This document discusses treatments for Gaucher disease, a genetic lysosomal storage disorder. It describes enzyme replacement therapy as the standard of care using imiglucerase, a recombinant human enzyme, which clinical trials found achieved therapeutic goals in 70-99% of patients and led to improvements in quality of life. Higher doses of imiglucerase were associated with greater achievement of therapeutic goals. While initially administered slowly, subsequent infusions can be increased to 1 unit/kg/min. Enzyme replacement with imiglucerase is established as the gold standard treatment with over 15 years of clinical experience supporting its safety and efficacy profile.
This document discusses criteria for ruling out pulmonary embolism (PE). It describes risk factors, signs and symptoms, laboratory findings, diagnostic tests, and clinical probability models used to evaluate PE. It provides guidelines for diagnostic testing and treatment based on pre-test probability. Special cases like allergy, pregnancy, and hemodynamic instability are also addressed. The goal is to safely rule out or diagnose PE using a structured clinical assessment and testing approach.
1) Carotid artery stenosis is a major risk factor for stroke. While carotid endarterectomy (CEA) has been shown to reduce stroke risk in selected low-risk patients, many patients are at high surgical risk or have exclusion criteria.
2) Early trials of carotid artery stenting (CAS) showed high complication rates but technology and experience have improved outcomes over time. Recent trials show CAS may have slightly better outcomes than CEA in high-risk patients.
3) Ongoing trials are further evaluating CAS compared to CEA in both high-risk and low-risk patients. The use of distal protection devices during CAS appears important for reducing complications.
1) A phase 3 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive metastatic castration-resistant prostate cancer patients showed improved radiographic progression-free and overall survival for the abiraterone arm.
2) At the first interim analysis when 425 overall survival events occurred, the hazard ratio for overall survival was 0.66 with a p-value of 0.0034, crossing the pre-specified boundary for statistical significance.
3) Secondary endpoints including time to opiate use, chemotherapy initiation, performance status deterioration, and prostate specific antigen progression were also all significantly prolonged in the abiraterone arm.
Niemann-Pick disease types A, B, and C are rare genetic disorders that cause cholesterol and other fatty substances to build up in cells. Type A is the most severe, with an average life expectancy of 2-3 years and profound brain damage by 6 months of age. Type B mainly affects the liver and spleen and patients usually live into adulthood. Type C can appear at any age and causes neurological problems. Treatments for type B include bone marrow transplantation, enzyme replacement therapy, and gene therapy. Miglustat is approved to treat neurological symptoms of type C in some countries. Research continues for new treatments.
Evaluation Of Type 1 Gaucher Disease Patients Treated Ith ImigluceraseMihaiela Fazacas
1) This study evaluated the clinical outcomes of 32 type 1 Gaucher disease patients treated with imiglucerase (Cerezyme) for 0.25-6.5 years.
2) The results showed improvements in hematological parameters, organ volumes, bone disease severity scores and quality of life over the treatment period. Hemoglobin levels, platelet counts, spleen and liver volumes significantly decreased.
3) Bone pain, bone crises and fractures were reduced. Bone mineral density improved or remained stable in most patients. Chitotriosidase levels and an overall severity score also decreased significantly. No side effects were reported from the treatment.
management of metastasis_bone_tumour.pptxzawmyohan2
Bone metastases are a common cause of morbidity in advanced cancer patients. The most common sites of bone metastases are the vertebrae, pelvis, and femur. Patients usually present with pain, pathological fractures, or neurological deficits. Diagnosis involves blood tests, imaging like x-rays, CT, MRI, PET, and biopsy. Treatment is multidisciplinary and aims to relieve symptoms, involving palliative care, radiotherapy, chemotherapy, and surgery to stabilize fractures or prevent impending fractures. Prognosis depends on primary cancer type, with lung cancer having the lowest 1-year survival and breast cancer having the highest.
Advances in gaucher disease priya kishnani modifiedSanjeev Kumar
This document summarizes advances in understanding and treating Gaucher disease. It discusses the metabolic defect, diagnostic testing, clinical heterogeneity including types 1-3, natural history, assessments, and treatment paradigms including enzyme replacement therapy. Long term follow up of over 1000 patients on enzyme therapy showed reversal of symptoms and normalization of markers. A multidisciplinary team approach is now standard for managing this condition.
This document discusses criteria for ruling out pulmonary embolism (PE). It describes risk factors, signs and symptoms, laboratory findings, diagnostic tests, and clinical probability models used to evaluate PE. It provides guidelines for diagnostic testing and treatment based on pre-test probability. Special cases like allergy, pregnancy, and hemodynamic instability are also addressed. The goal is to safely rule out or diagnose PE using a structured clinical assessment and testing approach.
1) Carotid artery stenosis is a major risk factor for stroke. While carotid endarterectomy (CEA) has been shown to reduce stroke risk in selected low-risk patients, many patients are at high surgical risk or have exclusion criteria.
2) Early trials of carotid artery stenting (CAS) showed high complication rates but technology and experience have improved outcomes over time. Recent trials show CAS may have slightly better outcomes than CEA in high-risk patients.
