Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are driven by diverse genetic alterations, including chromosomal rearrangements and mutations in genes that control the proliferation and differentiation of hematopoietic progenitor cells. Chromosomal translocations of the gene…
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 27 Απριλίου 2017
Stabilizing the Mixed Lineage Leukemia Protein
Proton beam radiotherapy as part of comprehensive regional nodal irradiation for locally advanced breast cancer
This study evaluates acute toxicity outcomes in breast cancer patients treated with adjuvant proton beam therapy (PBT).
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Preliminary investigation of preoperative pregabalin and total intravenous anesthesia doses: a randomized controlled trial
To determine the efficacy of 2 different doses (150-300mg) of preoperative pregabalin on propofol and remifentanil doses for total intravenous anesthesia in laparoscopic cholecystectomy.
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Unique and novel urinary metabolomic features in malignant versus benign adrenal neoplasms
Purpose: <p>Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.</p> <p>Experimental Design:</p> <p>Preoperative fasting urine specimens from patients with ACC (n=19) and benign adrenal tumors (n=46) were analyzed by unbiased ultra performance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t-test adjusted by false discovery rate. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n=11) and benign adrenal tumors (n=46) and in a subset of tissue samples from patients with ACC (n=15) and benign adrenal tumors (n=15) in the training set.</p> <p>Results:</p> <p>Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold(p=0.0001) in patients with ACC. L-tryptophan, N,N,N-trimethyl-L-lysine and 3-methylhistidine were lower 0.33-fold(p<0.0001), 0.56-fold(p<0.0001), and 0.33-fold(p=0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 (sensitivity 94.7%(CI 73.9-99.1%), specificity 82.6%(CI 68.6-92.2%), PPV 69.2%(CI 48.2-85.6%), and NPV 97.4%(CI 86.5-99.6%)) for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, N,N,N-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.</p> <p>Conclusions:</p> <p>There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC.
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Unique and novel urinary metabolomic features in malignant versus benign adrenal neoplasms
Purpose: <p>Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.</p> <p>Experimental Design:</p> <p>Preoperative fasting urine specimens from patients with ACC (n=19) and benign adrenal tumors (n=46) were analyzed by unbiased ultra performance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t-test adjusted by false discovery rate. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n=11) and benign adrenal tumors (n=46) and in a subset of tissue samples from patients with ACC (n=15) and benign adrenal tumors (n=15) in the training set.</p> <p>Results:</p> <p>Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold(p=0.0001) in patients with ACC. L-tryptophan, N,N,N-trimethyl-L-lysine and 3-methylhistidine were lower 0.33-fold(p<0.0001), 0.56-fold(p<0.0001), and 0.33-fold(p=0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 (sensitivity 94.7%(CI 73.9-99.1%), specificity 82.6%(CI 68.6-92.2%), PPV 69.2%(CI 48.2-85.6%), and NPV 97.4%(CI 86.5-99.6%)) for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, N,N,N-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.</p> <p>Conclusions:</p> <p>There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC.
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UK clinical practice guidelines for the management of gastrointestinal stromal tumours (GIST)
Abstract
Background
Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues. Gastrointestinal stromal tumour (GIST) is the commonest STS and arises within the wall of the gastrointestinal (GI) tract. While most GISTs occur in the stomach they do occur in all parts of the GI tract. As with other STS, it is important that GISTs are managed by expert teams, to ensure consistent and optimal treatment, as well as recruitment to clinical trials, and the ongoing accumulation of further knowledge of the disease. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field.
Methodology
British Sarcoma Group guidelines for the management of GIST were initially developed by a panel of physicians experienced in the management of GIST. This current version has been updated and amended with reference to other European and US guidance. We have received input from representatives of all diagnostic and treatment disciplines as well as patient representatives. Levels of evidence and strength of recommendation gradings are those used by ESMO adapted from those published by the Infectious Disease Society of America.
Conclusions
The guidelines cover aetiology, genetics and underlying molecular mechanisms, diagnosis and initial investigations, staging and risk stratification, surgery, neoadjuvant and adjuvant therapy, the management of advanced disease and follow-up. The importance of mutational analysis in guiding treatment is highlighted, since this can indicate the most effective treatment and avoid administration of ineffective drugs, emphasising the need for management in specialist centres.
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UK clinical practice guidelines for the management of gastrointestinal stromal tumours (GIST)
Abstract
Background
Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues. Gastrointestinal stromal tumour (GIST) is the commonest STS and arises within the wall of the gastrointestinal (GI) tract. While most GISTs occur in the stomach they do occur in all parts of the GI tract. As with other STS, it is important that GISTs are managed by expert teams, to ensure consistent and optimal treatment, as well as recruitment to clinical trials, and the ongoing accumulation of further knowledge of the disease. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field.
Methodology
British Sarcoma Group guidelines for the management of GIST were initially developed by a panel of physicians experienced in the management of GIST. This current version has been updated and amended with reference to other European and US guidance. We have received input from representatives of all diagnostic and treatment disciplines as well as patient representatives. Levels of evidence and strength of recommendation gradings are those used by ESMO adapted from those published by the Infectious Disease Society of America.
Conclusions
The guidelines cover aetiology, genetics and underlying molecular mechanisms, diagnosis and initial investigations, staging and risk stratification, surgery, neoadjuvant and adjuvant therapy, the management of advanced disease and follow-up. The importance of mutational analysis in guiding treatment is highlighted, since this can indicate the most effective treatment and avoid administration of ineffective drugs, emphasising the need for management in specialist centres.
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HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment
The incidence and mortality rates of hepatocellular carcinoma (HCC) have steadily increased in recent years. A hypoxic microenvironment is one of the most important characteristics of solid tumors which has be...
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Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer
The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC50, 1,100 nM) inhibits cancer cell migration and viability, and reduces tumor growth, metastasis, and angiogenesis in vivo. Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC50s of 103 nM and 78 nM respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of signal transducer and activator of transcription (STAT3), without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial to mesenchymal transition by a loss of cell polarity, and inhibition of cell surface actin-based extensions, to ultimately result in detachment from the substratum. Prolonged incubation (120 h) in MBQ-167 decreases metastatic cancer cell viability with a GI50 of ~130 nM, without affecting non-cancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G2/M cell cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by ~90%. In conclusion, MBQ-167 is 10X more potent than other currently available Rac/Cdc42 inhibitors, and has potential to be developed as an anticancer drug, as well as a dual inhibitory probe for Rac and Cdc42.
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Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer
The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC50, 1,100 nM) inhibits cancer cell migration and viability, and reduces tumor growth, metastasis, and angiogenesis in vivo. Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC50s of 103 nM and 78 nM respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of signal transducer and activator of transcription (STAT3), without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial to mesenchymal transition by a loss of cell polarity, and inhibition of cell surface actin-based extensions, to ultimately result in detachment from the substratum. Prolonged incubation (120 h) in MBQ-167 decreases metastatic cancer cell viability with a GI50 of ~130 nM, without affecting non-cancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167-mediated G2/M cell cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by ~90%. In conclusion, MBQ-167 is 10X more potent than other currently available Rac/Cdc42 inhibitors, and has potential to be developed as an anticancer drug, as well as a dual inhibitory probe for Rac and Cdc42.
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Patterns of care and predictors of adjuvant therapies in elderly patients with glioblastoma: An analysis of the National Cancer Database
BACKGROUND
The objectives of this study were to characterize patterns of care and to identify predictors for adjuvant therapy in elderly patients with glioblastoma in the modern era.
METHODS. The National Cancer Database was queried for patients aged 70 years and older with glioblastoma diagnosed from January 1, 2004 through December 31, 2012. Multinomial logistic regression was used to identify predictors for receiving adjuvant therapy. Survival outcomes were estimated using the Kaplan-Meier method and were analyzed using Cox regression models and the log-rank test.
