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Declan G Murphy - One of the best experts on this subject based on the ideXlab platform.

  • pelvic complications after prostate cancer radiation therapy and their management an international collaborative narrative review
    European Urology, 2019
    Co-Authors: Rano Matta, Christopher R Chapple, Margit Fisch, Axel Heidenreich, Sender Herschorn, Ronald T Kodama, Bridget F Koontz, Declan G Murphy
    Abstract:

    Abstract Context Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications. Objective To present a critical review of the literature regarding the incidence and risk factors of pelvic Toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management. Evidence acquisition A collaborative narrative review of the literature from 2010 to present was conducted. Evidence synthesis Regardless of the modality used, the incidence of acute high-grade pelvic Toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3–9% and 0–4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU Toxicity range from 6% to 8%, while late GI Toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU Toxicity is high, between 18% and 31%; however, the prevalence is lower at 4–14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI Toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar Toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms. Conclusions There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal Toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, Bone Toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management. Patient summary In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in Toxicity. Overall, high-grade long-term Toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

Rano Matta - One of the best experts on this subject based on the ideXlab platform.

  • pelvic complications after prostate cancer radiation therapy and their management an international collaborative narrative review
    European Urology, 2019
    Co-Authors: Rano Matta, Christopher R Chapple, Margit Fisch, Axel Heidenreich, Sender Herschorn, Ronald T Kodama, Bridget F Koontz, Declan G Murphy
    Abstract:

    Abstract Context Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications. Objective To present a critical review of the literature regarding the incidence and risk factors of pelvic Toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management. Evidence acquisition A collaborative narrative review of the literature from 2010 to present was conducted. Evidence synthesis Regardless of the modality used, the incidence of acute high-grade pelvic Toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3–9% and 0–4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU Toxicity range from 6% to 8%, while late GI Toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU Toxicity is high, between 18% and 31%; however, the prevalence is lower at 4–14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI Toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar Toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms. Conclusions There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal Toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, Bone Toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management. Patient summary In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in Toxicity. Overall, high-grade long-term Toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

Rauch A - One of the best experts on this subject based on the ideXlab platform.

  • Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0.
    'Wiley', 2018
    Co-Authors: Ryom L, Boesecke C, Bracchi M, Ambrosioni J, Pozniak A, Arribas J, Behrens G, Mallon P, Puoti M, Rauch A
    Abstract:

    BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. GUIDELINE HIGHLIGHTS: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and Bone Toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug-drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10 months. CONCLUSIONS: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages

  • Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0
    2018
    Co-Authors: Ryom L, Boesecke C, Bracchi M, Ambrosioni J, Pozniak A, Arribas J, Behrens G, Puoti M, Mallon P. G. M., Rauch A
    Abstract:

    The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and Bone Toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug-drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10 months. Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken language

Timothy R Gershon - One of the best experts on this subject based on the ideXlab platform.

  • poly 2 oxazoline nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving cns pharmacokinetics and reducing systemic Toxicity
    Nanomedicine: Nanotechnology Biology and Medicine, 2021
    Co-Authors: Duhyeong Hwang, Taylor Dismuke, Andrey P Tikunov, Elias P Rosen, John R Kagel, Jacob D Ramsey, Chaemin Lim, William C Zamboni, Alexander V Kabanov, Timothy R Gershon
    Abstract:

    We report a nanoparticle formulation of the SHH-pathway inhibitor vismodegib that improves efficacy for medulloblastoma, while reducing Toxicity. Limited blood-brain barrier (BBB) penetration and dose-limiting extitle/citraneural toxicities complicate systemic therapies for brain tumors. Vismodegib is FDA-approved for SHH-driven basal cell carcinoma, but implementation for medulloblastoma has been limited by inadequate efficacy and excessive Bone Toxicity. To address these issues through optimized drug delivery, we formulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo in transgenic mice that develop SHH-driven medulloblastomas with native vasculature and tumor microenvironment. POx-vismo improved CNS pharmacokinetics and reduced Bone Toxicity. Mechanistically, the nanoparticle carrier did not enter the CNS, and acted within the vascular compartment to improve drug delivery. Unlike conventional vismodegib, POx-vismo extended survival in medulloblastoma-bearing mice. Our results show the broad potential for non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to improve vismodegib therapy for SHH-driven cancers.

  • poly 2 oxazoline nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving cns pharmacokinetics and reducing systemic Toxicity
    bioRxiv, 2020
    Co-Authors: Duhyeong Hwang, Taylor Dismuke, Andrey P Tikunov, John R Kagel, Jacob D Ramsey, William C Zamboni, Alexander V Kabanov, Timothy R Gershon, Ellias Rosen, Marina Sokolskypapkov
    Abstract:

    We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing Toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and dose-limiting extraneural Toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHH-subgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and Bone Toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.

Duhyeong Hwang - One of the best experts on this subject based on the ideXlab platform.

  • poly 2 oxazoline nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving cns pharmacokinetics and reducing systemic Toxicity
    Nanomedicine: Nanotechnology Biology and Medicine, 2021
    Co-Authors: Duhyeong Hwang, Taylor Dismuke, Andrey P Tikunov, Elias P Rosen, John R Kagel, Jacob D Ramsey, Chaemin Lim, William C Zamboni, Alexander V Kabanov, Timothy R Gershon
    Abstract:

    We report a nanoparticle formulation of the SHH-pathway inhibitor vismodegib that improves efficacy for medulloblastoma, while reducing Toxicity. Limited blood-brain barrier (BBB) penetration and dose-limiting extitle/citraneural toxicities complicate systemic therapies for brain tumors. Vismodegib is FDA-approved for SHH-driven basal cell carcinoma, but implementation for medulloblastoma has been limited by inadequate efficacy and excessive Bone Toxicity. To address these issues through optimized drug delivery, we formulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo in transgenic mice that develop SHH-driven medulloblastomas with native vasculature and tumor microenvironment. POx-vismo improved CNS pharmacokinetics and reduced Bone Toxicity. Mechanistically, the nanoparticle carrier did not enter the CNS, and acted within the vascular compartment to improve drug delivery. Unlike conventional vismodegib, POx-vismo extended survival in medulloblastoma-bearing mice. Our results show the broad potential for non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to improve vismodegib therapy for SHH-driven cancers.

  • poly 2 oxazoline nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving cns pharmacokinetics and reducing systemic Toxicity
    bioRxiv, 2020
    Co-Authors: Duhyeong Hwang, Taylor Dismuke, Andrey P Tikunov, John R Kagel, Jacob D Ramsey, William C Zamboni, Alexander V Kabanov, Timothy R Gershon, Ellias Rosen, Marina Sokolskypapkov
    Abstract:

    We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing Toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and dose-limiting extraneural Toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHH-subgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and Bone Toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.