Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers doi: 10.3390/cancers10030064

Authors: Cosimo Lobello Vasilis Bikos Andrea Janikova Sarka Pospisilova

Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.

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Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers, Vol. 10, Pages 64: The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability

Cancers doi: 10.3390/cancers10030064

Authors: Cosimo Lobello Vasilis Bikos Andrea Janikova Sarka Pospisilova

Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.

http://ift.tt/2tfjEjD

Development of a Measurement Tool to Assess Students’ Knowledge and Perceptions About Cancer (SKPaC)

Abstract

Cancer literacy is currently one of the most important dimensions of cancer continuum. Objective assessment of cancer knowledge in populations remains a challenging field to public health entities. Different evaluation tools are currently available; still, some groups remain disregarded due to the absence of validated instruments. Cancer literacy in adolescents and young adults has been clearly overlooked being a subject that requires new tools to be properly studied. To address this topic, we developed a new instrument and field tested it in a classroom environment for internal reliability, construct, and face validity. "Students Knowledge and Perceptions about Cancer questionnaire" was designed in Portuguese language and adapted to the Portuguese context by a multidisciplinary team. The final version of the questionnaire includes 35 items organized in three sections, encompassing knowledge and perceptions about cancer and socio-biographic data. Cancer experts ensured content validity, while tailoring of contents was refined with high school teachers. Test and retest of the instrument showed a good reliability of the scale and construct validity. Also, the clarity of the questionnaire and suitability to proper evaluate cancer knowledge was consistent between test and retest. The Students' Knowledge and Perceptions About Cancer Questionnaire (SKPaC) showed to be a valid tool to assess adolescents' knowledge and perceptions about cancer that can be used in the educational context.

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Development of a Measurement Tool to Assess Students’ Knowledge and Perceptions About Cancer (SKPaC)

Abstract

Cancer literacy is currently one of the most important dimensions of cancer continuum. Objective assessment of cancer knowledge in populations remains a challenging field to public health entities. Different evaluation tools are currently available; still, some groups remain disregarded due to the absence of validated instruments. Cancer literacy in adolescents and young adults has been clearly overlooked being a subject that requires new tools to be properly studied. To address this topic, we developed a new instrument and field tested it in a classroom environment for internal reliability, construct, and face validity. "Students Knowledge and Perceptions about Cancer questionnaire" was designed in Portuguese language and adapted to the Portuguese context by a multidisciplinary team. The final version of the questionnaire includes 35 items organized in three sections, encompassing knowledge and perceptions about cancer and socio-biographic data. Cancer experts ensured content validity, while tailoring of contents was refined with high school teachers. Test and retest of the instrument showed a good reliability of the scale and construct validity. Also, the clarity of the questionnaire and suitability to proper evaluate cancer knowledge was consistent between test and retest. The Students' Knowledge and Perceptions About Cancer Questionnaire (SKPaC) showed to be a valid tool to assess adolescents' knowledge and perceptions about cancer that can be used in the educational context.

http://ift.tt/2tdlxNw

Nicorandil increased the cerebral blood flow via nitric oxide pathway and ATP-sensitive potassium channel opening in mice

Abstract

Purpose

Nicorandil has dual properties and acts as a nitric oxide donor and an ATP-sensitive potassium (K_ATP) channel opener. Considering its pharmacological profile, nicorandil might exert protective effects on the brain as well as on the heart. The purpose of this study was to directly evaluate the effect of nicorandil on cerebral blood flow (CBF) in mice using a transcranial Doppler method.

Methods

Under general anesthesia, the nicorandil groups received a single-bolus intraperitoneal injection of the respective doses of nicorandil (1, 5, or 10 mg/kg), while the control group received vehicle only. CBF was measured using a transcranial Doppler flowmeter. N^G-nitro-l-arginine methyl ester and glibenclamide were used to elucidate the underlying mechanisms.