RESULTS
In total, 14,886 patients were identified. Of these, 8214 patients (55.2%) received combined-modality therapy with chemotherapy and radiation (CRT), 3955 (26.6%) received no adjuvant therapy, 2065 (13.9%) received radiation therapy (RT) alone, and 652 (4.4%) received chemotherapy (CT) alone after undergoing resection. The receipt of CRT increased in frequency over the study interval, from 40.3% in 2004 to 59.8% in 2012. Younger patients (ages 70-75 years) were more likely to receive CRT than no adjuvant therapy (P < .0001 for all other age groups) or adjuvant RT alone (P < .0001 for all other age groups). Combined-modality therapy with adjuvant CRT produced improved survival outcomes, and the highest median overall survival was 9.2 months.
CONCLUSIONS
In this analysis of elderly patients who had glioblastoma diagnosed from 2004 through 2012, a significant increase in the receipt of combined-modality therapy was observed. Combined-modality treatment produces improved survival outcomes and should be considered as adjuvant treatment for carefully selected elderly patients. Cancer 2017. © 2017 American Cancer Society.
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Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long-term survivors of childhood acute lymphoblastic leukemia
BACKGROUND
Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, which may be associated with fatigue, sleep problems, systemic inflammation, and oxidative stress. We examined these associations among survivors of childhood ALL treated with chemotherapy only.
METHODS
Survivors of childhood ALL (male, n = 35 and female, n = 35; mean age, 14.3 years [standard deviation, 4.7 years] and mean years from diagnosis, 7.4 years [standard deviation, 1.9 years]) completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms 5 years after diagnosis. Serum was collected concurrently and assayed for interleukin (IL)-1β and IL-6, tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hsCRP), malondialdehyde, myeloperoxidase, and oxidized low-density lipoprotein. General linear modeling was used to assess associations among biomarkers and functional outcomes, adjusting for age and stratified by sex.
RESULTS
Survivors performed worse than population norms on executive function and processing speed and reported more behavioral problems (P < .05 adjusted for multiple comparison). In female survivors, fatigue was associated with poor executive function (r = 0.41; P = .02), processing speed (r = 0.56; P < .001), and attention (r = 0.36-0.55; P < .05). Female survivors with frequent nighttime awakening displayed more inattention (P = .01), hyperactivity (P = .03), and aggression (P = .01). Worse executive function, processing speed, and behavioral symptoms were observed in female survivors with higher levels of IL-6, IL-1β, and hsCRP (P < .05). Male survivors with high levels of TNF-α demonstrated worse organization (P = .03), but no significant associations between neurocognitive outcomes and sleep/fatigue measures were observed.
CONCLUSION
Neurocognitive function in female survivors of childhood ALL appears more susceptible to the effects of sleep disturbance and fatigue. Systemic inflammation may play a role in neurocognitive impairment and behavioral symptoms. Cancer 2017. © 2017 American Cancer Society.
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Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute lymphoblastic leukemia
BACKGROUND
Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)–matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome.
METHODS
Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared.
RESULTS
The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele–matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients.
CONCLUSIONS
In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017. © 2017 American Cancer Society.
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Patterns of care and predictors of adjuvant therapies in elderly patients with glioblastoma: An analysis of the National Cancer Database
BACKGROUND
The objectives of this study were to characterize patterns of care and to identify predictors for adjuvant therapy in elderly patients with glioblastoma in the modern era.
METHODS. The National Cancer Database was queried for patients aged 70 years and older with glioblastoma diagnosed from January 1, 2004 through December 31, 2012. Multinomial logistic regression was used to identify predictors for receiving adjuvant therapy. Survival outcomes were estimated using the Kaplan-Meier method and were analyzed using Cox regression models and the log-rank test.
RESULTS
In total, 14,886 patients were identified. Of these, 8214 patients (55.2%) received combined-modality therapy with chemotherapy and radiation (CRT), 3955 (26.6%) received no adjuvant therapy, 2065 (13.9%) received radiation therapy (RT) alone, and 652 (4.4%) received chemotherapy (CT) alone after undergoing resection. The receipt of CRT increased in frequency over the study interval, from 40.3% in 2004 to 59.8% in 2012. Younger patients (ages 70-75 years) were more likely to receive CRT than no adjuvant therapy (P < .0001 for all other age groups) or adjuvant RT alone (P < .0001 for all other age groups). Combined-modality therapy with adjuvant CRT produced improved survival outcomes, and the highest median overall survival was 9.2 months.
CONCLUSIONS
In this analysis of elderly patients who had glioblastoma diagnosed from 2004 through 2012, a significant increase in the receipt of combined-modality therapy was observed. Combined-modality treatment produces improved survival outcomes and should be considered as adjuvant treatment for carefully selected elderly patients. Cancer 2017. © 2017 American Cancer Society.
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Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long-term survivors of childhood acute lymphoblastic leukemia
BACKGROUND
Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, which may be associated with fatigue, sleep problems, systemic inflammation, and oxidative stress. We examined these associations among survivors of childhood ALL treated with chemotherapy only.
METHODS
Survivors of childhood ALL (male, n = 35 and female, n = 35; mean age, 14.3 years [standard deviation, 4.7 years] and mean years from diagnosis, 7.4 years [standard deviation, 1.9 years]) completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms 5 years after diagnosis. Serum was collected concurrently and assayed for interleukin (IL)-1β and IL-6, tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hsCRP), malondialdehyde, myeloperoxidase, and oxidized low-density lipoprotein. General linear modeling was used to assess associations among biomarkers and functional outcomes, adjusting for age and stratified by sex.
RESULTS
Survivors performed worse than population norms on executive function and processing speed and reported more behavioral problems (P < .05 adjusted for multiple comparison). In female survivors, fatigue was associated with poor executive function (r = 0.41; P = .02), processing speed (r = 0.56; P < .001), and attention (r = 0.36-0.55; P < .05). Female survivors with frequent nighttime awakening displayed more inattention (P = .01), hyperactivity (P = .03), and aggression (P = .01). Worse executive function, processing speed, and behavioral symptoms were observed in female survivors with higher levels of IL-6, IL-1β, and hsCRP (P < .05). Male survivors with high levels of TNF-α demonstrated worse organization (P = .03), but no significant associations between neurocognitive outcomes and sleep/fatigue measures were observed.
CONCLUSION
Neurocognitive function in female survivors of childhood ALL appears more susceptible to the effects of sleep disturbance and fatigue. Systemic inflammation may play a role in neurocognitive impairment and behavioral symptoms. Cancer 2017. © 2017 American Cancer Society.
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Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute lymphoblastic leukemia
BACKGROUND
Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)–matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome.
METHODS
Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared.
RESULTS
The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele–matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients.
CONCLUSIONS
In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017. © 2017 American Cancer Society.
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Anesthetic consideration for neuromuscular diseases.
Purpose of review: The aim of this review is to examine data relating to perioperative management of the patient with neuromuscular disorders Recent findings: Patients with pre-existing neuromuscular disorders are at risk for a number of postoperative complications that are related to anesthetic drugs that are administered intraoperatively. Careful preoperative assessment is necessary to reduce morbidity and mortality. In particular, the risk of postoperative respiratory failure and need for long-term ventilation should be reviewed with patients. The use of succinylcholine should be avoided in muscular dystrophies, motor neuron diseases, and intrinsic muscle disease due to a risk of malignant hyperthermia, hyperkalemia, rhabdomyolysis, and cardiac arrest. The use of quantitative neuromuscular monitoring should be strongly considered whenever nondepolarizing neuromuscular blocking agents are administered. A number of case series and reports have been recently published demonstrating that sugammadex can be safely used in patients with neuromuscular disease; the risk of residual neuromuscular is nearly eliminated when this agent is administered intraoperatively. Summary: Careful assessment and management of patients with underlying neuromuscular diseases is required to reduce postoperative complications. This article reviews the anesthetic implications of patients undergoing surgery with neuromuscular disorder. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.
