Τετάρτη 24 Μαΐου 2017

PROPIONIBACTERIUM ACNES AND CHRONIC DISEASES : P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,post-neurosurgical infection,joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.


P. acnes bacteria live deep within follicles and pores, away from the surface of the skin. In these follicles, P. acnes bacteria use sebum, cellular debris and metabolic byproducts from the surrounding skin tissue as their primary sources of energy and nutrients. Elevated production of sebum by hyperactive sebaceous glands (sebaceous hyperplasia) or blockage of the follicle can cause P. acnes bacteria to grow and multiply.[6]

P. acnes bacteria secrete many proteins, including several digestive enzymes.[7] These enzymes are involved in the digestion of sebum and the acquisition of other nutrients. They can also destabilize the layers of cells that form the walls of the follicle. The cellular damage, metabolic byproducts and bacterial debris produced by the rapid growth of P. acnes in follicles can trigger inflammation.[8] This inflammation can lead to the symptoms associated with some common skin disorders, such as folliculitis and acne vulgaris.[9][10][11]

The damage caused by P. acnes and the associated inflammation make the affected tissue more susceptible to colonization by opportunistic bacteria, such as Staphylococcus aureus. Preliminary research shows healthy pores are only colonized by P. acnes, while unhealthy ones universally include the nonpore-resident Staphylococcus epidermidis, amongst other bacterial contaminants. Whether this is a root causality, just opportunistic and a side effect, or a more complex pathological duality between P. acnes and this particular Staphylococcus species is not known.[12]

P. acnes has also been found in corneal ulcers, and is a common cause of chronic endophthalmitis following cataract surgery. Rarely, it infects heart valves leading to endocarditis, and infections of joints (septic arthritis) have been reported.[5] Furthermore, Propionibacterium species have been found in ventriculostomy insertion sites, and areas subcutaneous to suture sites in patients who have undergone craniotomy. It is a common contaminant in blood and cerebrospinal fluid cultures.

P. acnes has been found in herniated discs.[13] The propionic acid which it secretes creates micro-fractures of the surrounding bone. These micro-fractures are sensitive and it has been found that antibiotics have been helpful in resolving this type of low back pain.[14]

P. acnes can be found in bronchoalveolar lavage of approximately 70% of patients with sarcoidosis and is associated with disease activity, but it can be also found in 23% of controls.[15][16] The subspecies of P. acnes that cause these infections of otherwise sterile tissues (prior to medical procedures), however, are the same subspecies found on the skin of individuals who do not have acne-prone skin, so are likely local contaminants. Moderate to severe acne vulgaris appears to be more often associated with virulent strains.[17]

P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,[18] post-neurosurgical infection,[19] joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,[20] SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.[21]

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Dichotic Listening Deficit Associated With Solvent Exposure.Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes.


Dichotic Listening Deficit Associated With Solvent Exposure.
από Landry, Simon P.; Fuente, Adrian στο Otology & Neurotology Published Ahead-of-Print
Μετάφραση άρθρου
Hypothesis: A significant left ear deficit can be observed in solvent-exposed individuals using the dichotic digit test. Background: Solvents are ubiquitous in global industrial processes. Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes. Investigations in exposed populations suggest a decreased performance for dichotic listening. Methods: In this present study, we examined the lateralization of a dichotic digit test score for 49 solvent-exposed individuals along with 49 age- and sex-matched controls. We evaluated group differences between test scores and the right ear advantage using a laterality index (LI). Results: Individual ear results suggest that long-term workplace solvent exposure is associated with a significantly lower dichotic listening score for the left ear. A binaural compound score analysis using a laterality index supports this left-ear deficit. Conclusion: These results provide an insight on the effects of solvent exposure on dichotic listening abilities. Further research should investigate the importance of using dichotic listening tasks to screen for solvent-induced auditory dysfunction in exposed individuals. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

PARP Inhibitors in Prostate Cancer

Opinion Statement

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.



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PARP Inhibitors in Prostate Cancer

Opinion Statement

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.



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Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses are associated with multiple sclerosis



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

B7-H3 expression in NSCLC and its association with B7-H4, PD-L1 and Tumor Infiltrating Lymphocytes

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.



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Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules

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.



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Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma

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. 



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Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer (MBC)

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)



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BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAF V600E mutant melanoma

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.



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B7-H3 expression in NSCLC and its association with B7-H4, PD-L1 and Tumor Infiltrating Lymphocytes

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.



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Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules

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.



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Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma

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. 