Results

A single-bolus injection of 1 mg/kg of nicorandil increased the CBF (11.6 ± 3.6 vs. 0.5 ± 0.7%, p < 0.001) without affecting the heart rate and blood pressure. On the contrary, 5 and 10 mg/kg of nicorandil significantly decreased the cerebral blood flow by decreasing the mean blood pressure below the cerebral autoregulation range. The positive effect of 1 mg/kg of nicorandil on the cerebral blood flow was inhibited by co-administration of either N^G-nitro-l-arginine methyl ester or glibenclamide.

Conclusions

A clinical dose of nicorandil increases CBF without affecting systemic hemodynamics. The positive effect of nicorandil on CBF is most likely caused via both the nitric oxide pathway and K_ATP channel opening.

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Marshaling the Translational Potential of MC1R for Precision Risk Assessment of Melanoma

Melanoma rates have been increasing in the United States, and neither primary (sun protection and avoidance) nor secondary (skin examination) prevention is practiced consistently, even by those with melanoma risk factors. Inherited variation at MC1R is a robust marker for increased risk of melanoma, even among individuals with "sun-resistant" phenotypes. Although MC1R conveys important information about inherited melanoma risk for a broad spectrum of individuals, concerns that MC1R feedback could have negative consequences, including increased distress about melanoma, inappropriate use of health services, and development of a false sense of security, are valid and require empirical examination. The time is right for high-quality research focusing on the translation of MC1R genotype into clinical and public health practice. If studies show MC1R genetic risk screening is effective at motivating behavior change, more melanomas may be detected at earliest stages for which surgical excision is highly curative or a large number of melanomas may be prevented altogether. While other genetic markers for melanoma susceptibility may emerge in the coming years, the burgeoning research agenda on the public health translational potential of MC1R genetic risk screening will inform and usefully advance current and future precision risk assessment of melanoma. Cancer Prev Res; 11(3); 121–4. ©2017 AACR.

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Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity

We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (P < 0.05) and mutagenesis (P = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (P < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly (P < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. Cancer Prev Res; 11(3); 157–64. ©2017 AACR.

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Targeting Epigenetics to Prevent Obesity Promoted Cancers

Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue–promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity–cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125–8. ©2018 AACR.

See related article by Chakraborty et al., p. 129

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Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143–56. ©2017 AACR.

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A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo. We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivo. Cancer Prev Res; 11(3); 129–42. ©2017 AACR.

See related editorial by Berger and Scacheri, p. 125

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Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21-39 Years

Cervical intraepithelial neoplasia grade 2 (CIN2) frequently regresses, is typically slow-growing, and rarely progresses to cancer. Some women forgo immediate treatment, opting for conservative management (heightened surveillance with cytology and colposcopy), to minimize overtreatment and increased risk of obstetric complications; however, there are limited data examining clinical outcomes in these women. We performed a retrospective cohort analysis of younger women diagnosed with initially untreated CIN1/2, CIN2 and CIN2/3 lesions at Kaiser Permanente Northern California between 2003 and 2015. Clinical outcomes were categorized into five mutually exclusive hierarchical groups: cancer, treated, returned to routine screening, persistent high-grade lesion, or persistent low-grade lesion. Median follow-up for the 2,417 women was 48 months. Six women were diagnosed with cancer (0.2%), all with history of high-grade cytology, and none after a negative cotest. Thirty percent of women were treated, and only 20% returned to routine screening; 50% remained in continued intensive follow-up, of which 86% had either low-grade cytology/histology or high-risk human papillomavirus (HPV) positivity, but not necessarily persistence of a single HPV type. No cancers were detected after a single negative cotest in follow-up. Almost half of initially untreated women did not undergo treatment, but remained by protocol in colposcopy clinic for 2 or more years in the absence of persisting CIN2⁺. Their incomplete return to total negativity was possibly due to sequential new and unrelated low-grade abnormalities. The prolonged colposcopic surveillance currently required to return to routine screening in the absence of persisting CIN2⁺ might not be necessary after a negative cotest.

Significance: Many younger women under conservative management following an initial CIN2 result remain in a clinical protocol of prolonged intensified surveillance without a subsequent diagnosis of CIN2 or more severe diagnoses. More research is needed to determine whether such prolonged management might be unnecessary following a negative cotest for those women with an initial CIN2 but otherwise only low-grade findings. Cancer Prev Res; 11(3); 165–70. ©2018 AACR.