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miR-130A as a diagnostic marker to differentiate malignant mesothelioma from lung adenocarcinoma in pleural effusion cytology
BACKGROUND
Malignant pleural mesothelioma is a rare tumor with a dismal prognosis, usually presenting with recurrent effusions. However, the majority of malignant pleural effusions are due to lung adenocarcinoma (AdC). The distinction between these tumors has considerable therapeutic and medicolegal implications and can be very challenging both histologically and cytologically. Appropriate immunohistochemistry (IHC) is required to support the diagnosis. MicroRNA (miRNA) expression analysis could be a viable diagnostic tool for distinguishing between these tumors. The purpose of the current study was to assess the reliability of miRNAs as diagnostic markers to differentiate epithelioid malignant mesothelioma (MM) from lung AdC.
METHODS
Bioinformatic analysis of publicly searchable data sets regarding miRNA expression profiling was performed to select the most significant differentially expressed miRNAs. These were analyzed by quantitative polymerase chain reaction on histologic (41 MM cases and 40 lung AdC cases) and cytological (26 MM cases and 27 lung AdC cases) specimens and the diagnostic performances were assessed.
RESULTS
miR-130a, miR-193a, miR-675, miR-141, miR-205, and miR-375 were found to be the best distinguishing markers. Of these, only miR-130a was significantly overexpressed in MM compared with lung AdC (P =.029 in histologic and P =.014 in cytological samples). miR-130a demonstrated a sensitivity of 77%, a specificity of 67%, a positive predictive value of 69%, a negative predictive value of 75%, and an accuracy of 72% in identifying MM.
CONCLUSIONS
The diagnostic performances of miR-130a expression analysis and IHC appear to be similar. miR-130a quantification could be used reliably as second-level diagnostic tool to differentiate MM from lung AdC in pleural effusion cytology, mainly in those cases with ambiguous or negative IHC. Further validation is needed. Cancer Cytopathol 2017. © 2017 American Cancer Society.
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miR-130A as a diagnostic marker to differentiate malignant mesothelioma from lung adenocarcinoma in pleural effusion cytology
BACKGROUND
Malignant pleural mesothelioma is a rare tumor with a dismal prognosis, usually presenting with recurrent effusions. However, the majority of malignant pleural effusions are due to lung adenocarcinoma (AdC). The distinction between these tumors has considerable therapeutic and medicolegal implications and can be very challenging both histologically and cytologically. Appropriate immunohistochemistry (IHC) is required to support the diagnosis. MicroRNA (miRNA) expression analysis could be a viable diagnostic tool for distinguishing between these tumors. The purpose of the current study was to assess the reliability of miRNAs as diagnostic markers to differentiate epithelioid malignant mesothelioma (MM) from lung AdC.
METHODS
Bioinformatic analysis of publicly searchable data sets regarding miRNA expression profiling was performed to select the most significant differentially expressed miRNAs. These were analyzed by quantitative polymerase chain reaction on histologic (41 MM cases and 40 lung AdC cases) and cytological (26 MM cases and 27 lung AdC cases) specimens and the diagnostic performances were assessed.
RESULTS
miR-130a, miR-193a, miR-675, miR-141, miR-205, and miR-375 were found to be the best distinguishing markers. Of these, only miR-130a was significantly overexpressed in MM compared with lung AdC (P =.029 in histologic and P =.014 in cytological samples). miR-130a demonstrated a sensitivity of 77%, a specificity of 67%, a positive predictive value of 69%, a negative predictive value of 75%, and an accuracy of 72% in identifying MM.
CONCLUSIONS
The diagnostic performances of miR-130a expression analysis and IHC appear to be similar. miR-130a quantification could be used reliably as second-level diagnostic tool to differentiate MM from lung AdC in pleural effusion cytology, mainly in those cases with ambiguous or negative IHC. Further validation is needed. Cancer Cytopathol 2017. © 2017 American Cancer Society.
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A new predictive tool for postoperative radiotherapy in prostate cancer
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Downregulation of lncRNA ANRIL inhibits proliferation, induces apoptosis, and enhances radiosensitivity in nasopharyngeal carcinoma cells through regulating miR-125a
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Effect of NK cell immunotherapy on immune function in patients with hepatic carcinoma: A preliminary clinical study
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Expression and clinicopathologic significance of TUFM and p53 for the normal–adenoma–carcinoma sequence in colorectal epithelia
Abstract
Background
Evidence indicates that most cases of colorectal carcinoma (CRC) develop from adenoma. A previous study demonstrated that mitochondrial Tu translation elongation factor (TUFM) might serve as an independent prognostic factor for colorectal cancer. However, the expression and function of TUFM in the normal–adenoma–cancer sequence have not been reported. In this study, we investigated the clinicopathologic significance of TUFM and p53 expression for the normal–adenoma–carcinoma sequence in colorectal epithelia and evaluated the roles of TUFM during the progression of colorectal tumors.
Methods
Paraffin-embedded specimens from 261 colorectal normal mucosa samples, 157 adenomas, and 104 early carcinomas were analyzed for TUFM and p53 expression by immunohistochemistry.
Results
Expression of TUFM and p53 was significantly increased during the colorectal normal–adenoma–carcinoma sequence (all P < 0.05). The expression of TUFM and p53 was associated with histologic type of adenomas (P = 0.028; P = 0.001) and grade of dysplasia (all P = 0.001). Expression of TUFM was positively correlated with that of p53 (r = 0.319, P = 0.001).
Conclusions
Upregulated TUFM expression may play an important role in the transformation from colorectal normal mucosa to carcinoma through adenoma. Combined immunohistochemical detection of TUFM and p53 may be useful for evaluating the biological behavior of colorectal adenoma.
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Expression and clinicopathologic significance of TUFM and p53 for the normal–adenoma–carcinoma sequence in colorectal epithelia
Abstract
Background
Evidence indicates that most cases of colorectal carcinoma (CRC) develop from adenoma. A previous study demonstrated that mitochondrial Tu translation elongation factor (TUFM) might serve as an independent prognostic factor for colorectal cancer. However, the expression and function of TUFM in the normal–adenoma–cancer sequence have not been reported. In this study, we investigated the clinicopathologic significance of TUFM and p53 expression for the normal–adenoma–carcinoma sequence in colorectal epithelia and evaluated the roles of TUFM during the progression of colorectal tumors.
Methods
Paraffin-embedded specimens from 261 colorectal normal mucosa samples, 157 adenomas, and 104 early carcinomas were analyzed for TUFM and p53 expression by immunohistochemistry.
Results
Expression of TUFM and p53 was significantly increased during the colorectal normal–adenoma–carcinoma sequence (all P < 0.05). The expression of TUFM and p53 was associated with histologic type of adenomas (P = 0.028; P = 0.001) and grade of dysplasia (all P = 0.001). Expression of TUFM was positively correlated with that of p53 (r = 0.319, P = 0.001).
Conclusions
Upregulated TUFM expression may play an important role in the transformation from colorectal normal mucosa to carcinoma through adenoma. Combined immunohistochemical detection of TUFM and p53 may be useful for evaluating the biological behavior of colorectal adenoma.
http://ift.tt/2prdcCA
A Retrospective Study to Evaluate the Effect of Concentration of Hypertonic Saline on Efficacy and Safety of Epidural Adhesiolysis.