3) Ongoing trials are further evaluating CAS compared to CEA in both high-risk and low-risk patients. The use of distal protection devices during CAS appears important for reducing complications.
1) A phase 3 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive metastatic castration-resistant prostate cancer patients showed improved radiographic progression-free and overall survival for the abiraterone arm.
2) At the first interim analysis when 425 overall survival events occurred, the hazard ratio for overall survival was 0.66 with a p-value of 0.0034, crossing the pre-specified boundary for statistical significance.
3) Secondary endpoints including time to opiate use, chemotherapy initiation, performance status deterioration, and prostate specific antigen progression were also all significantly prolonged in the abiraterone arm.
Niemann-Pick disease types A, B, and C are rare genetic disorders that cause cholesterol and other fatty substances to build up in cells. Type A is the most severe, with an average life expectancy of 2-3 years and profound brain damage by 6 months of age. Type B mainly affects the liver and spleen and patients usually live into adulthood. Type C can appear at any age and causes neurological problems. Treatments for type B include bone marrow transplantation, enzyme replacement therapy, and gene therapy. Miglustat is approved to treat neurological symptoms of type C in some countries. Research continues for new treatments.
Evaluation Of Type 1 Gaucher Disease Patients Treated Ith ImigluceraseMihaiela Fazacas
1) This study evaluated the clinical outcomes of 32 type 1 Gaucher disease patients treated with imiglucerase (Cerezyme) for 0.25-6.5 years.
2) The results showed improvements in hematological parameters, organ volumes, bone disease severity scores and quality of life over the treatment period. Hemoglobin levels, platelet counts, spleen and liver volumes significantly decreased.
3) Bone pain, bone crises and fractures were reduced. Bone mineral density improved or remained stable in most patients. Chitotriosidase levels and an overall severity score also decreased significantly. No side effects were reported from the treatment.
management of metastasis_bone_tumour.pptxzawmyohan2
Bone metastases are a common cause of morbidity in advanced cancer patients. The most common sites of bone metastases are the vertebrae, pelvis, and femur. Patients usually present with pain, pathological fractures, or neurological deficits. Diagnosis involves blood tests, imaging like x-rays, CT, MRI, PET, and biopsy. Treatment is multidisciplinary and aims to relieve symptoms, involving palliative care, radiotherapy, chemotherapy, and surgery to stabilize fractures or prevent impending fractures. Prognosis depends on primary cancer type, with lung cancer having the lowest 1-year survival and breast cancer having the highest.
Advances in gaucher disease priya kishnani modifiedSanjeev Kumar
This document summarizes advances in understanding and treating Gaucher disease. It discusses the metabolic defect, diagnostic testing, clinical heterogeneity including types 1-3, natural history, assessments, and treatment paradigms including enzyme replacement therapy. Long term follow up of over 1000 patients on enzyme therapy showed reversal of symptoms and normalization of markers. A multidisciplinary team approach is now standard for managing this condition.
The study analyzed data from 5498 patients in the EUROSTAR registry who underwent endovascular aneurysm repair (EVAR) between 1996-2005. It found that the Glasgow Aneurysm Score (GAS), which considers a patient's age and medical comorbidities, predicted postoperative mortality after EVAR. Patients with a GAS over 83.6 had a 30-day mortality rate of 5.3%, compared to 1.1% for those under 74.4. GAS also predicted long-term survival rates out to 5 years, with higher GAS associated with lower survival.
The document provides information on the management of massive gastrointestinal hemorrhage. It discusses that the majority of massive GI bleeds originate from the upper GI tract. The initial management of a patient with massive GI hemorrhage involves airway protection, intravenous fluid resuscitation, monitoring of vital signs, and blood transfusions if indicated. Early endoscopy within 4 hours is advocated for diagnostic and therapeutic purposes such as locating the bleeding site and achieving hemostasis. Additional procedures like angiography may be used if endoscopy is unsuccessful or for lower GI bleeds. Antibiotic prophylaxis is recommended for patients with cirrhosis to reduce infectious complications. Restrictive blood transfusion strategies with a hemoglobin threshold of 7-8 g
Celiac plexus neurolysis is a pain management procedure that can provide relief for patients experiencing intractable abdominal pain from upper gastrointestinal malignancies. It involves injecting neurolytic agents such as ethanol to disrupt the celiac plexus, the main nerve structure supplying the upper abdominal organs. Key indications are pain from pancreatic, gastric, or biliary cancers. The procedure is image-guided and involves positioning needles anterior to the aorta to inject agents into the retroperitoneal space containing the celiac plexus. Potential complications include temporary diarrhea, hypotension, and rare neurological issues. Studies show it can reduce opioid usage and abolish pain in 70-90% of cancer patients when performed appropriately.
1. Metastatic spinal tumors occur in approximately 10% of cancer patients and often present with back pain that worsens with recumbency. 2. Treatment depends on the degree and rapidity of neurological involvement, and may include steroids, radiation therapy, and/or surgery to preserve neurological function and spinal stability and control pain. 3. The primary goals of treatment are palliative as no treatment significantly prolongs life; the most important prognostic factor is the ability to walk at the start of therapy.
