ANSWER
The correct answer is soft corn (choice “c”). They are caused by bony friction and almost always found between the fourth and fifth toes.

Soft corns are often mistaken for warts (choice “a”). But warts don’t present as painful, macerated lesions between the toes.

Morton neuroma (choice “b”) is actually a neurofibroma, not a virtual tumor. It is usually found on the plantar forefoot between the second and third toes.

Interdigital fungal infections (choice “d”) often develop between the fourth and fifth toes and are often macerated. However, they do not take the form of lesions and do not hurt.

DISCUSSION
Soft corns are known in podiatric circles as heloma molle but are sometimes called kissing corns because they’re caused by friction between bony prominences on the fourth and fifth phalanges, which rub together with every step. Normally, these toes are hourglass shaped, but in patients prone to develop soft corns, the proximal bases of the toes are too wide. The type of shoe the patient wears can be an important factor as well, especially when high heels and/or narrow toe boxes are involved.

The treatment of soft corns can be nonsurgical—sometimes as simple as separating the toes with a tuft of lambswool. However, surgical intervention is often required. In such cases, the head of the proximal phalanx is cut and removed to make the adjacent bones more parallel. Occasionally, the skin is so damaged that it too must be removed and the toes sewn together.

Removing corns with chemicals, shaving, or excision provides no lasting relief, since these  methods do not address the underlying structural issues.

Hard corns, also known as heloma durum, tend to develop on the dorsal aspect of the fifth toe secondary to pressure from shoes. Changing the type of shoe worn is one solution, but often, as with soft corns, the underlying bony prominence must be addressed.

There is a third type of corn, the periungual corn, which develops on or near the edge of a nail. These corns are often erroneously called warts.

This patient was referred to a podiatrist, who will likely solve the problem. There is no topical product that can help, and nonsurgical approaches will provide temporary relief at best.

ANSWER
The correct answer is soft corn (choice “c”). They are caused by bony friction and almost always found between the fourth and fifth toes.

Soft corns are often mistaken for warts (choice “a”). But warts don’t present as painful, macerated lesions between the toes.

Morton neuroma (choice “b”) is actually a neurofibroma, not a virtual tumor. It is usually found on the plantar forefoot between the second and third toes.

Interdigital fungal infections (choice “d”) often develop between the fourth and fifth toes and are often macerated. However, they do not take the form of lesions and do not hurt.

DISCUSSION
Soft corns are known in podiatric circles as heloma molle but are sometimes called kissing corns because they’re caused by friction between bony prominences on the fourth and fifth phalanges, which rub together with every step. Normally, these toes are hourglass shaped, but in patients prone to develop soft corns, the proximal bases of the toes are too wide. The type of shoe the patient wears can be an important factor as well, especially when high heels and/or narrow toe boxes are involved.

The treatment of soft corns can be nonsurgical—sometimes as simple as separating the toes with a tuft of lambswool. However, surgical intervention is often required. In such cases, the head of the proximal phalanx is cut and removed to make the adjacent bones more parallel. Occasionally, the skin is so damaged that it too must be removed and the toes sewn together.

Removing corns with chemicals, shaving, or excision provides no lasting relief, since these  methods do not address the underlying structural issues.

Hard corns, also known as heloma durum, tend to develop on the dorsal aspect of the fifth toe secondary to pressure from shoes. Changing the type of shoe worn is one solution, but often, as with soft corns, the underlying bony prominence must be addressed.

There is a third type of corn, the periungual corn, which develops on or near the edge of a nail. These corns are often erroneously called warts.

This patient was referred to a podiatrist, who will likely solve the problem. There is no topical product that can help, and nonsurgical approaches will provide temporary relief at best.

ANSWER
The correct answer is soft corn (choice “c”). They are caused by bony friction and almost always found between the fourth and fifth toes.

Soft corns are often mistaken for warts (choice “a”). But warts don’t present as painful, macerated lesions between the toes.

Morton neuroma (choice “b”) is actually a neurofibroma, not a virtual tumor. It is usually found on the plantar forefoot between the second and third toes.