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Marshaling the Translational Potential of MC1R for Precision Risk Assessment of Melanoma

Melanoma rates have been increasing in the United States, and neither primary (sun protection and avoidance) nor secondary (skin examination) prevention is practiced consistently, even by those with melanoma risk factors. Inherited variation at MC1R is a robust marker for increased risk of melanoma, even among individuals with "sun-resistant" phenotypes. Although MC1R conveys important information about inherited melanoma risk for a broad spectrum of individuals, concerns that MC1R feedback could have negative consequences, including increased distress about melanoma, inappropriate use of health services, and development of a false sense of security, are valid and require empirical examination. The time is right for high-quality research focusing on the translation of MC1R genotype into clinical and public health practice. If studies show MC1R genetic risk screening is effective at motivating behavior change, more melanomas may be detected at earliest stages for which surgical excision is highly curative or a large number of melanomas may be prevented altogether. While other genetic markers for melanoma susceptibility may emerge in the coming years, the burgeoning research agenda on the public health translational potential of MC1R genetic risk screening will inform and usefully advance current and future precision risk assessment of melanoma. Cancer Prev Res; 11(3); 121–4. ©2017 AACR.

http://ift.tt/2FgNcP8

Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity

We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (P < 0.05) and mutagenesis (P = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (P < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly (P < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. Cancer Prev Res; 11(3); 157–64. ©2017 AACR.

http://ift.tt/2FSQPft

Targeting Epigenetics to Prevent Obesity Promoted Cancers

Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET-762 can attenuate adipose tissue–promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments provide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity–cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combination, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125–8. ©2018 AACR.

See related article by Chakraborty et al., p. 129

http://ift.tt/2D11pO9

Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762

Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143–56. ©2017 AACR.

http://ift.tt/2FSAHKM

A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo. We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivo. Cancer Prev Res; 11(3); 129–42. ©2017 AACR.

See related editorial by Berger and Scacheri, p. 125

http://ift.tt/2CZdymX

Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21-39 Years

Cervical intraepithelial neoplasia grade 2 (CIN2) frequently regresses, is typically slow-growing, and rarely progresses to cancer. Some women forgo immediate treatment, opting for conservative management (heightened surveillance with cytology and colposcopy), to minimize overtreatment and increased risk of obstetric complications; however, there are limited data examining clinical outcomes in these women. We performed a retrospective cohort analysis of younger women diagnosed with initially untreated CIN1/2, CIN2 and CIN2/3 lesions at Kaiser Permanente Northern California between 2003 and 2015. Clinical outcomes were categorized into five mutually exclusive hierarchical groups: cancer, treated, returned to routine screening, persistent high-grade lesion, or persistent low-grade lesion. Median follow-up for the 2,417 women was 48 months. Six women were diagnosed with cancer (0.2%), all with history of high-grade cytology, and none after a negative cotest. Thirty percent of women were treated, and only 20% returned to routine screening; 50% remained in continued intensive follow-up, of which 86% had either low-grade cytology/histology or high-risk human papillomavirus (HPV) positivity, but not necessarily persistence of a single HPV type. No cancers were detected after a single negative cotest in follow-up. Almost half of initially untreated women did not undergo treatment, but remained by protocol in colposcopy clinic for 2 or more years in the absence of persisting CIN2⁺. Their incomplete return to total negativity was possibly due to sequential new and unrelated low-grade abnormalities. The prolonged colposcopic surveillance currently required to return to routine screening in the absence of persisting CIN2⁺ might not be necessary after a negative cotest.

Significance: Many younger women under conservative management following an initial CIN2 result remain in a clinical protocol of prolonged intensified surveillance without a subsequent diagnosis of CIN2 or more severe diagnoses. More research is needed to determine whether such prolonged management might be unnecessary following a negative cotest for those women with an initial CIN2 but otherwise only low-grade findings. Cancer Prev Res; 11(3); 165–70. ©2018 AACR.

http://ift.tt/2FSVLAJ

Can Prostate Imaging Reporting and Data System Version 2 reduce unnecessary prostate biopsies in men with PSA levels of 4–10 ng/ml?