This document discusses the role of statins in plaque stabilization and regression. It provides evidence that statins can induce plaque regression and stabilization through several mechanisms, including reducing inflammation, lipid content, and macrophage infiltration of plaques while increasing collagen and smooth muscle cell content. Several studies are summarized that used imaging techniques like intravascular ultrasound to demonstrate plaque regression with intensive statin therapy. The concept of the vulnerable or high-risk plaque is also introduced. Overall, the document argues that statin therapy can promote plaque stabilization and regression, contributing to their clinical benefits in reducing cardiovascular events.
Osteros Biomedica presentation for Adam Smith Conference 2012MaxwellBiotech
This document summarizes a new treatment for cancer-induced bone diseases called MBC-11 Compound. MBC-11 is a conjugate of a bisphosphonate (which targets bone) and a cytotoxic agent. It has been shown to accumulate in bone microenvironments, delivering high local concentrations of chemotherapy with reduced systemic toxicity compared to conventional treatments. Preclinical studies in rodent models of multiple myeloma, breast cancer, and prostate cancer bone metastases demonstrated MBC-11's ability to treat bone disease and reduce cancer progression with improved survival rates and reduced pain. A pilot study in spontaneous canine osteosarcoma also showed reduction in tumor activity and pain with improved quality of life. An upcoming Phase I/IIa clinical
Multiple myeloma is characterized by neoplastic proliferation of plasma cells producing monoclonal immunoglobulin. It commonly affects elderly individuals and presents with bone disease, anemia, infections and renal failure. Diagnosis involves finding monoclonal proteins in serum or urine and plasma cell infiltration in bone marrow. Treatment aims to improve quality of life and may include chemotherapy, stem cell transplant, supportive care and management of complications.
Musculoskeletal tumors can originate from a multistep accumulation of mutations leading to unregulated cell proliferation. Osteosarcoma is the most common type of bone tumor, arising from osteoblasts. It is diagnosed through radiography, cytology, and histopathology. Grading is based on features like pleomorphism and mitoses. Treatment involves surgery with chemotherapy. Variants include osteoblastic, chondroblastic, telangiectatic and fibroblastic subtypes. Multilobular tumor of bone is a slow growing but potentially malignant tumor appearing as islands of bone or cartilage surrounded by spindle cells. Chondrosarcoma arises from cartilage and osteochondroma involves cartilage capped bone protrusions.
1) Brain metastases are most commonly from lung cancer and breast cancer and occur when cancer cells spread to the brain from a primary tumor in another organ.
2) Patients typically present with new neurological symptoms and MRI is the standard imaging method to detect metastatic brain tumors.
3) Treatment options include corticosteroids to reduce edema, surgical resection for select cases, whole-brain radiotherapy, and radiosurgery as a boost to the tumor site. Adjuvant whole-brain radiotherapy after surgery or radiosurgery can help prevent future brain metastases.
- A 12-year-old boy presented with pain and swelling in his left tibia for one month with a history of intermittent fever. Differential diagnoses included osteomyelitis, osteoid osteoma, Ewing's sarcoma, and osteosarcoma.
- Ewing's sarcoma most commonly affects children and young adults between 5-25 years old and presents with pain, swelling, and sometimes pathological fractures. Definitive diagnosis is based on histology, immunohistochemistry, and detection of specific gene fusions.
- Treatment involves chemotherapy with VACA/IE cycles alternating every 2-3 weeks for 17 cycles along with possible surgery and/or radiation therapy based on response and margins. The goal is
This document discusses stereotactic radiosurgery and radiotherapy. It begins with an introduction to stereotaxy and how it allows for highly precise radiation targeting. It then covers radiobiology concepts relevant to stereotactic radiation and lists some common indications for its use, including brain metastases and early stage prostate cancer. The document provides details on patient immobilization, planning techniques, and treatment procedures for conditions like pituitary adenomas, trigeminal neuralgia, and arteriovenous malformations.
Acs0610 Carotid Angioplasty And Stentingmedbookonline
This document discusses carotid angioplasty and stenting (CAS) as an alternative to carotid endarterectomy (CEA) for treating carotid artery stenosis. It describes studies that have identified criteria for defining patients at high risk for CEA. Such high-risk patients may be better candidates for CAS. The document outlines the indications for CAS in high-risk patients and reviews important anatomical considerations for the procedure. Contraindications to CAS are also presented.
Clinical Outcomes in 995 Unselected Real-world Patients Treated With an Ultra-thin Biodegradable Polymer-coated
Sirolimus-eluting Stent:
12 Months Results from the FLEX Registry
Dr. David Vesole, Co-Chief, Multiple Myeloma at John Theurer Cancer Center at HackensackUMC presentation at the MMRF Clinical Insights program in April 2012.