Interdigital fungal infections (choice “d”) often develop between the fourth and fifth toes and are often macerated. However, they do not take the form of lesions and do not hurt.

DISCUSSION
Soft corns are known in podiatric circles as heloma molle but are sometimes called kissing corns because they’re caused by friction between bony prominences on the fourth and fifth phalanges, which rub together with every step. Normally, these toes are hourglass shaped, but in patients prone to develop soft corns, the proximal bases of the toes are too wide. The type of shoe the patient wears can be an important factor as well, especially when high heels and/or narrow toe boxes are involved.

The treatment of soft corns can be nonsurgical—sometimes as simple as separating the toes with a tuft of lambswool. However, surgical intervention is often required. In such cases, the head of the proximal phalanx is cut and removed to make the adjacent bones more parallel. Occasionally, the skin is so damaged that it too must be removed and the toes sewn together.

Removing corns with chemicals, shaving, or excision provides no lasting relief, since these  methods do not address the underlying structural issues.

Hard corns, also known as heloma durum, tend to develop on the dorsal aspect of the fifth toe secondary to pressure from shoes. Changing the type of shoe worn is one solution, but often, as with soft corns, the underlying bony prominence must be addressed.

There is a third type of corn, the periungual corn, which develops on or near the edge of a nail. These corns are often erroneously called warts.

This patient was referred to a podiatrist, who will likely solve the problem. There is no topical product that can help, and nonsurgical approaches will provide temporary relief at best.

Health care utilization for concussion among children has increased significantly, partly because of increased awareness but also because of the introduction of health care legislation mandating medical intervention before return to play, new data suggest.

Analysis of health insurance claims for insured children aged 12-18 years from the MarketScan database showed a 92% increase in concussion-related health care utilization between 2008-2009 and 2011-2012 in states with concussion legislation, compared with a 75% overall increase in states without the legislation, according Teresa B. Gibson, Ph.D., of the department of health care policy at Harvard Medical School, Boston, and her colleagues (JAMA Pediatrics 2014 Dec. 22 [doi:10.1001/jamapediatrics.2014.2320]).

After 2009, when the first state concussion laws were passed, states without those laws still demonstrated a 20.9% annual increase in health care utilization for concussion, while states with those laws showed, on average, an additional 13.1% increase, they noted.

At the end of the 2011-2012 school year, 35 states (70%) plus the District of Columbia had laws about sports-related concussion in children.

“We estimate that slightly more than half (60%) the increase in states without laws in effect resulted from the continued trend of increasing health care utilization established before the first law was passed,” the investigators wrote. Although the sources leading to the remaining 40% increase in utilization were not studied, it is likely that increased awareness of concussion brought by local and national media attention played a role.

The study was partly supported by Truven Health from the National Institute of Child Health and Human Development. No other conflicts of interest were declared.

Health care utilization for concussion among children has increased significantly, partly because of increased awareness but also because of the introduction of health care legislation mandating medical intervention before return to play, new data suggest.

Analysis of health insurance claims for insured children aged 12-18 years from the MarketScan database showed a 92% increase in concussion-related health care utilization between 2008-2009 and 2011-2012 in states with concussion legislation, compared with a 75% overall increase in states without the legislation, according Teresa B. Gibson, Ph.D., of the department of health care policy at Harvard Medical School, Boston, and her colleagues (JAMA Pediatrics 2014 Dec. 22 [doi:10.1001/jamapediatrics.2014.2320]).

After 2009, when the first state concussion laws were passed, states without those laws still demonstrated a 20.9% annual increase in health care utilization for concussion, while states with those laws showed, on average, an additional 13.1% increase, they noted.

At the end of the 2011-2012 school year, 35 states (70%) plus the District of Columbia had laws about sports-related concussion in children.

“We estimate that slightly more than half (60%) the increase in states without laws in effect resulted from the continued trend of increasing health care utilization established before the first law was passed,” the investigators wrote. Although the sources leading to the remaining 40% increase in utilization were not studied, it is likely that increased awareness of concussion brought by local and national media attention played a role.

The study was partly supported by Truven Health from the National Institute of Child Health and Human Development. No other conflicts of interest were declared.