Abstract

Purpose

To explore the value of Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) for predicting prostate biopsy results in patients with prostate specific antigen (PSA) levels of 4–10 ng/ml.

Methods

We retrospectively reviewed multi-parameter magnetic resonance images from 528 patients with PSA levels of 4–10 ng/ml who underwent transrectal ultrasound-guided prostate biopsies between May 2015 and May 2017. Among them, 137 were diagnosed with prostate cancer (PCa), and we further subdivided them according to pathological results into the significant PCa (S-PCa) and insignificant significant PCa (Ins-PCa) groups (121 cases were defined by surgical pathological specimen and 16 by biopsy). Age, PSA, percent free PSA, PSA density (PSAD), prostate volume (PV), and PI-RADS score were collected. Logistic regression analysis was performed to determine predictors of pathological results. Receiver operating characteristic curves were constructed to analyze the diagnostic value of PI-RADS v2 in PCa.

Results

Multivariate analysis indicated that age, PV, percent free PSA, and PI-RADS score were independent predictors of biopsy findings, while only PI-RADS score was an independent predictor of S-PCa (P < 0.05). The areas under the receiver operating characteristic curve for diagnosing PCa with respect to age, PV, percent free PSA, and PI-RADS score were 0.570, 0.430, 0.589 and 0.836, respectively. The area under the curve for diagnosing S-PCa with respect to PI-RADS score was 0.732. A PI-RADS score of 3 was the best cutoff for predicting PCa, and 4 was the best cutoff for predicting S-PCa. Thus, 92.8% of patients with PI-RADS scores of 1–2 would have avoided biopsy, but at the cost of missing 2.2% of the potential PCa cases. Similarly, 83.82% of patients with a PI-RADS score ≤ 3 would have avoided biopsy, but at the cost of missing 3.3% of the potential S-PCa cases.

Conclusions

PI-RADS v2 could be used to reduce unnecessary prostate biopsies in patients with PSA levels of 4–10 ng/ml.

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Can Prostate Imaging Reporting and Data System Version 2 reduce unnecessary prostate biopsies in men with PSA levels of 4–10 ng/ml?

Abstract

Purpose

To explore the value of Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2) for predicting prostate biopsy results in patients with prostate specific antigen (PSA) levels of 4–10 ng/ml.

Methods

We retrospectively reviewed multi-parameter magnetic resonance images from 528 patients with PSA levels of 4–10 ng/ml who underwent transrectal ultrasound-guided prostate biopsies between May 2015 and May 2017. Among them, 137 were diagnosed with prostate cancer (PCa), and we further subdivided them according to pathological results into the significant PCa (S-PCa) and insignificant significant PCa (Ins-PCa) groups (121 cases were defined by surgical pathological specimen and 16 by biopsy). Age, PSA, percent free PSA, PSA density (PSAD), prostate volume (PV), and PI-RADS score were collected. Logistic regression analysis was performed to determine predictors of pathological results. Receiver operating characteristic curves were constructed to analyze the diagnostic value of PI-RADS v2 in PCa.

Results

Multivariate analysis indicated that age, PV, percent free PSA, and PI-RADS score were independent predictors of biopsy findings, while only PI-RADS score was an independent predictor of S-PCa (P < 0.05). The areas under the receiver operating characteristic curve for diagnosing PCa with respect to age, PV, percent free PSA, and PI-RADS score were 0.570, 0.430, 0.589 and 0.836, respectively. The area under the curve for diagnosing S-PCa with respect to PI-RADS score was 0.732. A PI-RADS score of 3 was the best cutoff for predicting PCa, and 4 was the best cutoff for predicting S-PCa. Thus, 92.8% of patients with PI-RADS scores of 1–2 would have avoided biopsy, but at the cost of missing 2.2% of the potential PCa cases. Similarly, 83.82% of patients with a PI-RADS score ≤ 3 would have avoided biopsy, but at the cost of missing 3.3% of the potential S-PCa cases.