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Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer (MBC)

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)



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BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in BRAF V600E mutant melanoma

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.



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The pattern of cervical lymph node metastasis in thoracic esophageal squamous cell carcinoma may affect the target decision for definitive radiotherapy

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.

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ETV1-positive cells give rise to BRAFV600E mutant gastrointestinal stromal tumors

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.

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ETV1-positive cells give rise to BRAFV600E mutant gastrointestinal stromal tumors

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.

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Lipid levels and risk of venous thrombosis: results from the MEGA-study

Abstract

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.



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Hopefully devoted to Q: targeting glutamine addiction in cancer

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



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Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial

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



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Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer

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



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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

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



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Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

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



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Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators

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



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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

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



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The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

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



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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

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



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Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

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



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Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity

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



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Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

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



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Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk

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



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Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

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



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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

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



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Hopefully devoted to Q: targeting glutamine addiction in cancer

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



http://ift.tt/2oI09Zb

Self-sampling to improve cervical cancer screening coverage in Switzerland: a randomised controlled trial

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



http://ift.tt/2oWnGHA

Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer

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



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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

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



http://ift.tt/2oWDxWV

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

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



http://ift.tt/2oWELRW

Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators

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



http://ift.tt/2oHQP7V

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

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



http://ift.tt/2oWt6SY

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

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



http://ift.tt/2oHPaix

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

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



http://ift.tt/2prFZH9

Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

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



http://ift.tt/2oHOglW

Excess of a Rassf1-targeting microRNA, miR-193a-3p, perturbs cell division fidelity

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



http://ift.tt/2ps1QxX

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

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



http://ift.tt/2oWyV30

Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk

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



http://ift.tt/2qvXUu5

Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers

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



http://ift.tt/2oHSURa

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

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



http://ift.tt/2oHydVw

Risque de radionécrose après radiothérapie hypofractionnée en conditions stéréotaxiques du lit opératoire de métastases cérébrales

S12783218.gif

Publication date: Available online 24 May 2017
Source:Cancer/Radiothérapie
Author(s): A. Keller, M. Doré, D. Antoni, I. Menoux, F. Thillays, J.B. Clavier, G. Delpon, D. Jarnet, C. Bourrier, F. Lefebvre, S. Chibbaro, I. Darié, F. Proust, G. Noël
ObjectifIdentifier les facteurs prédictifs de radionécrose après l'irradiation en conditions stéréotaxiques de la cavité d'exérèse de métastases cérébrales opérées.Matériels et méthodesUne analyse rétrospective a été réalisée dans deux centres français utilisant un protocole d'irradiation trifractionnée (trois séances de 7,7Gy, prescrites sur l'isodose 70 %), comme traitement adjuvant des lits opératoires de métastases cérébrales. Les patients initialement irradiés dans l'encéphale en totalité ont été exclus de l'étude. Le diagnostic de radionécrose cérébrale a été posé après avis d'experts d'après un faisceau d'arguments clinicoradiologiques, ou après confirmation histologique. Des analyses uni- et multifactorielles ont été réalisées afin de déterminer les facteurs prédictifs de radionécrose, en testant plusieurs variables cliniques et dosimétriques, notamment le volume de tissu sain recevant une dose spécifique (V8Gy à V22Gy).RésultatsCent quatre-vingt-un patients (189 cavités) ont été pris en charge entre mars 2008 et février 2015. Trente-cinq patients (18,5 %) ont vu se développer des signes de radionécrose en médiane 15 mois (extrêmes : 3–38 mois) après l'irradiation. Un tiers des radionécroses étaient symptomatiques. En analyse multifactorielle, la localisation sous-tentorielle de la métastase opérée était prédictive de radionécrose (hazard ratio [HR] : 2,97 ; intervalle de confiance à 95 % [IC 95 %] : 1,47–6,01 ; p=0,0025). Aucun des Vx analysés n'était associé au délai d'apparition de radionécrose, le V14Gy approchait la signification (p=0,059).ConclusionL'analyse des différents facteurs cliniques et dosimétriques a montré que la localisation sous-tentorielle d'une métastase cérébrale était prédictive de radionécrose après irradiation en conditions stéréotaxiques du lit opératoire.PurposeTo investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases.Methods and materialsA retrospective analysis conducted in two French centres, was performed in patients treated with trifractionated stereotactic radiotherapy (3×7.7Gy prescribed to the 70% isodose line) for resected brain metastases. Patients with previous whole-brain irradiation were excluded of the analysis. Radionecrosis was diagnosed according to a combination of criteria including clinical, serial imaging or, in some cases, histology. Univariate and multivariate analyses were performed to determine the predictive factors of radionecrosis including clinical and dosimetric variables such as volume of brain receiving a specific dose (V8Gy–V22Gy).ResultsOne hundred eighty-one patients, with a total of 189 cavities were treated between March 2008 and February 2015. Thirty-five patients (18.5%) developed radionecrosis after a median follow-up of 15 months (range: 3–38 months) after hypofractionated stereotactic radiotherapy. One third of patients with radionecrosis were symptomatic. Multivariate analysis showed that infra-tentorial location was predictive of radionecrosis (hazard ratio [HR]: 2.97; 95% confidence interval [95% CI]: 1.47–6.01; P=0.0025). None V8Gy–V22Gy was associated with appearance of radionecrosis, even if V14Gy trended toward significance (P=0.059).ConclusionAnalysis of patients and treatment variables revealed that infratentorial location of brain metastases was predictive for radionecrosis after hypofractionated stereotactic radiotherapy for postoperative resection cavities.