BACKGROUND: Percutaneous epidural adhesiolysis (PEA) is a minimally invasive procedure that is performed to relieve low back and/or lower limb pain secondary to adhesions or scarring in the epidural space that is refractory to conservative treatment. The optimal concentration of hypertonic saline might be an important factor in the safety and efficacy of PEA. We evaluated differences in the efficacy and safety of 2 concentrations of hypertonic saline (5% and 10%) used in lumbar PEA at our institutions in a retrospective study. METHODS: Patients who received lumbar PEA between January 2009 and June 2014 at either of 2 large civilian teaching institutions in South Korea were assigned to the 5% or 10% groups according to the osmolality of saline. The primary outcome of this study was the difference in change in the 11-point numerical rating scale (NRS) scores of low back and leg pain from baseline to 6 months after PEA between patients in the 2 groups. The number of additional epidural injections, patients' satisfaction with PEA, and any complications that occurred within 6 months after PEA were reviewed. RESULTS: This study included 543 patients (5% group, 333; 10% group, 210). Post-PEA NRS pain scores were significantly lower compared with those at baseline in both groups; however, there were no significant differences between the 2 groups at 6 months or any time point after PEA with regard to any of the clinical characteristics, except infusion-related pain, which exhibited borderline significance for greater scores in the 10% group compared with those in the 5% group (P = .041). Multivariable linear regression analysis with adjustments for covariates, including the number of additional epidural injections, revealed no significant association between patient group and the decrease in NRS pain scores at 6 months of follow-up. Transient adverse events related to PEA were recorded in 3 patients (10% group, 2; 5% group, 1). CONCLUSIONS: In PEA, 5% hypertonic saline exhibited similar positive outcomes after 6 months of follow-up as 10% hypertonic saline, with less infusion-related pain. This result suggests that infusion of 5% hypertonic saline may be considered as an alternative to 10% hypertonic saline in lumbar PEA. Further prospective randomized studies are required to better appreciate the outcome with regard to the use of different concentrations of hypertonic saline for PEA. (C) 2017 International Anesthesia Research Society
http://ift.tt/2p8URJH
http://ift.tt/2p8URJH
Prophylactic Pentazocine Reduces the Incidence of Pruritus After Cesarean Delivery Under Spinal Anesthesia With Opioids: A Prospective Randomized Clinical Trial.
BACKGROUND: The incidence of pruritus after cesarean delivery under spinal anesthesia with opioids is high, ranging from 50% to 100%. Pruritus is difficult to prevent; however, pentazocine has been shown to be an effective treatment. Despite this, the prophylactic effect of pentazocine on pruritus has not been defined. This randomized double-blind trial aimed to evaluate the effect of intraoperative IV pentazocine on the incidence of opioid-induced pruritus within the first 24 hours after administration of neuraxial opioids. METHODS: We obtained institutional review board approval and written informed consent from the 122 patients (American Society of Anesthesiologists [ASA] physical status II; aged 20-40 years) scheduled for elective cesarean delivery who were included in this study. Spinal anesthesia was performed with 10 mg of 0.5% hyperbaric bupivacaine, 10 [mu]g of fentanyl, and 100 [mu]g of morphine. After delivery of the baby and placenta, the parturient women were randomized to intravenously receive 15 mg (1 mL) of pentazocine or 1 mL of saline. All women received postoperative analgesia with the epidural infusion of 0.15% levobupivacaine. The presence of pruritus within the first 24 hours after intrathecal administration of opioids was recorded, and severity of itch, numerical rating scale (NRS) for pain, and adverse effects were also recorded at the time of the arrival on the ward, as well as 3, 6, 12, and 24 hours after the intrathecal administration of opioids. RESULTS: A total of 119 women completed the study. IV pentazocine reduced the overall incidence of pruritus within the first 24 hours compared to IV saline, with an estimated relative risk of 69% (95% confidence interval [CI], 52%, 90%; P = .007). IV pentazocine also reduced the severity of pruritus. The incidence of nausea and vomiting was not significantly different. There were no significant differences in postoperative NRS scores. CONCLUSIONS: A single 15-mg dose of IV pentazocine after delivery can reduce both the incidence and severity of pruritus in women who have received subarachnoid opioids during cesarean delivery. (C) 2017 International Anesthesia Research Society
http://ift.tt/2pndYyt
http://ift.tt/2pndYyt
Intrathecal Morphine Versus Extended-Release Epidural Morphine for Postoperative Pain Control in Pediatric Patients Undergoing Posterior Spinal Fusion.
BACKGROUND: Posterior spinal fusion for scoliosis is one of the most painful elective pediatric surgeries. Good postoperative pain control allows early ambulation and return of ability to tolerate oral intake. Options for analgesia in this patient population are suboptimal. We hypothesized that extended-release epidural morphine (EREM) would provide better pain control and less adverse effects compared to intrathecal (IT) morphine. METHODS: The primary outcome was total IV morphine consumption during 0-48 hours postoperatively. Secondary outcomes included time until first patient-controlled analgesia (PCA) demand, pain scores, and adverse opioid effects. After institutional review board approval, 71 subjects undergoing posterior spinal fusion for idiopathic scoliosis completed the study. The subjects were randomly allocated to 7.5 [mu]g/kg IT morphine or 150 [mu]g/kg EREM. The final IT morphine and EREM groups contained 37 and 34 subjects, respectively. Postoperative pain was treated with morphine PCA, ketorolac, oral oxycodone, and acetaminophen. Morphine consumption, pain scores, nausea and vomiting, pruritus, and respiratory depression were measured every 4 hours. Parents completed a caregiver questionnaire about their child's pain control regimen after the first postoperative day. RESULTS: There was no difference in total morphine consumption over the first 48 hours between subjects in the EREM and IT morphine groups: median (range) 42.2 (5.5-123.0) and 34.0 (4.5-128.8) mg, respectively (P = .27). EREM and IT morphine groups had no difference in time until first PCA demand. Pain scores were no different between the groups from 8 to 24 hours after surgery. Compared to IT morphine, EREM subjects had lower pain scores from 28 to 36 hours after surgery. The reported incidence of pruritus was lower in the EREM subjects. CONCLUSIONS: There was no difference in total morphine consumption or time until first PCA demand between the EREM and IT morphine groups. EREM provides a longer duration of analgesia after posterior spinal fusion for scoliosis and may be associated with less opioid-induced pruritus. (C) 2017 International Anesthesia Research Society
http://ift.tt/2pE62eZ
http://ift.tt/2pE62eZ
Quality Assessment of Meta-analyses Published in Leading Anesthesiology Journals From 2005 to 2014.
Meta-analysis, when preceded by a systematic review, is considered the "gold standard" in data aggregation; however, the quality of meta-analyses is often questionable, leading to uncertainty about the accuracy of results. In this study, we evaluate the quality of meta-analyses published in 5 leading anesthesiology journals from 2005 to 2014. A total of 220 meta-analyses published in Anesthesiology, Pain, British Journal of Anaesthesia, Anaesthesia, or Anesthesia & Analgesia were identified for inclusion. The quality of each meta-analysis was determined using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR). R-AMSTAR rated 11 questions related to systematic reviews and meta-analyses on a scale of 1-4, with 4 representing the highest quality. Overall meta-analyses quality was evaluated using a Spearmen regression analysis and found to positively correlate with time (rs = 0.24, P
http://ift.tt/2p8D997
http://ift.tt/2p8D997
Comparison of Postoperative Respiratory Monitoring by Acoustic and Transthoracic Impedance Technologies in Pediatric Patients at Risk of Respiratory Depression.