Health care utilization for concussion among children has increased significantly, partly because of increased awareness but also because of the introduction of health care legislation mandating medical intervention before return to play, new data suggest.

Analysis of health insurance claims for insured children aged 12-18 years from the MarketScan database showed a 92% increase in concussion-related health care utilization between 2008-2009 and 2011-2012 in states with concussion legislation, compared with a 75% overall increase in states without the legislation, according Teresa B. Gibson, Ph.D., of the department of health care policy at Harvard Medical School, Boston, and her colleagues (JAMA Pediatrics 2014 Dec. 22 [doi:10.1001/jamapediatrics.2014.2320]).

After 2009, when the first state concussion laws were passed, states without those laws still demonstrated a 20.9% annual increase in health care utilization for concussion, while states with those laws showed, on average, an additional 13.1% increase, they noted.

At the end of the 2011-2012 school year, 35 states (70%) plus the District of Columbia had laws about sports-related concussion in children.

“We estimate that slightly more than half (60%) the increase in states without laws in effect resulted from the continued trend of increasing health care utilization established before the first law was passed,” the investigators wrote. Although the sources leading to the remaining 40% increase in utilization were not studied, it is likely that increased awareness of concussion brought by local and national media attention played a role.

The study was partly supported by Truven Health from the National Institute of Child Health and Human Development. No other conflicts of interest were declared.

Ewing sarcomas are characterized as primitive malignant round cell tumors.¹ These tumors are diagnosed by neuroectodermal differentiation and by their common histologic and immunohistochemical properties.² Ewing sarcoma is the second most common malignant bone tumor in adolescents and young adults. It is the fourth most common primary malignant tumor, accounting for about 9% of all malignant tumors of bone. The most common primary bone tumors are multiple myeloma, osteosarcoma, and chondrosarcoma.³

The diaphyses of long bones (eg, femur, tibia, humerus) and flat bones (eg, pelvis, scapula) are the most commonly involved sites. Involvement of bones in the hands and feet is uncommon (3%-5% of reported cases).⁴ The foot bones most commonly involved include the calcaneus and the metatarsals, in the series by Casadei and colleagues.⁵

About 90% of Ewing sarcoma cases present before age 20 years (mean age, 13 years).⁶ Typical presentation is that of localized pain at the involved site. Some patients have systemic symptoms, such as fever, malaise, weight loss, leukocytosis, and increased erythrocyte sedimentation rate (ESR) mimicking infection. Radiographically, Ewing sarcoma appears as a permeative destructive bone lesion with a moth-eaten appearance (almost 76% of cases).⁷ This is usually associated with lamellated periosteal new bone formation or an “onion skin” appearance. Less commonly, a sunburst configuration with an associated soft-tissue mass can be seen. Computed tomography (CT) and magnetic resonance imaging (MRI) show the osseous extent of the tumor and the presence or absence of the soft-tissue component of the tumor. Radionuclide bone scans show increased technetium-99m methylene diphosphonate accumulation and are typically hot.⁶

Histopathologically, the tumor is composed of small, uniformly sized cells characterized by an almost clear eosinophilic cytoplasm and very little intercellular matrix. There are lobules and strands divided by prominent septa. Macroscopically, appearance can range from a soft, fleshy solid mass to an almost liquid form, as the lesion does not produce any matrix. At time of surgery, the tumor may have a liquefied component and the appearance of pus.⁶ Prognostic factors are tumor site in foot and treatment according to the series by Casadei and colleagues.⁵ Patients with large central tumors, especially in the pelvis, have worse outcomes than patients with distal tumors.⁸

In this article, we report a case of multifocal Ewing sarcoma involving multiple bones in the foot. Given the multifocal nature of the disease confined to the foot, the initial impression was that of osteomyelitis. We describe the histologic, radiologic, and diagnostic features of the tumor and outline treatment and prognosis. To our knowledge, this is the first report of multifocal Ewing sarcoma involving multiple bones in the foot. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old man visited our clinic with the chief complaints of left foot pain and swelling. The pain started 10 months earlier and was followed by swelling. Complaints started after a minor local trauma. The man sought outside medical attention 8 months after pain onset. At his first visit at another institution, an initial radiograph was reported as normal, and all laboratory measures, including complete blood cell count (CBC) differential, ESR, and C-reactive protein (CRP) level, were within normal limits. Under the erroneous diagnosis of infection, the patient was treated with cloxacillin 500 mg 4 times a day for 4 weeks.