Conclusions

PI-RADS v2 could be used to reduce unnecessary prostate biopsies in patients with PSA levels of 4–10 ng/ml.

http://ift.tt/2FTG4JA

Effects of Intraneural Injection of Dexmedetomidine in Combination With Ropivacaine in Rat Sciatic Nerve Block

Background and Objectives Dexmedetomidine is known to have neural protection effect via attenuation of inflammatory responses induced by local anesthetics. We investigated whether intraneural dexmedetomidine is effective for attenuating or preventing neural injury resulting from inadvertent intraneural injection of local anesthetic. Methods Rats were randomly divided, and left sciatic nerve was surgically exposed. The rats received no injection (control group) or intraneural injections of 0.2 mL of normal saline (saline group), 0.2 mL of 0.5% ropivacaine (ropivacaine group), or 0.2 mL of 0.5% ropivacaine and 0.5 μg/kg of dexmedetomidine (ropivacaine plus dexmedetomidine group). Interleukin (IL)-6 and IL-1β messenger RNA (mRNA) levels were detected at 60 minutes after intraneural injection in experiment 1 (5 per group). Sensory and motor functions were assessed until the return of normal sensory and motor functions, and histopathological and ultrastructure analysis were performed at 4 weeks after intraneural injection in experiment 2 (8 per group). Results Dexmedetomidine with ropivacaine better enhanced sensory and motor blockade than ropivacaine alone. IL-6 (3.2 ± 1.0 vs 5.9 ± 2.1), IL-1β (1.1 ± 0.1 vs 2.2 ± 0.7) levels, scores of axon and myelinated fiber degeneration (1 [0–2] vs 2 [1–3]), and demyelinated fiber percentages (20.1 ± 10.4 vs 48.3 ± 12.7) were lower in the ropivacaine plus dexmedetomidine group than in the ropivacaine group. No animals showed any signs of permanent neurological deficit. Conclusions Intraneural dexmedetomidine has sensory and motor blockade-enhancing effects, anti-inflammatory properties, and protective effects against neural injury. These findings suggest that dexmedetomidine as an adjuvant has beneficial effects in rat when intraneural injection of local anesthetic occurs. Accepted for publication October 4, 2017. Address correspondence to: Deok-hee Lee, MD, PhD, Department of Anesthesiology and Pain Medicine, College of Medicine, Yeungnam University, 170, Hyeonchung-ro, Nam-gu, Daegu, Republic of Korea (e-mail: dhlee415@ynu.ac.kr). The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Classic biphasic pulmonary blastoma: a case report and review of the literature

Publication date: Available online 3 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Hervé Le Caer




http://ift.tt/2CZHUWf

Classic biphasic pulmonary blastoma: a case report and review of the literature

Publication date: Available online 3 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Hervé Le Caer




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Intraoperative Neuromonitoring During Sciatic Nerve Schwanomma Excision: Utility of Evoked Potentials

No abstract available

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Renal Interstitial Exhaustion and SGLT2 Blockers

No abstract available

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Pulse Pressure and Carotid Artery Doppler Velocimetry as Indicators of Maternal Volume Status: A Prospective Cohort Study

BACKGROUND: Narrow pulse pressure has been demonstrated to indicate low central volume status. In critically ill patients, volume status can be qualitatively evaluated using Doppler velocimetry to assess hemodynamic changes in the carotid artery in response to autotransfusion with passive leg raise (PLR). Neither parameter has been prospectively evaluated in an obstetric population. The objective of this study was to determine if pulse pressure could predict the response to autotransfusion using carotid artery Doppler in healthy intrapartum women. We hypothesized that the carotid artery Doppler response to PLR would be greater in women with a narrow pulse pressure, indicating relative hypovolemia. METHODS: Intrapartum women with singleton gestations ≥35 weeks without acute or chronic medical conditions were recruited to this prospective cohort study. Participants were grouped by admission pulse pressure as

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The Amazing Language of Medicine: Understanding Medical Terms and Their Backstories

No abstract available

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The Effect of Repeated Versus Initial Procalcitonin Measurements on Diagnosis of Infection in the Intensive Care Setting: A Prospective Observational Study