BACKGROUND: In children, postoperative respiratory rate (RR) monitoring by transthoracic impedance (TI), capnography, and manual counting has limitations. The rainbow acoustic monitor (RAM) measures continuous RR noninvasively by a different methodology. Our primary aim was to compare the degree of agreement and accuracy of RR measurements as determined by RAM and TI to that of manual counting. Secondary aims include tolerance and analysis of alarm events. METHODS: Sixty-two children (2-16 years old) were admitted after tonsillectomy or receiving postoperative patient/parental-controlled analgesia. RR was measured at regular intervals by RAM, TI, and manual count. Each TI or RAM alarm resulted in a clinical evaluation to categorize as a true or false alarm. To assess accuracy and degree of agreement of RR measured by RAM or TI compared with manual counting, a Bland-Altman analysis was utilized showing the average difference and the limits of agreement. Sensitivity and specificity of RR alarms by TI and RAM are presented. RESULTS: Fifty-eight posttonsillectomy children and 4 patient/parental-controlled analgesia users aged 6.5 +/- 3.4 years and weighting 35.3 +/- 22.7 kg (body mass index percentile 76.6 +/- 30.8) were included. The average monitoring time per patient was 15.9 +/- 4.8 hours. RAM was tolerated 87% of the total monitoring time. The manual RR count was significantly different from TI (P = .007) with an average difference +/- SD of 1.39 +/- 10.6 but were not significantly different from RAM (P = .81) with an average difference +/- SD of 0.17 +/- 6.8. The proportion of time when RR measurements differed by >=4 breaths was 22% by TI and was 11% by RAM. Overall, 276 alarms were detected (mean alarms/patient = 4.5). The mean number of alarms per patient were 1.58 +/- 2.49 and 2.87 +/- 4.32 for RAM and TI, respectively. The mean number of false alarms was 0.18 +/- 0.71 for RAM and 1.00 +/- 2.78 for TI. The RAM was found to have 46.6% sensitivity (95% confidence interval [CI], 0.29-0.64), 95.9% specificity (95% CI, 0.90-1.00), 88.9% positive predictive value (95% CI, 0.73-1.00), and 72.1% negative predictive value (95% CI, 0.61-0.84), whereas the TI monitor had 68.5% sensitivity (95% CI, 0.53-0.84), 72.0% specificity (95% CI, 0.60-0.84), 59.0% positive (95% CI, 0.44-0.74), and 79.5% negative predictive value (95% CI, 0.69-0.90). CONCLUSIONS: In children at risk of postoperative respiratory depression, RR assessment by RAM was not different to manual counting. RAM was well tolerated, had a lower incidence of false alarms, and had better specificity and positive predictive value than TI. Rigorous evaluation of the negative predictive value is essential to determine the role of postoperative respiratory monitoring with RAM. (C) 2017 International Anesthesia Research Society
http://ift.tt/2oNSLM2
http://ift.tt/2oNSLM2
Psychological characteristics of early-stage melanoma patients: a cross-sectional study on 204 patients
The presence of psychological distress has a negative impact not only on cancer patients' quality of life but also on the course of the disease, with slower recovery and increased morbidity. These issues are of particular importance in melanoma patients (MP), who remain at risk of disease progression for many years after diagnosis. This study aimed to investigate psychological distress, coping strategies, and their possible relationships with demographic–clinical features in patients with early-stage melanoma in follow-up. The investigation focused in particular on whether the psychological profile differed between patients at different melanoma stages. Data of 118 patients with melanoma in the Tis-Ia stages (MP_Tis-Ia) and 86 patients with melanoma in the Ib–IIa–IIb stages (MP_Ib–II) were gathered through a self-administered survey and compared using a cross-sectional design. The results evidenced a high percentage of anxiety (25%) and distress symptoms (44%), whereas depressive symptoms seemed less frequent (8%). Psychological distress was higher in women than in men, and in patients with a higher educational level. Nevertheless, no significant differences were found between MP_Tis-Ia and MP_Ib–II. With respect to coping style, the patients in this sample adopted predominantly positive and active strategies. Correlational analyses showed that maladaptive coping strategies such as behavioral disengagement, denial, self-distraction, and self-blame were most strongly related to increased levels of psychological distress. The high presence of anxiety and distress symptoms, their relationship, and the use of negative coping strategies underline the importance of psychological distress screening also in early-stage MP, including at long-term follow-up.http://ift.tt/2oBAJBk
Altered integrin expression patterns shown by microarray in human cutaneous melanoma
A large variety of molecular pathways in melanoma progression suggests that no individual molecular alteration is crucial in itself. Our aim was to define the molecular alterations underlying metastasis formation. Gene expression profiling was performed using microarray and qRT-PCR to define alterations between matched primary and metastatic melanoma cell lines. These data were integrated with publicly available unmatched tissue data. The invasiveness of cell lines was determined by Matrigel invasion assays and invasive clones from primary melanoma-derived cell lines were also selected. Two metastatic cell line models were created: the regional lymph node WM983A–WM983AINV–WM983B and the distant lung WM793B–WM793BINV–1205Lu metastatic models. The majority of metastasis genes were downregulated and enriched in adhesion and ITGA6-B4 pathways. Upregulation of immune pathways was characteristic of distant metastases, whereas increased Rap1 signaling was specific for regional (sub)cutaneous metastases. qRT-PCR analysis of selected integrins (A2, A3, A4, A9, B5, B8, A6, B1, and B3) highlighted the possible importance of ITGA3/4 and B8 in the metastatic process, distinguishing regional and distant metastases. We identified functionally relevant gene clusters that influenced metastasis formation. Our data provide further evidence that integrin expression patterns may be important in distant metastasis formation.http://ift.tt/2oBsrt9
Characterization of melanoma susceptibility genes in high-risk patients from Central Italy
Genetic susceptibility to cutaneous melanoma has been investigated in Italian high-risk melanoma patients from different geographical regions. CDKN2A, CDK4, and MC1R genes have been screened in most studies, MITF and POT1 were screened in only one study, and none analyzed the TERT promoter. We carried out a mutational analysis of CDKN2A, CDK4 exon 2, POT1 p.S270N, MITF exon 10, MC1R, and the TERT promoter in 106 high-risk patients with familial melanoma (FM) and sporadic multiple primary melanoma (spMPM) from Central Italy and evaluated mutations according to the clinicopathological characteristics of patients and lesions. In FM, CDKN2A mutations were detected in 8.3% of the families, including one undescribed exon 1β mutation (p.T31M), and their prevalence increased with the number of affected relatives within the family. MC1R variants were identified in 65% of the patients and the TERT rs2853669 promoter polymorphism was identified in 58% of the patients. A novel synonymous mutation detected in MITF exon 10 (c.861A>G, p.E287E), although predicted as a splice site mutation by computational tools, could not functionally be confirmed to alter splicing. For spMPM, 3% carried CDKN2A mutations, 79% carried MC1R variants, and 47% carried the TERT rs2853669 promoter polymorphism. MC1R variants were associated with fair skin type and light hair color both in FM and in spMPM, and with a reduction of age at diagnosis in FM patients. Mutations in CDK4 exon 2 and the POT1 p.S270N mutation were not detected. A low frequency of CDKN2A mutations and a high prevalence of MC1R variants characterize high-risk melanoma patients from Central Italy.http://ift.tt/2oBx3jf
Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma
Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (Phttp://ift.tt/2oBx46N
A multireferral centre retrospective cohort analysis on the experience in treatment of metastatic uveal melanoma and utilization of sequential liver-directed treatment and immunotherapy
Metastatic uveal melanoma is a rare malignancy with a poor prognosis. To date, systemic therapy has been ineffective; however, there are few data on the benefits of anti-CTLA4 or anti-PD-1 antibodies in sequence with liver-directed therapy. A retrospective cohort analysis was carried out on 37 consecutive patients managed in a tertiary referral centre examining the safety and efficacy of treatment; patterns of care; and impact on survival. The sequential treatment with transarterial chemotherapy (TAC), systemic immunotherapy (IT) and systemic chemotherapy was reviewed. In all, 18 patients in the series received sequential therapy. The median overall survival (OS) was 17 months (n=37), which compared favourably with previously reported series. Patients treated with TAC first or second line had an overall progression-free survival (PFS) of 9 months (n=29) and IT PFS 7 months (n=26). The overall response rate (ORR) for TAC first line was 26% and the disease control rate (DCR) was 65% (n=23). ORR for IT first line was 7%, DCR 77% (n=14). Second-line (cross-over) IT ORR was 16%, DCR 58% (n=12). For second-line (cross-over) TAC, ORR was 50% and DCR was 66% (n=6). Toxicity was manageable. There were no cases of autoimmune hepatitis. In this retrospective small series analysis in uveal melanoma, liver-directed therapy and IT in sequence have shown to be active and reasonably well tolerated. Further prospective clinical trials should clarify the role of these treatments and their potential survival benefit.http://ift.tt/2oBzeTG
M1 and M2 macrophages’ clinicopathological significance in cutaneous melanoma