The patient’s pain had started 10 months before presentation (2 months after antibiotic therapy was initiated) (Figure 1). Physical examination at our institution revealed a palpable mass on the dorsum of the left foot. Anteroposterior and lateral plain radiographs showed a permeative lytic lesion with cortical destruction in the left calcaneus, navicular, cuboid, and cuneiform bones and in all metatarsal bones except the first (Figure 2). A soft-tissue mass around the involved bones was noted as well. The talus was not involved (Figure 3).

CT showed permeative destruction of left foot bones, including the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first. Invasion through the overlying cortex of the involved bones indicated aggressive biological activity of the tumor (Figure 4). MRI showed a destructive bony lesion of the mentioned bones associated with the soft-tissue mass (Figure 3).

Bone scan showed increased uptake in the involved areas (Figure 5). Chest plain radiographs and CT showed no distant metastasis. An incisional biopsy was performed, and histopathology showed a malignant small round cell tumor, identified as Ewing sarcoma (Figure 6). An immunohistochemistry study demonstrated positive CD99 and negative cytokeratin, leukocyte common antigen, desmin, and synaptophysin.

The patient was started on 4 cycles of adjuvant chemotherapy. Cycles 1 and 3 involved cyclophosphamide 2 g, vincristine 2 g, and doxorubicin 50 mg; cycles 2 and 4 involved ifosfamide 3.5 g and etoposide 200 mg. Tumor shrinkage occurred after chemotherapy. Clinical response to preoperative chemotherapy was documented by a decrease in tumor size at follow-ups. The patient underwent below-knee amputation.

Postoperative histopathology confirmed the diagnosis of Ewing sarcoma of the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first (Figure 7). At 2-year follow-up, the patient had no evidence of local recurrence or distant metastasis based on chest CT and clinical examination of the affected site.

Discussion

Ewing sarcoma is the prototype of round small cell malignancies that arise from the long bones and the flat bones. It seldom involves the hands or feet. To our knowledge, this is the first report of Ewing sarcoma of the foot with multiple-bone involvement. Our literature review found a case of Ewing sarcoma of the first phalanx of the third toe, the second metatarsal bone, the cuneiform, the cuboid, and the talus, with lesser soft-tissue extension compared with our patient’s case.⁹

As this foot tumor is rare, there are few reports on its clinical aspects, appropriate treatment, and long-term outcome. For treatment of nonmetastatic Ewing sarcoma, limb-salvage surgery is advised if response has been good and there is a reasonable expectation of negative margins and good functional results.

Radiation and surgery may be part of the overall treatment plan. Radiation without surgery has a unique role in pelvic Ewing sarcoma, in contrast to extremity Ewing sarcoma. In our opinion, margins and histologic necrosis in the resection specimen are examined after surgery, and, if the margins are widely negative and histologic response is good, no further local control is advised. If the margin is positive, postoperative radiation therapy is recommended.¹ Amputation has gradually become a (rare) choice in the treatment of extremity sarcomas.⁹ In our patient’s case, surgery was preferred over radiation therapy after chemotherapy because of the low risk of local side effects and the expected high efficacy. In addition, radiation at such high doses for Ewing sarcoma in the foot causes functional impairment. Because of the multiple-bone involvement, a salvage procedure was not possible for our patient. Given the calcaneal involvement, however, below-knee amputation was considered safer than ankle disarticulation.

Multiple-bone involvement occurs in the advanced stage of Ewing sarcoma, usually after visceral and pulmonary metastases are detected.⁹ The case reported by Rammal and colleagues⁹ had both multiple-bone involvement in the foot and pulmonary metastasis. The authors indicated that hematogenous spread of the tumor was discerned because the lesions were noncontiguous.⁹ Our patient had no distant metastases. We think his tumor originated in a tarsal or midtarsal bone and extended to adjacent bones. Therefore, it probably spread through its capsular and ligamentous attachment among tarsal and midtarsal bones, as the involvement was contiguous rather than distinct.