Procalcitonin (PCT) measurement has been proposed to direct antibiotic use. We examined whether repeated PCT measurements (0, 6, and/or 12 hours) versus the initial measurement only (time 0) increased the sensitivity and specificity of PCT for diagnosing infection in intensive care unit patients. Infection was identified in 67/176 (38%) patients. The sensitivity of repeated versus the initial PCT measurement (with a cutoff value 0.5 ng/mL) was 52/67 (77%; 95% confidence interval [CI], 66%–87%) vs 46/67 (69%; 95% CI, 56%–79%; P = .04) and specificity 60/109 (55%; 95% CI, 45%–65%) vs 59/109 (54%; 95% CI, 44%–64%; P = 1.0). Repeat PCT evaluations over 12 hours did not provide a clinically significant improvement in diagnostic accuracy when compared to the initial single test. Accepted for publication January 17, 2018. P. D. Levin and M. J. Cohen contributed equally to this article. Funding: This study was supported by Brahms and Siemens, which provided the procalcitonin kits at no cost. The authors declare no conflicts of interest. The information in this study was presented in part at the European Society of Intensive Care Medicine (ESICM) 27th Annual Congress, Barcelona, 2014. Reprints will not be available from the authors. Address correspondence to Shmuel Benenson, MD, MSc, Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem 9112001, Israel. Address e-mail to Benenson@Hadassah.org.il. © 2018 International Anesthesia Research Society

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Description of a Novel Set-Up for Functional Echocardiographic Assessment of Left Ventricular Performance During Ex Vivo Heart Perfusion

Ex vivo heart perfusion (EVHP) is a new technology aimed at decreasing cold ischemia time and evaluating cardiac function before transplanting a donor heart. In an experimental EVHP swine model, we tested a 3D-printed custom-made set-up to perform surface echocardiography on an isolated beating heart during left ventricular loading. The views obtained at any time point were equivalent to standard transesophageal and transthoracic views. A decrease in left ventricular function during EVHP was observed in all experiments. Accepted for publication December 29, 2017. Funding: This study was supported by the Peter Munk Cardiac Foundation, private donation, and the University of Toronto Anesthesia Merit Award. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Massimiliano Meineri, MD, FASE, Department of Anesthesia, Toronto General Hospital, 200 Elizabeth St EN 3–442, Toronto, ON, M5G 2C4, Canada. Address e-mail to Massimiliano.Meineri@uhn.ca. © 2018 International Anesthesia Research Society

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The Association of Targeted Cell Salvage Blood Transfusion During Cesarean Delivery With Allogeneic Packed Red Blood Cell Transfusions in a Maternity Hospital in China

BACKGROUND: Autologous transfusion of intraoperative cell salvage blood may be a potential method to decrease the need for allogeneic packed red blood cell transfusions after cesarean delivery, although there are limited data on the benefits of this method. This study evaluated the implementation of targeted intraoperative cell salvage during cesarean delivery in women at increased risk for hemorrhage at the Women's and Children's Hospital in Ningbo, China. METHODS: All women who underwent cesarean delivery >28 weeks of gestation were included in the study. The period before intraoperative cell collection (October 1, 2010, to August 31, 2012, n = 11,322) was compared with the postimplementation period (September 1, 2012, to June 30, 2015, n = 17,456) using an interrupted time series analysis. In the postimplementation period, women suspected to be at increased risk of the need for a blood transfusion (1604, 9.2%) underwent intraoperative cell salvage collection. The primary outcomes were the monthly rate of allogeneic packed red blood cell use and the incidence of clinical manifestation of acute blood transfusion reactions. RESULTS: The mean (standard deviation) estimated monthly allogeneic packed blood cell transfusion rate at the end of the 57-month study was 2.2% ± 0.7% with the implementation compared with 2.7% ± 0.9% without, difference −0.5%, 95% CI, −1.4% to 0.3%; P = .22. The mean number of allogeneic units transfused per patient was 4.1 ± 0.4 units with implementation and 3.9 ± 0.9 units without, difference 0.2, 95% CI, −1.7 to 1.1 units; P = .69. Intraoperative cell salvage blood was reinfused in 757 (47%) and wasted in 847 (53%) cases. The monthly intraoperative allogeneic packed red blood cells use rate was lower after implementation (difference −0.7%, 95% CI, −0.1% to −1.4%; P = .03); however, the monthly postpartum allogeneic packed red blood cell use rate was unchanged (difference −0.2%, 95% CI, −0.4% to 0.7%; P = .56). The clinical manifestation of acute blood transfusion reactions rate was unchanged (difference −2%, 99% CI, −9% to 5%; P = .55) between the periods. CONCLUSIONS: Our findings suggest that targeted intraoperative cell salvage in women undergoing cesarean delivery was associated with less allogeneic blood exposure in the operating room, but not in the postoperative period. Intraoperative cell salvage in targeted cesarean deliveries was not associated with a lesser allogeneic red blood cell exposure over the hospital admission period. The lack of adverse events associated with intraoperative cell salvage supports the safety of intraoperative cell salvage in cesarean delivery. Accepted for publication January 8, 2018. Funding: None. R. J. McCarthy is currently affiliated with the Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois. Conflicts of Interest: See Disclosures at the end of the article. The study was presented at the 2015 Annual Meeting of the American Society of Anesthesiologists, October 24–28, San Diego, CA. Reprints will not be available from the authors. Address correspondence to Robert J. McCarthy, PharmD, Department of Anesthesiology, Rush University Medical Center, 1653 W. Congress Pkwy, Chicago, IL 60612. Address e-mail to robert_j_mccarthy@rush.edu. © 2018 International Anesthesia Research Society