Skin malignant melanoma (MM) is an aggressive cancer with an increasing incidence with limited therapies in advanced stages. Tumor-associated macrophages (TAMs) are the major immune constituent of the MM microenvironment and contribute toward its prognosis. TAMs' characterization and localization in human cancer is important to understand cancer progression and to identify molecular personalized therapies. M2 TAMs in stage I–II MMs are associated with worse prognostic parameters. A comprehensive M1-macrophage and M2-macrophage intratumoral localization and quantification in all stages of skin MMs is documented here with its clinical significance. To highlight immune pathways and possible early indicators of MM progression, we evaluated the number of M1 and M2 TAMs and intratumoral distribution in a large series of skin MMs. CD68 double immunostaining with MRP8–14 or inducible nitric oxide synthase (M1 macrophages) and with CD163 or CD204 (M2 macrophages) was performed in 94 stage I–IV skin MMs with a long duration of follow-up. The accumulation and distribution of M1 and M2 TAMs in intratumoral nests, stroma, and at the invasive front was correlated with clinicopathological variables. Since the early stage of MMs, M1 intratumoral macrophages were fewer than the M2 population; their recruitment was rapidly and progressively overwhelmed by an increase in M2 TAMs during MM progression. Independent of their intratumoral distribution, the accumulation of both M1 and M2 TAMs is associated with poor prognostic indicators and patients' survival. M1-recruited macrophages shift to the M2 phenotype early in MM development, possibly induced by high inducible nitric oxide synthase intratumoral increase peculiarly occurring since the initial MM stages. M2-recruited TAMs overwhelm M1 accumulation in all stages of MM progression, thus favoring neoplastic growth and dissemination. Independent of their intratumoral distribution, the prevalent accumulation of M2 TAMs in MM is statistically confirmed to be a poor indicator of patients' outcome and a potential target of immune therapies.http://ift.tt/2oBkR1M
Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome
Drug reaction with eosinophilia and systemic symptom syndrome is a potentially fatal drug reaction that must be recognized quickly. Ipilimumab and nivolumab are both important agents in the treatment of melanoma and continue to be studied in other malignancies. We believe the mainstay of therapy for immunotherapy-induced drug reaction with eosinophilia and systemic symptom syndrome is early recognition, discontinuation of the inciting agent, supportive care, and treatment with high dose corticosteroids with appropriate tapers that may reduce the length of internal organ injury in cases with liver or kidney involvement.http://ift.tt/2oBorsC
The heterogeneity of tumor-infiltrating CD8+ T cells in metastatic melanoma distorts their quantification: how to manage heterogeneity?
CD8+ T-cell infiltration of metastatic melanoma may be a useful biomarker for prediction of prognosis and response to therapy. The heterogeneous distribution of CD8+ T cells within a single tumor, and across different tumors within a single patient, may complicate quantification of infiltration. However, the impact of heterogeneity has not been quantified sufficiently. To address this, we have assessed intratumoral heterogeneity of CD8+ T-cell counts, as well as intertumoral heterogeneity for synchronous and metachronous metastases. In a tissue microarray containing 189 melanoma metastases from 147 patients, the density of CD8+ T cells per sample was determined by immunohistochemistry. The mean density and coefficient of variation were calculated for each tumor and the rates of discordant values were determined. CD8 counts varied widely among different core samples of the same tumors (average coefficient of variation=0.77, 95% confidence interval: 0.70–0.85), with discordance occurring in 40% of tumors. CD8 densities were similar among pairs of simultaneous tumors; however, significant changes in CD8 densities were observed among 35 pairs of metachronous tumors. CD8+ T-cell density is not well represented by a single 1 mm diameter sample. Differences in CD8+ T-cell counts, observed in clinical trials, from pretreatment to post-treatment specimens may be explained by the spatial and temporal heterogeneity of CD8 distribution, especially if the assessed samples are small (i.e. 1 mm2). A sufficiently large biopsy of one of several synchronous tumors may be representative of CD8+ T-cell infiltration of a patient's disease.http://ift.tt/2oBu61O
The role of 5-hydroxymethylcytosine in melanoma
Malignant melanoma is a highly aggressive neoplasia of melanocytic origin. In part because of the lack of effective treatment methods, the incidence and mortality rates of this disease continue to increase. Rapidly accumulating evidence suggests that dysregulation of epigenetic mechanisms, including DNA methylation/demethylation, chromatin modification, and remodeling, and diverse activities of noncoding RNAs, play a central role in the pathogenesis of melanoma. The epigenetic mark 5-hydroxymethylcytosine (5-hmC) has attracted interest since 2009, when it was shown that ten-eleven translocation proteins can enzymatically convert 5-methylcytosine into 5-hmC, a key intermediate of DNA demethylation. Factors that regulate DNA hydroxymethylation are frequently altered in cancer, leading to deregulation of 5-hmC levels. In this review, we will discuss the relationship between melanoma and DNA hydroxymethylation, the regulation of DNA hydroxymethylation, and defects in this pathway in melanoma.http://ift.tt/2oBuais
Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma
The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.http://ift.tt/2oBiNqK
PET/CT surveillance detects asymptomatic recurrences in stage IIIB and IIIC melanoma patients: a prospective cohort study
AJCC stage IIIB and IIIC melanoma patients are at risk for disease relapse or progression. The advent of effective systemic therapies has made curative treatment of progressive disease a possibility. As resection of oligometastatic disease can confer a survival benefit and as immunotherapy is possibly most effective in a low tumor load setting, there is a likely benefit to early detection of progression. The aim of this pilot study was to evaluate a PET/computed tomography (CT) surveillance schedule for resected stage IIIB and IIIC melanoma. From 1–2015, stage IIIB and IIIC melanoma patients at our institution underwent 6-monthly surveillance with PET/CT, together with 3-monthly S100B assessment. When symptoms or elevated S100B were detected, an additional PET/CT was performed. Descriptive statistics were used to evaluate outcomes for this surveillance schedule. Fifty-one patients were followed up, 27 patients developed a recurrence before surveillance imaging, five were detected by an elevated S100B, and one patient was not scanned according to protocol. Eighteen patients were included. Thirty-two scans were acquired. Eleven relapses were suspected on PET/CT. Ten scans were true positive, one case was false positive, and one case was false negative. All recurrences detected by PET/CT were asymptomatic at that time, with a normal range of S100B. The number of scans needed to find one asymptomatic relapse was 3.6. PET/CT surveillance imaging seems to be an effective strategy for detecting asymptomatic recurrence in stage IIIB and IIIC melanoma patients in the first year after complete surgical resection.http://ift.tt/2oBAfv1
Clinical and dermoscopic features of truly amelanotic plantar melanoma
Currently, there are no specific clinical and dermoscopic features for diagnosing truly amelanotic plantar melanoma (TAPM). The present study aimed to investigate the dermoscopic features of all clinical variants of TAMPS and to evaluate their histopathological correlations. A retrospective analysis of prospectively collected data was carried out during a 10-year period (2003–2013). We analyzed the clinical data of 1321 patients, who had received a histological diagnosis of melanoma at the Melanoma Unit of the University of Florence. We selected the clinical and dermoscopic images of TAPMs and analyzed the presence of dermoscopic parameters. Incorrect preoperative diagnoses were analyzed to highlight peculiar dermoscopic features of pinkish plantar melanomas, the clinical diagnosis of which is extremely challenging for the dermatologist. Of all 1321 patients, 29 (24%) had TAPMs. Importantly, only 20.7% of patients with TAPMs had a correct preoperative diagnosis of suspicious melanocytic lesion. On the basis of the initial misdiagnosis, TAPMs were categorized as eczema-like, verruca-like, angioma-like lesions. Dermoscopically, all TAPMs showed the presence of a well-defined 'erythematous homogeneous area' with an atypical polymorphous vascular pattern with dotted, globular, and glomerular vessels. Our study highlights a crucial dermoscopic feature of TAPMs, the 'erythematous homogeneous area' that is characteristic of the plantar region, and, to our knowledge and experience, has not been described in nonacral amelanotic melanomas.http://ift.tt/2oBqlJT
β-Blocker use and reduced disease progression in patients with thick melanoma: 8 years of follow-up
Previous observational studies have reported the protective effect of β-blockers on the progression of different types of cancers. In 2011, we published a prospective study, including patients with histologically confirmed malignant melanoma in stage II–IIIA. In total, 25% of them reported previous use of β-blockers that were administered at any time for any other diseases. After a median follow-up of 2.5 years, 34% of the patients in the untreated group showed disease progression. In contrast, only 3% of the patients in the treated group showed progression. We report the findings obtained in the same cohort after a longer period of β-blocker therapy and follow-up (8 years). We prospectively reviewed data of the patients enrolled in the original prospective study. Disease progression was assessed by evaluating the presence of lymphatic, in-transit or visceral metastases. Deaths by any cause and deaths because of melanoma were recorded. A multivariate Cox proportional hazards model was used to evaluate the effect of β-blocker use on disease-free survival and overall survival, adjusting for significant confounders. After a median follow-up of 8 years and a median duration of β-blocker use of 7.6 years, 45% of the patients in the untreated group and 30% of the patients in the treated group showed disease progression. Notably, in the untreated group 35% patients died from melanoma and only 17% patients died from melanoma in the treated group. Results of this hospital-based prospective cohort study with a median follow-up of 8 years confirmed our previous results that the use of β-blockers significantly reduced the risk of recurrence and mortality in melanoma patients.http://ift.tt/2oBgHXO
Does the distribution pattern of brain metastases during BRAF inhibitor therapy reflect phenotype switching?