Consecutive Aneurysms Treated by Endovascular ApproachDr Vipul Gupta
Endovascular coiling is now the primary treatment approach for ruptured intracranial aneurysms based on evidence from trials like ISAT showing improved outcomes compared to clipping. The presenter's experience with 33 patients with 35 consecutive aneurysms showed high rates of aneurysm occlusion (95%) and good clinical outcomes (87.6% had mRS 0-2) when treated using a protocol-based endovascular approach with neurosurgical and critical care support. Complications were low when meticulous techniques were used along with protocols for management of issues like vasospasm.
Ain-shams University,Urology department, ,Angiomyolipoma, by Mahmoud RedaMahmoud Reda badr
Angiomyolipoma is the most common benign renal tumor, accounting for less than 0.5% of renal tumors. It consists of thick-walled blood vessels, smooth muscle, and fat tissue. Around 20-30% of cases are associated with tuberous sclerosis. While often asymptomatic, angiomyolipoma can cause pain, bleeding, or compression symptoms. Treatment depends on size and symptoms, ranging from observation for small asymptomatic tumors to embolization or surgery for larger tumors or complications.
Richard, a 51-year-old male, presented with epigastric distress, weight loss, anemia, and renal failure. Bone marrow testing revealed he had multiple myeloma, a cancer of plasma cells which produces monoclonal proteins that can cause organ and tissue damage. He was diagnosed based on his bone marrow containing over 20% plasma cells and laboratory findings showing monoclonal proteins. Multiple myeloma is typically treated with chemotherapy like melphalan and prednisone or stem cell transplants, though newer agents like thalidomide and bortezomib have improved outcomes in some patients.
1) Four studies examined the extent of resection of parasagittal meningiomas involving the superior sagittal sinus. Greater extent of resection and reconstruction of the sinus was associated with lower recurrence rates in some studies.
2) Total resection of the tumor with reconstruction of the sinus had recurrence rates of 4-11% while subtotal resection was associated with higher recurrence rates.
3) Reconstruction techniques including suturing, patching, and vein bypass grafts showed good patency rates, while total resection without reconstruction was associated with mortality in some studies.
The study analyzed data from 5498 patients in the EUROSTAR registry who underwent endovascular aneurysm repair (EVAR) between 1996-2005. It found that the Glasgow Aneurysm Score (GAS), which considers a patient's age and medical comorbidities, predicted postoperative mortality after EVAR. Patients with a GAS over 83.6 had a 30-day mortality rate of 5.3%, compared to 1.1% for those under 74.4. GAS also predicted long-term survival rates out to 5 years, with higher GAS associated with lower survival.
The document provides information on the management of massive gastrointestinal hemorrhage. It discusses that the majority of massive GI bleeds originate from the upper GI tract. The initial management of a patient with massive GI hemorrhage involves airway protection, intravenous fluid resuscitation, monitoring of vital signs, and blood transfusions if indicated. Early endoscopy within 4 hours is advocated for diagnostic and therapeutic purposes such as locating the bleeding site and achieving hemostasis. Additional procedures like angiography may be used if endoscopy is unsuccessful or for lower GI bleeds. Antibiotic prophylaxis is recommended for patients with cirrhosis to reduce infectious complications. Restrictive blood transfusion strategies with a hemoglobin threshold of 7-8 g
Celiac plexus neurolysis is a pain management procedure that can provide relief for patients experiencing intractable abdominal pain from upper gastrointestinal malignancies. It involves injecting neurolytic agents such as ethanol to disrupt the celiac plexus, the main nerve structure supplying the upper abdominal organs. Key indications are pain from pancreatic, gastric, or biliary cancers. The procedure is image-guided and involves positioning needles anterior to the aorta to inject agents into the retroperitoneal space containing the celiac plexus. Potential complications include temporary diarrhea, hypotension, and rare neurological issues. Studies show it can reduce opioid usage and abolish pain in 70-90% of cancer patients when performed appropriately.
1. Metastatic spinal tumors occur in approximately 10% of cancer patients and often present with back pain that worsens with recumbency. 2. Treatment depends on the degree and rapidity of neurological involvement, and may include steroids, radiation therapy, and/or surgery to preserve neurological function and spinal stability and control pain. 3. The primary goals of treatment are palliative as no treatment significantly prolongs life; the most important prognostic factor is the ability to walk at the start of therapy.
This document discusses the role of statins in plaque stabilization and regression. It provides evidence that statins can induce plaque regression and stabilization through several mechanisms, including reducing inflammation, lipid content, and macrophage infiltration of plaques while increasing collagen and smooth muscle cell content. Several studies are summarized that used imaging techniques like intravascular ultrasound to demonstrate plaque regression with intensive statin therapy. The concept of the vulnerable or high-risk plaque is also introduced. Overall, the document argues that statin therapy can promote plaque stabilization and regression, contributing to their clinical benefits in reducing cardiovascular events.
