Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LONDON – The investigational agent blinatumomab could help more patients with relapsed or refractory acute lymphoblastic leukemia achieve remission, compared with conventional treatment strategies, interim findings of an exploratory phase II trial suggest.

Although a small study – just 12 patients were included in the analysis – "we saw a response rate of 75%," principal study investigator Dr. Max S. Topp said in an interview at the annual European Hematology Association congress.

"Obviously it’s a very small number of patients," Dr. Topp, a professor of medicine and consultant in hematology at the University of Wurzburg in Munich, conceded. "Nevertheless it’s basically more than double what you would expect."

The outlook for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) is often grim, Dr. Topp noted, with low response rates to intensive chemotherapy (17%-45%), and a high chance of further relapse with a median duration of 4-5 months for complete remission (CR).There is also a high rate of treatment-related mortality, with up to a quarter of patients dying during their treatment.

"Blinatumomab is a new kind of drug. It’s not actually an antibody in the classical sense, which is more passive. This is actually something that is actively looking for the tumor, as it uses the T cells to exert its action," Dr. Topp explained.

According to Micromet, the company developing the novel agent, blinatumomab is the most advanced of a new class of agents called BiTE (bispecific T-cell engager) antibodies. These agents are designed to direct cytotoxic T-cells to CD19-expressing cancer cells (Science 2008;321:974-7).

Data from a phase I study have already shown that blinatumomab is active in the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphoma (American Society of Hematology annual meeting, abstract 2880). Dr. Topp and team have also demonstrated its tolerability and activity in patients with ALL who had minimal residual disease (MRD) (J. Clin. Oncol. 2011;29:2493-8).

"We then asked the question if you can actually treat full-blown relapse, and it looks like we can make a difference here," Dr. Topp observed.

The ongoing, open-label phase II study currently involves seven patients aged a median of 37 years who are being treated with blinatumomab at a dose of 15 mcg/m² per day over three cycles and for maintenance treatment. Another five patients, with a median age of 60 years, are receiving the drug at an initial dose of 5 mcg/m² per day, then at a dose of 15 or 30 mcg/m² per day (cohort 2). Blinatumomab is delivered via continuous intravenous infusion for 2 weeks, with a 2-week treatment-free period.

Although the agent is in its very early days, results show that it has great promise in the treatment of relapsed or refractory ALL. The overall CR rate was 75%, and 71% in patients given the steady 15-mcg dose of blinatumomab and 80% in those whose dose was increased in subsequent cycles.

The increasing dosing regimen appears to be associated with better tolerability. "Adapting the system to have a slow start with 5 mcg and going up to 15 mcg we have had no severe adverse events ... and that is great news," Dr. Topp observed.

Some of the most common side effects seen in the trial to date include raised gamma-glutamyltransferase and C-reactive protein, peripheral edema, fatigue, pyrexia. Blood fibrinogen and fibrin d-dimer have also been increased, suggesting that thrombotic complications could be a future concern.

The bottom line, said Dr. Topp, is that "we have a non-chemotherapy, immunotherapy-based, effective treatment for patients with relapsed ALL, with very good safety profile."

Research is ongoing and a further 10 patients are likely to be included in the current trial. "We’re looking at the safety issues. We have to find the most likely regimen which we would like to use," Dr. Topp said.

The study was funded by Micromet AG. Dr. Topp is the principal investigator for the trial and disclosed acting as a consultant to the company.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.

LOS ANGELES – For the first time, a pediatric stroke severity scale has been validated in a prospective clinical trial.

The study in 15 North American medical centers showed excellent interrater reliability when neurologists used a pediatric version of the National Institutes of Health Stroke Scale for adults to examine children aged 2-18 years with acute arterial ischemic stroke.

The neurologists used the Pediatric NIH Stroke Scale (PedNIHSS) on 113 patients who were examined daily from admission to discharge, or through day 7 of hospitalization.

Interrater reliability was tested in a subset of 25 patients who underwent simultaneous examinations by two pediatric neurologists.

Characteristics of the subgroup were similar to those of the entire cohort, Dr. Rebecca N. Ichord reported at the International Stroke Conference.

The simultaneous raters’ scores were identical in 60% of ratings and were within a 1-point difference in 84% of ratings (Stroke 2011;42:613-7).

Research into potential ways of preventing or treating childhood stroke has been stymied in the past by the lack of a validated and reliable pediatric stroke scale.

The PedNIHSS provides a way to index the severity of a child’s stroke, to make comparisons across treatment groups, and to get a baseline for predicting outcome, said Dr. Ichord, director of the pediatric stroke program at the Children’s Hospital of Philadelphia.

Clinicians, too, have been hungering for such a scale. "I have been asked over and over again [for a pediatric stroke scale] by clinicians who want to have a method of describing the severity of a child’s stroke," she said at the meeting, which was sponsored by the American Heart Association.

"It helps them with clinical decision making. It helps them to prepare parents and counsel parents. It helps to guide them as to how quickly and how urgently the child’s care should move forward. [Such a scale] is absolutely needed and wanted right now by clinicians on the front line," according to Dr. Ichord.

Characteristics of the patients and the strokes in the study were similar to those reported in previous pediatric stroke cohort studies, which suggests the current findings are generalizable and the PedNIHSS should be applicable in other settings.

Because all of the raters in the current study were pediatric neurologists or trainees, a separate study is needed to assess the PedNIHSS in the hands of other specialists, Dr. Ichord said.

The interrater reliability in the study compared favorably with that seen in studies of the adult NIHSS.

The pediatric version also found good interrater reliability for facial weakness, dysarthria, and ataxia, which was not seen with the adult stroke scale. The reasons for this difference are unclear.

The PedNIHSS was drafted by a consensus panel of pediatric and adult stroke experts. They limited the use of the pediatric scale to ages 2-18 years because younger children have limited language abilities, which are needed for use of the PedNIHSS.

Neonates and children younger than 2 years of age with acute ischemic stroke also frequently present without focal deficits, and so may require a scale with less emphasis on focal sensorimotor deficits, the investigators suggested.

A study is underway to compare PedNIHSS scores with infarct volume and with functional outcomes at 3 and 12 months.

Stroke affects 25 in 100,000 newborns and 12 in 100,000 children under 18 years of age. It is the sixth leading cause of death in children, according to the PedNIHSS Web site.

Ischemic stroke, in particular, is one of the top 10 causes of death among children, affecting 1.2-7.9 per 100,000 children aged 1 month to 18 years in North America and Europe, the investigators noted. Some 40%-60% of survivors are left with long-term motor and cognitive deficits that interfere with function.

Dr. Ichord and one of her associates in the study are on the clinical event committee for the Berlin Heart Trial for pediatric ventricular assist devices.