Brain metastases (brain mets) are frequent in metastatic melanoma patients. The aim of this study was to investigate the morphology and progression pattern of brain mets in melanoma patients treated with BRAF inhibitors (BRAFi) compared with patients who did not receive targeted therapy (BRAFi group and control group). The number and size of brain mets were compared between a baseline and a comparative MRI at progression. The number of brain mets was grouped into seven number classes (N=1–4, N=5–10, N=11–20, N=21–30, N=31–40, N=41–50, and N>50) and its difference was reported as the change of class that occurred. The mean size of the newly developed lesions was determined by representative measurements and the evolution of three persisting target lesions was assessed on the basis of modified RECIST criteria. Of 96 patients studied, 42 were in the BRAFi group and 54 were in the control group. Patients under BRAFi treatment had a significantly greater increase in the number of brain mets, where the median change of class for the BRAFi compared with the control group was 2 versus 0 (Phttp://ift.tt/2oBnTmN
Lymph nodes’ capsular naevi are associated with high naevus count in melanoma patients: a case–control study
Capsular naevi (CNs) in lymph nodes (LNs) are relatively common, occurring in 3–22% of patients who undergo LN surgery for melanoma. Naevus count is one of the principal risk factors for melanoma, as well as a prognostic factor in melanoma patients. However, little is known about the occurrence of CN in melanoma patients on the basis of their naevus count. A case–control study was performed, to look at the naevus count differences between CN-positive and CN-negative melanoma patients. Cases (CN positive) were matched for age, sex and Breslow thickness with controls (CN negative). Total naevus count was recorded at diagnosis and compared between the two groups. This study was conducted in a tertiary referral academic centre for skin cancer. Twenty-two positive CN patients were matched with 22 negative CN patients. The mean Breslow thickness was 2.66 mm (range: 0.6–9). Positive CN patients were significantly associated with an increasing naevus count on their skin (P=0.02). Patients with more than 100 naevi reported an odds ratio of 7.78 on having a CN compared with patients with fewer than 50 naevi on their skin (P=0.02). An increased melanocytic migration to LNs might be the reason for the association between CNs and a high number of melanocitic naevi on the skin. This could shed some light on the physiology of melanocytes and could be an easy way to predict patients at greater risk of having CNs.http://ift.tt/2oBqlcR
Interactions from complementary and alternative medicine in patients with melanoma
Biological-based (BbCAM) methods from complementary and alternative medicine (CAM) may interact with cancer treatments, reduce efficacy, or enhance adverse effects. Although CAM usage has been evaluated well in other cancer entities, data on melanoma patients are still missing. The aim of this study was to determine CAM usage of melanoma patients using a standardized questionnaire to identify potential interactions with established and new systemic melanoma therapies. This multicenter study was carried out in seven German skin cancer centers. During routine care contact, CAM usage of former and current melanoma treatment was assessed in melanoma patients. The probability of interaction was classified into four categories ranging from 'interaction unlikely' (I), 'possible' (II), 'likely' (III), or 'no data' (IV). The questionnaire was filled out by 1157 patients, of whom 1089 were eligible for evaluation. CAM usage was reported by 41% of melanoma patients, of whom 63.1% took BbCAM such as vitamins, trace elements, supplements, or phytotherapeuticals. Of 335 patients with former or current therapy, 28.1% used BbCAM. The melanoma treatment included interferon, radiotherapy, chemotherapy, BRAF-inhibitor, or other tyrosine kinase inhibitors and ipilimumab. On the basis of our model of likelihood of interaction, we found that 23.9% of those on cancer therapy and 85.1% of those also using BbCAM were at some risk of interactions. The main limitation of our study is that no reliable and comprehensive database on clinical relevant interactions with CAM in oncology exists. Most patients receiving a melanoma-specific treatment and using BbCAM methods are at risk for interactions, which raises concerns on the safety and treatment efficacy of these patients. To protect melanoma patients from potential harm by the combination of their cancer treatment and CAM usage, patients should systematically be encouraged to report their CAM use, while oncologists should be trained on evidence of CAM, and patient guidance for saver CAM use.http://ift.tt/2oBhtDX
BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response
BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29–341) days. The median follow-up after BRAFi initiation was 769 (435–1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27–322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34–322) days versus 82 (27–144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15–425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.http://ift.tt/2oBu6ik
HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia
Abstract
Background
Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH).
Methods
The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16+ uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry.
Results
Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4+ and/or CD8+ T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1β (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients.
Conclusion
DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.
http://ift.tt/2qbWnw1
KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma
Abstract
It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
http://ift.tt/2oNkMmI
Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy
Abstract
Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.
http://ift.tt/2oPSuZQ
HPV16 E7 DNA tattooing: safety, immunogenicity, and clinical response in patients with HPV-positive vulvar intraepithelial neoplasia
Abstract
Background
Usual type vulvar intraepithelial neoplasia (uVIN) is caused by HPV, predominantly type 16. Several forms of HPV immunotherapy have been studied, however, clinical results could be improved. A novel intradermal administration route, termed DNA tattooing, is superior in animal models, and was tested for the first time in humans with a HPV16 E7 DNA vaccine (TTFC-E7SH).
Methods
The trial was designed to test safety, immunogenicity, and clinical response of TTFC-E7SH in twelve HPV16+ uVIN patients. Patients received six vaccinations via DNA tattooing. The first six patients received 0.2 mg TTFC-E7SH and the next six 2 mg TTFC-E7SH. Vaccine-specific T-cell immunity was evaluated by IFNγ-ELISPOT and multiparametric flow cytometry.
Results
Only grade I-II adverse events were observed upon TTFC-E7SH vaccination. The ELISPOT analysis showed in 4/12 patients a response to the peptide pool containing shuffled E7 peptides. Multiparametric flow cytometry showed low CD4+ and/or CD8+ T-cell responses as measured by increased expression of PD-1 (4/12 in both), CTLA-4 (2/12 and 3/12), CD107a (5/12 and 4/12), or the production of IFNγ (2/12 and 1/12), IL-2 (3/12 and 4/12), TNFα (2/12 and 1/12), and MIP1β (3/12 and 6/12). At 3 months follow-up, no clinical response was observed in any of the twelve vaccinated patients.
Conclusion
DNA tattoo vaccination was shown to be safe. A low vaccine-induced immune response and no clinical response were observed in uVIN patients after TTFC-E7SH DNA tattoo vaccination. Therefore, a new phase I/II trial with an improved DNA vaccine format is currently in development for patients with uVIN.