Osteros Biomedica presentation for Adam Smith Conference 2012MaxwellBiotech
This document summarizes a new treatment for cancer-induced bone diseases called MBC-11 Compound. MBC-11 is a conjugate of a bisphosphonate (which targets bone) and a cytotoxic agent. It has been shown to accumulate in bone microenvironments, delivering high local concentrations of chemotherapy with reduced systemic toxicity compared to conventional treatments. Preclinical studies in rodent models of multiple myeloma, breast cancer, and prostate cancer bone metastases demonstrated MBC-11's ability to treat bone disease and reduce cancer progression with improved survival rates and reduced pain. A pilot study in spontaneous canine osteosarcoma also showed reduction in tumor activity and pain with improved quality of life. An upcoming Phase I/IIa clinical
Multiple myeloma is characterized by neoplastic proliferation of plasma cells producing monoclonal immunoglobulin. It commonly affects elderly individuals and presents with bone disease, anemia, infections and renal failure. Diagnosis involves finding monoclonal proteins in serum or urine and plasma cell infiltration in bone marrow. Treatment aims to improve quality of life and may include chemotherapy, stem cell transplant, supportive care and management of complications.
Musculoskeletal tumors can originate from a multistep accumulation of mutations leading to unregulated cell proliferation. Osteosarcoma is the most common type of bone tumor, arising from osteoblasts. It is diagnosed through radiography, cytology, and histopathology. Grading is based on features like pleomorphism and mitoses. Treatment involves surgery with chemotherapy. Variants include osteoblastic, chondroblastic, telangiectatic and fibroblastic subtypes. Multilobular tumor of bone is a slow growing but potentially malignant tumor appearing as islands of bone or cartilage surrounded by spindle cells. Chondrosarcoma arises from cartilage and osteochondroma involves cartilage capped bone protrusions.
1) Brain metastases are most commonly from lung cancer and breast cancer and occur when cancer cells spread to the brain from a primary tumor in another organ.
2) Patients typically present with new neurological symptoms and MRI is the standard imaging method to detect metastatic brain tumors.
3) Treatment options include corticosteroids to reduce edema, surgical resection for select cases, whole-brain radiotherapy, and radiosurgery as a boost to the tumor site. Adjuvant whole-brain radiotherapy after surgery or radiosurgery can help prevent future brain metastases.
- A 12-year-old boy presented with pain and swelling in his left tibia for one month with a history of intermittent fever. Differential diagnoses included osteomyelitis, osteoid osteoma, Ewing's sarcoma, and osteosarcoma.
- Ewing's sarcoma most commonly affects children and young adults between 5-25 years old and presents with pain, swelling, and sometimes pathological fractures. Definitive diagnosis is based on histology, immunohistochemistry, and detection of specific gene fusions.
- Treatment involves chemotherapy with VACA/IE cycles alternating every 2-3 weeks for 17 cycles along with possible surgery and/or radiation therapy based on response and margins. The goal is
This document discusses stereotactic radiosurgery and radiotherapy. It begins with an introduction to stereotaxy and how it allows for highly precise radiation targeting. It then covers radiobiology concepts relevant to stereotactic radiation and lists some common indications for its use, including brain metastases and early stage prostate cancer. The document provides details on patient immobilization, planning techniques, and treatment procedures for conditions like pituitary adenomas, trigeminal neuralgia, and arteriovenous malformations.
Acs0610 Carotid Angioplasty And Stentingmedbookonline
This document discusses carotid angioplasty and stenting (CAS) as an alternative to carotid endarterectomy (CEA) for treating carotid artery stenosis. It describes studies that have identified criteria for defining patients at high risk for CEA. Such high-risk patients may be better candidates for CAS. The document outlines the indications for CAS in high-risk patients and reviews important anatomical considerations for the procedure. Contraindications to CAS are also presented.
Clinical Outcomes in 995 Unselected Real-world Patients Treated With an Ultra-thin Biodegradable Polymer-coated
Sirolimus-eluting Stent:
12 Months Results from the FLEX Registry
Dr. David Vesole, Co-Chief, Multiple Myeloma at John Theurer Cancer Center at HackensackUMC presentation at the MMRF Clinical Insights program in April 2012.
Consecutive Aneurysms Treated by Endovascular ApproachDr Vipul Gupta
Endovascular coiling is now the primary treatment approach for ruptured intracranial aneurysms based on evidence from trials like ISAT showing improved outcomes compared to clipping. The presenter's experience with 33 patients with 35 consecutive aneurysms showed high rates of aneurysm occlusion (95%) and good clinical outcomes (87.6% had mRS 0-2) when treated using a protocol-based endovascular approach with neurosurgical and critical care support. Complications were low when meticulous techniques were used along with protocols for management of issues like vasospasm.
Ain-shams University,Urology department, ,Angiomyolipoma, by Mahmoud RedaMahmoud Reda badr
Angiomyolipoma is the most common benign renal tumor, accounting for less than 0.5% of renal tumors. It consists of thick-walled blood vessels, smooth muscle, and fat tissue. Around 20-30% of cases are associated with tuberous sclerosis. While often asymptomatic, angiomyolipoma can cause pain, bleeding, or compression symptoms. Treatment depends on size and symptoms, ranging from observation for small asymptomatic tumors to embolization or surgery for larger tumors or complications.