Average delay from symptom onset to diagnosis was reported to be 34 weeks.³ Average physician delay from initial visit to correct diagnosis was reported to be 19 weeks.³ Patients may have erythema, fever, and swelling, suggestive of osteomyelitis.³ Laboratory results may show increased white blood cell count and elevated ESR and CRP level.³ In addition, needle biopsy of the tumor may reveal an appearance grossly similar to that of pus.³ Therefore, physicians may send all the tissue out for microbiological analysis (according to the erroneous diagnosis of infection) and none out for pathologic analysis. The situation can be further complicated when Ewing sarcoma occurs in the foot, an uncommon site. In this special case, multiple-bone involvement can present a misleading clinical picture of infection.¹⁰ In other words, infection is one of the best choices in the differential diagnosis.⁷ Also to be considered are multicentric giant cell tumor, fibrosarcoma,¹¹ and osteosarcoma.¹²

Ewing sarcomas are characterized as primitive malignant round cell tumors.¹ These tumors are diagnosed by neuroectodermal differentiation and by their common histologic and immunohistochemical properties.² Ewing sarcoma is the second most common malignant bone tumor in adolescents and young adults. It is the fourth most common primary malignant tumor, accounting for about 9% of all malignant tumors of bone. The most common primary bone tumors are multiple myeloma, osteosarcoma, and chondrosarcoma.³

The diaphyses of long bones (eg, femur, tibia, humerus) and flat bones (eg, pelvis, scapula) are the most commonly involved sites. Involvement of bones in the hands and feet is uncommon (3%-5% of reported cases).⁴ The foot bones most commonly involved include the calcaneus and the metatarsals, in the series by Casadei and colleagues.⁵

About 90% of Ewing sarcoma cases present before age 20 years (mean age, 13 years).⁶ Typical presentation is that of localized pain at the involved site. Some patients have systemic symptoms, such as fever, malaise, weight loss, leukocytosis, and increased erythrocyte sedimentation rate (ESR) mimicking infection. Radiographically, Ewing sarcoma appears as a permeative destructive bone lesion with a moth-eaten appearance (almost 76% of cases).⁷ This is usually associated with lamellated periosteal new bone formation or an “onion skin” appearance. Less commonly, a sunburst configuration with an associated soft-tissue mass can be seen. Computed tomography (CT) and magnetic resonance imaging (MRI) show the osseous extent of the tumor and the presence or absence of the soft-tissue component of the tumor. Radionuclide bone scans show increased technetium-99m methylene diphosphonate accumulation and are typically hot.⁶

Histopathologically, the tumor is composed of small, uniformly sized cells characterized by an almost clear eosinophilic cytoplasm and very little intercellular matrix. There are lobules and strands divided by prominent septa. Macroscopically, appearance can range from a soft, fleshy solid mass to an almost liquid form, as the lesion does not produce any matrix. At time of surgery, the tumor may have a liquefied component and the appearance of pus.⁶ Prognostic factors are tumor site in foot and treatment according to the series by Casadei and colleagues.⁵ Patients with large central tumors, especially in the pelvis, have worse outcomes than patients with distal tumors.⁸

In this article, we report a case of multifocal Ewing sarcoma involving multiple bones in the foot. Given the multifocal nature of the disease confined to the foot, the initial impression was that of osteomyelitis. We describe the histologic, radiologic, and diagnostic features of the tumor and outline treatment and prognosis. To our knowledge, this is the first report of multifocal Ewing sarcoma involving multiple bones in the foot. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old man visited our clinic with the chief complaints of left foot pain and swelling. The pain started 10 months earlier and was followed by swelling. Complaints started after a minor local trauma. The man sought outside medical attention 8 months after pain onset. At his first visit at another institution, an initial radiograph was reported as normal, and all laboratory measures, including complete blood cell count (CBC) differential, ESR, and C-reactive protein (CRP) level, were within normal limits. Under the erroneous diagnosis of infection, the patient was treated with cloxacillin 500 mg 4 times a day for 4 weeks.