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Acute Respiratory Distress Syndrome

No abstract available

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Predicting Persistent Pain After Surgery: Can Predicting the Weather Serve as an Example?

No abstract available

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Excipients in Anesthesia Medications

Medications used in anesthesiology contain both pharmacologically active compounds and additional additives that are usually regarded as being pharmacologically inactive. These additives, called excipients, serve diverse functions. Despite being labeled inert, excipients are not necessarily benign substances. Anesthesiologists should have a clear understanding of their chemical properties and the potential for adverse reactions. This report catalogs the excipients found in drugs commonly used in anesthesiology, provides a brief description of their function, and documents examples from the literature regarding their adverse effects. Accepted for publication January 8, 2018. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Funding: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Mark A. Burbridge, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94304. Address e-mail to markburb@stanford.edu. © 2018 International Anesthesia Research Society

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A Device for the Quantification of Oxygen Consumption and Caloric Expenditure in the Neonatal Range

BACKGROUND: The accurate measurement of oxygen consumption (VO2) and energy expenditure (EE) may be helpful to optimize the treatment of critically ill patients. However, current techniques are limited in their ability to accurately quantify these end points in infants due to a low VO2, low tidal volume, and rapid respiratory rate. This study describes and validates a new device intended to perform in this size range. METHODS: We created a customized device that quantifies inspiratory volume using a pneumotachometer and concentrations of oxygen and carbon dioxide gas in the inspiratory and expiratory limbs. We created a customized algorithm to achieve precise time alignment of these measures, incorporating bias flow and compliance factors. The device was validated in 3 ways. First, we infused a certified gas mixture (50% oxygen/50% carbon dioxide) into an artificial lung circuit, comparing measured with simulated VO2 and carbon dioxide production (VCO2) within a matrix of varying tidal volume (4–20 mL), respiratory rate (20–80 bpm), and fraction of inspired oxygen (0.21–0.8). Second, VO2, VCO2, and EE were measured in Sprague Dawley rats under mechanical ventilation and were compared to simultaneous Douglas bag collections. Third, the device was studied on n = 14 intubated, spontaneously breathing neonates and infants, comparing measured values to Douglas measurements. In all cases, we assessed for difference between the device and reference standard by linear regression and Bland–Altman analysis. RESULTS: In vitro, the mean ± standard deviation difference between the measured and reference standard VO2 was +0.04 ± 1.10 (95% limits of agreement, −2.11 to +2.20) mL/min and VCO2 was +0.26 ± 0.31 (−0.36 to +0.89) mL/min; differences were similar at each respiratory rate and tidal volume measured, but higher at fraction of inspired oxygen of 0.8 than at 0.7 or lower. In rodents, the mean difference was −0.20 ± 0.55 (−1.28 to +0.89) mL/min for VO2, +0.16 ± 0.25 (−0.32 to +0.65) mL/min for VCO2, and −0.84 ± 3.29 (−7.30 to +5.61) kcal/d for EE. In infants, the mean VO2 was 9.0 ± 2.5 mL/kg/min by Douglas method and was accurately measured by the device (bias, +0.22 ± 0.87 [−1.49 to +1.93] mL/kg/min). The average VCO2 was 8.1 ± 2.3 mL/kg/min, and the device exhibited a bias of +0.33 ± 0.82 (−1.27 to +1.94) mL/kg/min. Mean bias was +2.56% ± 11.60% of the reading for VO2 and +4.25% ± 11.20% of the reading for VCO2; among 56 replicates, 6 measurements fell outside of the 20% error range, and no patient had >1 of 4 replicates with a >20% error in either VO2 or VCO2. CONCLUSIONS: This device can measure VO2, VCO2, and EE with sufficient accuracy for clinical decision-making within the neonatal and pediatric size range, including in the setting of tachypnea or hyperoxia. Accepted for publication January 5, 2018. Funding: This work was supported by grants from the Gerber Foundation, Hess Family Philanthropic Fund, and the Boston Children's Hospital Heart Center Strategic Investment Fund. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Boston Children's Hospital (B. D. Polizzotti and J. N. Kheir) and InnoCC (P. Clemensen.) are in the process of filing a patent entitled "Oxygen Consumption and Energy Expenditure Monitoring in Infants and Children" describing the methods described herein. Clinical trial registry number: NCT03154112; http://ift.tt/2FfBHI0. Reprints will not be available from the authors. Address correspondence to John N. Kheir, MD, Department of Cardiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115. Address e-mail to john.kheir@childrens.harvard.edu. © 2018 International Anesthesia Research Society

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Pain Medicine: An Essential Review

No abstract available

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In Response

No abstract available

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Questions Regarding Perioperative Surgical Home by Kim et al

No abstract available

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In Response

No abstract available

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[Implementation of a remote oncology-monitoring program for cancer patients in outpatient care unit: A major challenge for the different actors].

[Implementation of a remote oncology-monitoring program for cancer patients in outpatient care unit: A major challenge for the different actors].

Bull Cancer. 2018 Feb 27;:

Authors: Peyrilles E, Lepage-Seydoux C, Sejean K, Bonan B

Abstract
INTRODUCTION: The development of outpatient departments requires health professionals to reorganize practices for a better patient monitoring and a better patient care pathway.
OBJECTIVE: To evaluate, using indicators, the impact of an oncology-monitoring program on activity and organizational fluidity in a Cytotoxic Preparation Unit and clinical departments. Method the clinical and biological data are collected between two injections by calling the patient two days prior chemotherapy is performed by a specialist nurse of an outsourced medical call center. After medical and pharmaceutical validation, early preparations (D-1) for expensive and non-expensive molecules are performed.
RESULTS: The program is started in February 2016. After 3 months, 382 patients were included into the program. Twenty-three patients on average are called per day related to 1162 completed clinical questionnaires (87%). Among the files, 47% are complete at D-2 (biological and clinical data). The early preparation rate of expensive drugs, zero before the program for financial reasons, has reached 40% at 3 months. The destroyed preparation rate because of non-administration decreased from 5 to 2%.
DISCUSSION: Preliminary results show a significant patient compliance, feasibility of early preparation of expensive and non-expensive chemotherapy. These are preliminary results of a one-year study. They will be completed by an evaluation of patients' and health professionals' satisfaction, evaluation of length of stay, optimization of operations for clinical departments and CPU. The D-2 biological data collection must be improved. A strong doctor/pharmacist collaboration is essential for better patient care pathway.

PMID: 29499998 [PubMed - as supplied by publisher]

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Adenocarcinoma and polyposis of the colon in a 20-year-old patient with Trisomy 13: a case report

Trisomy 13 is one of the most common autosomal trisomies, and although increasing in number, patients surviving past the neonatal period remain rare. The natural history and expected complications in these pat...

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