Richard, a 51-year-old male, presented with epigastric distress, weight loss, anemia, and renal failure. Bone marrow testing revealed he had multiple myeloma, a cancer of plasma cells which produces monoclonal proteins that can cause organ and tissue damage. He was diagnosed based on his bone marrow containing over 20% plasma cells and laboratory findings showing monoclonal proteins. Multiple myeloma is typically treated with chemotherapy like melphalan and prednisone or stem cell transplants, though newer agents like thalidomide and bortezomib have improved outcomes in some patients.
1) Four studies examined the extent of resection of parasagittal meningiomas involving the superior sagittal sinus. Greater extent of resection and reconstruction of the sinus was associated with lower recurrence rates in some studies.
2) Total resection of the tumor with reconstruction of the sinus had recurrence rates of 4-11% while subtotal resection was associated with higher recurrence rates.
3) Reconstruction techniques including suturing, patching, and vein bypass grafts showed good patency rates, while total resection without reconstruction was associated with mortality in some studies.
Similar to Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt (20)
Cattaneo le urgenze in ematologia 21 maggio 2011cmid
This document discusses antiplatelet drugs used to prevent blood clots, including aspirin, clopidogrel, prasugrel, ticagrelor, cangrelor, and elinogrel. It summarizes the mechanisms of action, metabolism, efficacy, and safety profiles of these drugs. Resistance or variable response to certain antiplatelet drugs is also addressed. The ideal properties of an antithrombotic agent are outlined. Later generation drugs like prasugrel, ticagrelor, and cangrelor demonstrate more consistent platelet inhibition compared to clopidogrel. However, some such as ticagrelor and elinogrel are associated with higher rates of dyspnea.
Linfedema torino 4 e 5 marzo gaal palma [modalità compatibilità]
Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt
1. 14°Convegno Patologia Immune e Malattie
Orfane 2011
La Malattia di Gaucher come prototipo di
malattia genetica curabile: attuali certezze e
nuove frontiere
M.Domenica Cappellini
Fondazione “Ca Granda” Policlinico
Università di Milano
2. Treatment of Gaucher
Disease
• Gaucher disease
– Chronic
– Multisystemic
– Highly variable (pattern, severity, progression)
• Disease heterogeneity management cannot be
homogeneous
• Patient-centered
• Goal-oriented approach is critical for individual
tailoring of therapy
3. Treatment of Gaucher Disease
Which kind of treatment ?
• Supportive and palliative measures
• Enzyme replacement Therapy
(ERT)
• Substrate inhibition therapy (SIT)
• Small molecules
• Bone marrow transplantation
• Gene therapy
4. Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
Therapies Therapies
* A recombinant human glucocerebrosidase
Imiglucerase* expressed in genetically engineered Chinese
hamster ovary cells.
4
5. Achievement of Therapeutic Goals:
Are to “achieve normal life expectancy & well-being for Gaucher patients”
Adapted from
Pastores et al. Semin Hematol (suppl 5):4-14. 2004
6. Success of treatment with Imiglucerase
Therapeutic Goals
Patients achieving therapeutic goals (%) • Prevention of bone crisis (99%)
by clinical parameter around initiation
and at 4 years after initiation of Imiglucerase:
• Amelioration of bone pain (71%)
– Persistence of bone pain= Burden of pre-treatment irreversible
skeletal complications*
99
100
91,8 90,8 91,8
90
79,5 78,5
• Correction of symptomatic anemia (92%)
Percentage of Patients
80
70,3
68,2
70
62,6
60 • Reversion of hepatomegaly (91%)
50 45,6 – Prevent hepatic fibrosis, cirrhosis, and portal hypertension
40
30 24,6 25,5 • Reversion of splenomegaly (79%)
20
– Diminished reservoir of Gaucher cells= Prevent
immunoproliferative disorders
10
0
Haemaglobin Platelet count Liver volume Spleen volume Bone pain Bone crisis
• Improvement of platelet counts (80%)
Clinical Parameters
– Prevent the risk of spontaneous, post-traumatic, surgical or
obstetrical bleeding
– Splenic fibrosis may limit spleen response= Persistent
hypersplenism renders goal platelet count unachievable
Average dose of CZ over 4 yrs:
67.5 ± 31.7 U/kg/4 wks
Weinreb et al. Am. J. Hematol. 83:890–895, 2008.
7. Patients who received higher doses of Imiglucerase
achieved a greater number of therapeutic goals
Mean dose Median Percentage of patients
80 100
Percentage of Patients
70
80
Dose of Cerezyme
60
(U/kg/4wks)
50 60
40
30 40
20
20
10
0 0
1-3 out of 6 4 out of 6 5 out of 6 6 out of 6 Total
Number of Therapeutic Goals Achieved
Average dose of Imiglucerase (U/kg/4 wks) by number of therapeutic goals achieved
at 4 years after initiation of Imiglucerase
Adapted from Table III.
Weinreb et al. Am. J. Hematol. 83:890–895, 2008.