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KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma
Abstract
It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
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Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy
Abstract
Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.
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Increased risk of paclitaxel-induced peripheral neuropathy in patients using clopidogrel: a retrospective pilot study
Abstract
Paclitaxel-induced peripheral neuropathy (PIPN) is one of the serious adverse events associated with paclitaxel-based cancer treatments. A recent case study showed that the antiplatelet agent clopidogrel inhibits paclitaxel metabolism via cytochrome P450 (CYP) 2C8, resulting in severe PIPN. The aim of this study was to determine the impact of clopidogrel as a risk factor for the development of PIPN, using a retrospective cohort study. Data from paclitaxel-treated patients with or without clopidogrel and low-dose aspirin treatment were retrieved from medical charts. A total of 161 adult patients were included in this study: 135 were controls, 9 were clopidogrel-treated and 17 were aspirin-treated. The clopidogrel group had a greater proportion of males and a higher rate of comorbidities, such as diabetes mellitus and dyslipidemia, than the control group. However, patient characteristics were similar between the clopidogrel and aspirin groups. Severe PIPN was diagnosed in 3 (2.2%) and 2 (22.2%) patients in the control and clopidogrel groups, respectively (odds ratio: 12.0; p = 0.031). No patients in the aspirin group presented with severe neuropathy. These pilot data suggest that concomitant treatment with clopidogrel leads to a greater risk of PIPN. The avoidance of concomitant clopidogrel use may be effective in reducing clopidogrel-associated PIPN.
http://ift.tt/2pDBLwO
Temporalis Muscle Flap in Head and Neck Reconstructions Is That Forgotten or Forbidden? Our Case Series and Review of Literature
Abstract
Temporalis muscle flap is a versatile flap which can be used for reconstruction after major head and neck resections, owing to its optimal bulk, constant and reliable vascularity, ease of access to recipient site, minimal donor site morbidity and relatively better cosmetic outcome compared to more bulky flaps like pectoralis major myocutaneous flap or deltopectoral flap. The flap can be used as a muscle flap, myofascial flap (muscle with temporalis fascia). We present our series of 12 cases of temporalis muscle flap reconstruction for various head and neck reconstructions. The aim of this study was to analyse the application of temporalis muscle flap in head and neck reconstructions and its outcome.
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Temporalis Muscle Flap in Head and Neck Reconstructions Is That Forgotten or Forbidden? Our Case Series and Review of Literature
Abstract
Temporalis muscle flap is a versatile flap which can be used for reconstruction after major head and neck resections, owing to its optimal bulk, constant and reliable vascularity, ease of access to recipient site, minimal donor site morbidity and relatively better cosmetic outcome compared to more bulky flaps like pectoralis major myocutaneous flap or deltopectoral flap. The flap can be used as a muscle flap, myofascial flap (muscle with temporalis fascia). We present our series of 12 cases of temporalis muscle flap reconstruction for various head and neck reconstructions. The aim of this study was to analyse the application of temporalis muscle flap in head and neck reconstructions and its outcome.
http://ift.tt/2p8chGp
KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma
Abstract
It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
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Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study
Abstract
Objective
Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT.
Methods
Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin–etoposide–cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease.
Results
Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4–92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II–IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6–100%) and 84.5% (95% CI: 76.5–93.5%).
Conclusions
We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.
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The frequency of QTc prolongation among pediatric and young adult patients receiving methadone for cancer pain
Abstract
Introduction
A prolonged corrected QT (QTc) interval in pediatric patients is defined as ≥470 msec. Methadone can cause a prolonged QTc interval that can lead to ventricular arrhythmias. The risk of methadone-induced prolongation of the QTc interval in children and young adults is unknown. The purpose of the study was to determine the frequency of QTc prolongation among pediatric and young adult patients with cancer pain on methadone treatment.
Methods
We retrospectively reviewed data for all patients on methadone during the study period. Qualifying patient data were reviewed to determine whether these patients had an electrocardiogram (ECG) while on methadone. The QTc values for analysis were manually calculated using the standard formula described by Bazett.
Results
Twenty-five patients were identified that met eligibility criteria. The median QTc decreased from baseline after initiation of methadone. QTc prolongation occurred in four of 25 (16%) patients and only one patient had a QTc greater than 500 msec. This patient had 17 normal QTc intervals on methadone prior to the prolongation. After resolution of electrolyte abnormalities, six subsequent ECGs on methadone had a normal QTc interval.
Conclusions
Prolongation of the QTc interval is infrequent. The only observed case was transient during multiple comorbid conditions. A prospective study is justified to better understand what role methadone plays as one of many risk factors for prolongation of the QTc interval in children and young adults.
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Effects of malnutrition on treatment-related morbidity and survival of children with cancer in Nicaragua
Abstract
Background
Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions.
Procedure
We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS).
Results
Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05–10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015).
Conclusions
In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes.
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A phase 1 study of the c-Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors: A Children's Oncology Group study phase 1 and pilot consortium trial (ADVL1111)
Abstract
Background
The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors.
Methods
Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2/dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed.
Results
Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response.
Conclusions
The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2/dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.
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Characterization of the anti-CD22 targeted therapy, moxetumomab pasudotox, for B-cell precursor acute lymphoblastic leukemia
Abstract
Moxetumomab pasudotox is a second-generation recombinant immunotoxin against CD22 on B-cell lineages. Antileukemic activity has been demonstrated in children with chemotherapy-refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL), with variable responses. Here, we report in vitro and in vivo evaluation of moxetumomab pasudotox treatment of human cell lines and patient-derived cells as a preliminary study to understand characteristics of sensitivity to treatment. Binding, internalization, and apoptosis were evaluated using fluorescently tagged moxetumomab pasudotox. Studies in NOD-scid IL2Rgnull mice showed a modest survival benefit in mice engrafted with 697 cells but not in NALM6 or the two patient-derived xenograft models.
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Evaluation of the utility of 99mTc-MDP bone scintigraphy versus MIBG scintigraphy and cross-sectional imaging for staging patients with neuroblastoma
Abstract
Purpose
Accurate staging of neuroblastoma requires multiple imaging examinations. The purpose of this study was to determine the relative contribution of 99mTc-methylene diphosphonate (MDP) bone scintigraphy (bone scan) versus metaiodobenzylguanidine scintigraphy (MIBG scan) for accurate staging of neuroblastoma.
Methods
A medical record search by the identified patients with neuroblastoma from 1993 to 2012 who underwent both MIBG and bone scan for disease staging. Cross-sectional imaging was used to corroborate the scintigraphy results. Clinical records were used to correlate imaging findings with clinical staging and patient management.
Results
One hundred thirty-two patients underwent both MIBG and bone scan for diagnosis. All stage 1 (n = 12), 2 (n = 8), and 4S (n = 4) patients had a normal bone scan with no skeletal MIBG uptake. Six of 30 stage 3 patients had false (+) bone scans. In the 78 stage 4 patients, 58/78 (74%) were both skeletal MIBG(+)/bone scan (+). In 56 of the 58 cases, skeletal involvement detected with MIBG was equal to or greater than that detected by bone scan. Only 3/78 had (–) skeletal MIBG uptake and (+) bone scans; all 3 had other sites of metastatic disease. Five of 78 had (+) skeletal MIBG with a (–) bone scan, while 12/78 had no skeletal involvement by either MIBG or bone scan. In no case did a positive bone scan alone determine a stage 4 designation.
Conclusion
In the staging of neuroblastoma, 99mTc-MDP bone scintigraphy does not identify unique sites of disease that affect disease stage or clinical management, and in the majority of cases bone scans can be omitted from the routine neuroblastoma staging algorithm.
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Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study
Abstract
Objective
Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT.
Methods
Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin–etoposide–cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease.
Results
Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4–92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II–IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6–100%) and 84.5% (95% CI: 76.5–93.5%).
Conclusions
We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.
http://ift.tt/2pmhdWK
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