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Risque de radionécrose après radiothérapie hypofractionnée en conditions stéréotaxiques du lit opératoire de métastases cérébrales

S12783218.gif

Publication date: Available online 24 May 2017
Source:Cancer/Radiothérapie
Author(s): A. Keller, M. Doré, D. Antoni, I. Menoux, F. Thillays, J.B. Clavier, G. Delpon, D. Jarnet, C. Bourrier, F. Lefebvre, S. Chibbaro, I. Darié, F. Proust, G. Noël
ObjectifIdentifier les facteurs prédictifs de radionécrose après l'irradiation en conditions stéréotaxiques de la cavité d'exérèse de métastases cérébrales opérées.Matériels et méthodesUne analyse rétrospective a été réalisée dans deux centres français utilisant un protocole d'irradiation trifractionnée (trois séances de 7,7Gy, prescrites sur l'isodose 70 %), comme traitement adjuvant des lits opératoires de métastases cérébrales. Les patients initialement irradiés dans l'encéphale en totalité ont été exclus de l'étude. Le diagnostic de radionécrose cérébrale a été posé après avis d'experts d'après un faisceau d'arguments clinicoradiologiques, ou après confirmation histologique. Des analyses uni- et multifactorielles ont été réalisées afin de déterminer les facteurs prédictifs de radionécrose, en testant plusieurs variables cliniques et dosimétriques, notamment le volume de tissu sain recevant une dose spécifique (V8Gy à V22Gy).RésultatsCent quatre-vingt-un patients (189 cavités) ont été pris en charge entre mars 2008 et février 2015. Trente-cinq patients (18,5 %) ont vu se développer des signes de radionécrose en médiane 15 mois (extrêmes : 3–38 mois) après l'irradiation. Un tiers des radionécroses étaient symptomatiques. En analyse multifactorielle, la localisation sous-tentorielle de la métastase opérée était prédictive de radionécrose (hazard ratio [HR] : 2,97 ; intervalle de confiance à 95 % [IC 95 %] : 1,47–6,01 ; p=0,0025). Aucun des Vx analysés n'était associé au délai d'apparition de radionécrose, le V14Gy approchait la signification (p=0,059).ConclusionL'analyse des différents facteurs cliniques et dosimétriques a montré que la localisation sous-tentorielle d'une métastase cérébrale était prédictive de radionécrose après irradiation en conditions stéréotaxiques du lit opératoire.PurposeTo investigate the factors that potentially lead to brain radionecrosis after hypofractionated stereotactic radiotherapy targeting the postoperative resection cavity of brain metastases.Methods and materialsA retrospective analysis conducted in two French centres, was performed in patients treated with trifractionated stereotactic radiotherapy (3×7.7Gy prescribed to the 70% isodose line) for resected brain metastases. Patients with previous whole-brain irradiation were excluded of the analysis. Radionecrosis was diagnosed according to a combination of criteria including clinical, serial imaging or, in some cases, histology. Univariate and multivariate analyses were performed to determine the predictive factors of radionecrosis including clinical and dosimetric variables such as volume of brain receiving a specific dose (V8Gy–V22Gy).ResultsOne hundred eighty-one patients, with a total of 189 cavities were treated between March 2008 and February 2015. Thirty-five patients (18.5%) developed radionecrosis after a median follow-up of 15 months (range: 3–38 months) after hypofractionated stereotactic radiotherapy. One third of patients with radionecrosis were symptomatic. Multivariate analysis showed that infra-tentorial location was predictive of radionecrosis (hazard ratio [HR]: 2.97; 95% confidence interval [95% CI]: 1.47–6.01; P=0.0025). None V8Gy–V22Gy was associated with appearance of radionecrosis, even if V14Gy trended toward significance (P=0.059).ConclusionAnalysis of patients and treatment variables revealed that infratentorial location of brain metastases was predictive for radionecrosis after hypofractionated stereotactic radiotherapy for postoperative resection cavities.