8. Clinical Benefits
Quality of Life
Adapted from Fig.2
• After 48 months of treatment with Imiglucerase®, the majority of
patients achieve normal mean physical and mental standardized
aggregate scores as compared to the U.S. reference population
Weinreb et al. Clin Genet, 71: 576–588. 2007
9. Convenience: Infusion frequency and rate
• The usual frequency of infusion is
(p= 0,060) once every 2 weeks
• Maintenance therapy every 4 weeks
(Q4) at the same cumulative dose as
the bi-weekly (Q2) may be a
therapeutic option for some adult
patients with stable residual Gaucher
disease, but clinical data remain
limited
• At initial infusions, Imiglucerase®
should be administered at a rate not
exceeding 0.5 U/kg/min
• At subsequent administrations,
infusion rate may be increased but
should not exceed 1 U/kg/min
Difference not statistically significant
(95% CI)
Kishnani et al. Mol Genet Metab. 96(4):164–170, 2009; Imiglucerase SmPC, section 4.2
10. Imiglucerase® is the gold standard of care
for Gaucher patients
• Imiglucerase is the gold standard of care with a
trusted, proven and well understood clinical profile
of safety and efficacy well documented for more
than 15 years, representing some 40,000
accumulated years of patient use
• Genzyme continues to support the ICGG Registry,
which provides physicians with the necessary tools
to optimally manage Gaucher patients and advance
their knowledge of the disease
11. Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
Therapies Therapies
Imiglucerase Velaglucerase Taliglucerase
Although Cerezyme remains the standard care for the treatment of Gaucher disease and there is a burgeoning
literature on its use over time in the mature phase of enzyme therapy, two emerging biosimilar agents, also based
on the principle of macrophage targeting through the mannose lectin membrane receptor system, have been
introduced. T.Cox. Dovepress J.Biologics:Targets and Therapy, Dec 210 11
12. Velaglucerase (VPRIV)
• This agent is generated by gene activation of the
endogenous human glucocerebrosidase gene in an
immortalized human fibrosarcoma cell line
• The engineered cells are cultured in a medium containing
the powerful inhibitor kifunesine which blocks the action of
one of the processing glycosidases and as a result, a
human glucocerebrosidase protein displaying terminal
mannose sugars is produced.
13. Velaglucerase granted marketing authorization
in EU (26 Aug ‘10)
• Velaglucerase granted marketing authorization by
European Commission
– Velaglucerase has been authorized as an orphan medicine through
the Centralized Procedure, making it available in 30 countries
across Europe
– Exact timing of launch will depend on local pricing and
reimbursement procedures
• ≈ 850 patients on Velaglucerase therapy
– Capacity to support ≈1000 in 2010
– Currently implementing a program to monitor and manage requests
from new patients
13
14. Taliglucerase
• Taliglucerase is produced as a
recombinant glycoprotein expressed in
genetically engineered plant cells.
• To secure secretion through the vacuolar
pathway, the protein is modified: it harbors
additional amino acids, as well as xylose
and other sugars in its intermediate glycan
sequence
15. Taliglucerase-α status in US and EU
• July 12, 2010: New Drug Application (NDA) for taliglucerase has been
accepted for review by FDA
– The FDA granted Taliglucerase a standard review time of 10 months,
assigning a Prescription Drug User Fee Act (PDUFA) action date of
February 25, 2011
• Nov 29, 2010: Submission of a Marketing Authorization Application to the
EMA for Taliglucerase
– Assuming a standard review period of 10 months, approval would be
expected in September 2011; an expedited review could push up this
deadline to July 2011.
15
16. Clinical data
• Velaglucerase
– “Non-inferiority” and NOT “superiority” for Velaglucerase at 60U/kg
– Robustness of bone data still to be demonstrated
– No pregnancy data
– Antigenic differences in patients receiving vela or Cz has become
a top topic of discussion among KOLs
• Taliglucerase
– Different molecule + clinical data are scarce… but approval in the
EU & US moving forward
16
17. Disadvantages of enzyme
replacement therapy
• Blood–brain barrier which is largely impermeable to proteins
• Enzyme therapy has no direct therapeutic effect on the neurological
manifestations of Gaucher disease
• Enzyme therapy has no direct therapeutic effect on the neurological
manifestations of Gaucher disease
• Cost
PS:hypersensitivity and immune reactions directed against the therapeutic proteins in
type I Gaucherdisease are very rare,
19. Substrate depletion (inhibitor)
therapy
• The biochemical target for this stratagem in Gaucher
disease is the first committed step for glycosphingolipid
biosynthesis catalyzed by uridine diphosphate (UDP)
glucosylceramide synthetase (UDP-glucose: N-
acylsphingosine transferase)
• Two chemical classes of inhibitor are undergoing
comprehensive therapeutic exploration:
- iminosugars (Miglustat) derived from naturally
occurring plant products
- another class of compounds containing a pyrrolidine
ring that serve as ceramide analogs (Eliglustat)
20. Inhibitors of Glucosylceramide
Synthase
OH OH
HO
O O
N
HO O
HN O
HO OH HN O
O
ceramide
glucose Ceramide-based analogue
Genz-112638
HO CH2OH
N
HO
OH
Imino sugar-based analogue
Glucosylceramide Miglustat (Zavesca®)
21. Miglustat (Zavesca)
• At a dose of 100 mg thrice daily, the agent reduced
visceral enlargement and slowly improved hematologic
parameters, as well as surrogate plasma biomarkers, in
patients with type I Gaucher disease
• Miglustat was considered to have acceptable safety and
tolerability and to be effective for the long-term
maintenance of patients with type I Gaucher disease
who had previouslyreceived enzyme therapy
Pastores GM, et al Clin Ther. 2005;27(8):1215–1227.
