroid nodules with a suspicious GEC result in the study institution have undergone total thyroidectomy. This finding raises concerns over reliance on a suspicious GEC result by clinicians to justify total thyroidectomy. Cancer Cytopathol 2017. © 2017 American Cancer Society.