http://ift.tt/2rREVuU

A gene polymorphism in PD-L1 promoter region is not associated with PD-L1 expression and patients’ survival in gastric cancer



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Multidisciplinary Management of Mycosis Fungoides/Sézary Syndrome

Abstract

Purpose of Review

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.

Recent Findings

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).

Summary

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.



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Multidisciplinary Management of Mycosis Fungoides/Sézary Syndrome

Abstract

Purpose of Review

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.

Recent Findings

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).

Summary

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.



http://ift.tt/2qdet1J

Erratum to: Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters



http://ift.tt/2qheJZx

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes

Abstract

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.



http://ift.tt/2qgc5mF

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes

Abstract

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.



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BK polyomavirus nephropathy in two kidney transplant patients with distinct diagnostic strategies for BK virus and similar clinical outcomes: two case reports

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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A gene polymorphism in PD-L1 promoter region is not associated with PD-L1 expression and patients’ survival in gastric cancer



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The central effect of 3-iodothyronamine on brain neuropeptides in mice

Abstract

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.



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In vivo and in situ programming of tumor immunity by combining oncolytics and PD-1 immune checkpoint blockade

Abstract

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.



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Evaluation of mitochondrial respiratory function in highly glycolytic glioma cells reveals low ADP phosphorylation in relation to oxidative capacity

Abstract

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.



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Neurocognitive functioning in pediatric craniopharyngioma: performance before treatment with proton therapy

Abstract

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.



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Fatigue in patients with low grade glioma: systematic evaluation of assessment and prevalence

Abstract

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.



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In vivo and in situ programming of tumor immunity by combining oncolytics and PD-1 immune checkpoint blockade

Abstract

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.



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A gene polymorphism in PD-L1 promoter region is not associated with PD-L1 expression and patients’ survival in gastric cancer



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A gene polymorphism in PD-L1 promoter region is not associated with PD-L1 expression and patients’ survival in gastric cancer



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Erratum to: Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters



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Prognostic value of maximum standardized uptake value measured by pretreatment 18F-FDG PET/CT in locally advanced head and neck squamous cell carcinoma

Abstract

Purpose/objectives

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.

Materials/methods

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.

Results

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).

Conclusions

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.



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Prognostic value of maximum standardized uptake value measured by pretreatment 18F-FDG PET/CT in locally advanced head and neck squamous cell carcinoma

Abstract

Purpose/objectives

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.

Materials/methods

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.

Results

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).

Conclusions

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.



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Evaluation of mitochondrial respiratory function in highly glycolytic glioma cells reveals low ADP phosphorylation in relation to oxidative capacity

Abstract

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.



http://ift.tt/2rUWZ6q

Neurocognitive functioning in pediatric craniopharyngioma: performance before treatment with proton therapy

Abstract

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.



http://ift.tt/2qXbMjL

Fatigue in patients with low grade glioma: systematic evaluation of assessment and prevalence

Abstract

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.



http://ift.tt/2rUSQj0

Evaluation of mitochondrial respiratory function in highly glycolytic glioma cells reveals low ADP phosphorylation in relation to oxidative capacity

Abstract

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.



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Neurocognitive functioning in pediatric craniopharyngioma: performance before treatment with proton therapy

Abstract

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.



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Fatigue in patients with low grade glioma: systematic evaluation of assessment and prevalence

Abstract

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.



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A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders

Abstract

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.



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Nalmefene in Alcohol Use Disorder Subjects with Psychiatric Comorbidity: A Naturalistic Study

Abstract

Introduction

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.

Methods

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).

Results

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.

Conclusion

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.

Funding

Lundbeck Italia S.P.A.



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A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders

Abstract

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.



http://ift.tt/2rQRrLf

Nalmefene in Alcohol Use Disorder Subjects with Psychiatric Comorbidity: A Naturalistic Study

Abstract

Introduction

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.

Methods

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).

Results

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.

Conclusion

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.

Funding

Lundbeck Italia S.P.A.



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The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the performance of the Afirma gene expression classifier

BACKGROUND

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).

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.



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