Elstein et al. J Inherit Metab Dis. 2004;27(6):757–766
22. Miglustat: Side effects
• An unwanted effect of Miglustat treatment was
diarrhea, caused by an inhibition of intestinal
disaccharidase activity
• Some patients also developed tremor and/or
peripheral neuropathy
• The drug has been licensed in the United States
and Europe as a second-line treatment for
patients with mild to moderate type1 Gaucher
Disease
Giraldo P, et al Haematologica. 2009;94(12):1771–1775.
23. Genz 112638: Phase I:
Therapeutic Plasma Levels and Safety
1000
Cardiac AEs In the Phase Ib
240 ng/mL clinical trial,
Plasma Concentration (ng/mL)
GI AEs 1.6 mg/kg/day
> 100 ng/mL
100
(50 mg BID) produced
a mean Cmax of
Therapeutic 7 ng/mL
10
window
6 ng/mL
In vitro IC50
Sub-therapeutic?
1
24. Genz 112638: Phase II
2 yrs treatment
• These trials were undertaken in adults with type I
Gaucher disease, for which the entry criteria required
splenic enlargement of at least 10-fold normal,together
with thrombocytopenia and/or anemia
• The dose of drug was either started at 50 mg twice daily
or with monitoring for pharmacokinetics adjusted to 100
mg twice daily to ensure that rapid metabolizers would
have concentrations of the drug of ≈10 ng/mL.
Lukina E et al. Blood. 2010;116(6):893–899..
25. Genz 112638: Phase II
2 yrs treatment outcomes
• Continuing improvement in spleen and liver volumes (the former
decreased by a mean of 52%) with improvement in
hemoglobin concentration and a rise in platelet counts have
been observed.
• All these changes were accompanied by improvements in surrogate
biomarkers, including the chemokine CCL18-PARC and
chitotriosidase activity
• Of the 18 patients with abnormal dark signal independently identified
on magnetic resonance imaging, six had improved by 1
year and an additional two patients had shown improvements by 2
years on the trial
Lukina E, Watman N, Avila Arreguin E, et al. Blood. 2010 Aug 16. [Epub ahead of print].
26. Genz 112638: Phase III
• Randomized, open-label study foradults with type I
Gaucher disease, designed to compare the efficacy and
safety of eliglustat tartrate with that of Cerezyme.
Recruited patients should have received enzyme therapy
for at least 3 years
• Randomized,blind, placebo-controlled study for patients
with a confirmed diagnosis of type I Gaucher disease,
who have not been treated for at least 12 months
• A final trial has been registered, which will seek to
compare the effects of one daily dosing of eliglustat
tartrate with twice daily administration.
27. Treatment of Gaucher Disease
Which kind of treatment ?
• Supportive and palliative measures
• Enzyme replacement Therapy (ERT)
• Substrate inhibition therapy (SIT)
• Small molecules (chaperone therapy)
• Bone marrow transplantation
• Gene therapy
28. Chaperone therapy
The chaperone concept involves the binding of
the agent to the active site of the mutant
lysosomal protein,thus stabilizing it for delivery
to its normal site of action in the acidic
environment of the organelle.
• AT2101(Plicera)
• Only for patients with
mutations affecting the
protein folding
• Phase I/II completed
Parenti G. Treating lysosomal storage diseases with pharmacologicalchaperones:
from concept to clinics. EMBO Mol Med.2009;1(5):268–279.
29. Bone Marrow transplantation
• Bone marrow and contemporary hematopoietic
stem-cell transplantation is not in current general
use for Gaucher disease,partly because of the
shortage of ideal donors (human leukocyte
antigen matched) and procedural risks, as well
as the introduction of successful enzymatic
augmentation which has superseded this
treatment in many countries.
T. Cox. Dove press J, Biologics:targets and Therapy. Dec 2010
30. Gene Therapy
• Given the current state of knowledge and
preclinical studies, credible clinical trials could
soon be initiated
• A key requirement, however, would be sustained
expression of the therapeutic gene in
hepatocytes transduced: an issue that has yet to
be overcome
• The location of appropriate investigative centers
and selection of patients will be of critical
importance
T. Cox. Dove press J, Biologics:targets and Therapy. Dec 2010
31. Conclusions
• Gaucher Disease was the first lysosomal disease for
which a specific therapy was introduced in the US
orphan legislative milieu
• The success of enzyme replacement therapy has driven
pharmaceutical investment in other lysosomal diseases
• Orphan drug legislation is anticompetitive, but we now
know that even this cannot guarantee the survival of any
given drug, particularly a biologic agent like a therapeutic
enzyme
• The catastrophe has brought home not simply the
desirability but the absolute necessity of competition for
the safe provision of alternative biosimilar agents