The patient’s pain had started 10 months before presentation (2 months after antibiotic therapy was initiated) (Figure 1). Physical examination at our institution revealed a palpable mass on the dorsum of the left foot. Anteroposterior and lateral plain radiographs showed a permeative lytic lesion with cortical destruction in the left calcaneus, navicular, cuboid, and cuneiform bones and in all metatarsal bones except the first (Figure 2). A soft-tissue mass around the involved bones was noted as well. The talus was not involved (Figure 3).

CT showed permeative destruction of left foot bones, including the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first. Invasion through the overlying cortex of the involved bones indicated aggressive biological activity of the tumor (Figure 4). MRI showed a destructive bony lesion of the mentioned bones associated with the soft-tissue mass (Figure 3).

Bone scan showed increased uptake in the involved areas (Figure 5). Chest plain radiographs and CT showed no distant metastasis. An incisional biopsy was performed, and histopathology showed a malignant small round cell tumor, identified as Ewing sarcoma (Figure 6). An immunohistochemistry study demonstrated positive CD99 and negative cytokeratin, leukocyte common antigen, desmin, and synaptophysin.

The patient was started on 4 cycles of adjuvant chemotherapy. Cycles 1 and 3 involved cyclophosphamide 2 g, vincristine 2 g, and doxorubicin 50 mg; cycles 2 and 4 involved ifosfamide 3.5 g and etoposide 200 mg. Tumor shrinkage occurred after chemotherapy. Clinical response to preoperative chemotherapy was documented by a decrease in tumor size at follow-ups. The patient underwent below-knee amputation.

Postoperative histopathology confirmed the diagnosis of Ewing sarcoma of the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first (Figure 7). At 2-year follow-up, the patient had no evidence of local recurrence or distant metastasis based on chest CT and clinical examination of the affected site.

Discussion

Ewing sarcoma is the prototype of round small cell malignancies that arise from the long bones and the flat bones. It seldom involves the hands or feet. To our knowledge, this is the first report of Ewing sarcoma of the foot with multiple-bone involvement. Our literature review found a case of Ewing sarcoma of the first phalanx of the third toe, the second metatarsal bone, the cuneiform, the cuboid, and the talus, with lesser soft-tissue extension compared with our patient’s case.⁹

As this foot tumor is rare, there are few reports on its clinical aspects, appropriate treatment, and long-term outcome. For treatment of nonmetastatic Ewing sarcoma, limb-salvage surgery is advised if response has been good and there is a reasonable expectation of negative margins and good functional results.

Radiation and surgery may be part of the overall treatment plan. Radiation without surgery has a unique role in pelvic Ewing sarcoma, in contrast to extremity Ewing sarcoma. In our opinion, margins and histologic necrosis in the resection specimen are examined after surgery, and, if the margins are widely negative and histologic response is good, no further local control is advised. If the margin is positive, postoperative radiation therapy is recommended.¹ Amputation has gradually become a (rare) choice in the treatment of extremity sarcomas.⁹ In our patient’s case, surgery was preferred over radiation therapy after chemotherapy because of the low risk of local side effects and the expected high efficacy. In addition, radiation at such high doses for Ewing sarcoma in the foot causes functional impairment. Because of the multiple-bone involvement, a salvage procedure was not possible for our patient. Given the calcaneal involvement, however, below-knee amputation was considered safer than ankle disarticulation.

Multiple-bone involvement occurs in the advanced stage of Ewing sarcoma, usually after visceral and pulmonary metastases are detected.⁹ The case reported by Rammal and colleagues⁹ had both multiple-bone involvement in the foot and pulmonary metastasis. The authors indicated that hematogenous spread of the tumor was discerned because the lesions were noncontiguous.⁹ Our patient had no distant metastases. We think his tumor originated in a tarsal or midtarsal bone and extended to adjacent bones. Therefore, it probably spread through its capsular and ligamentous attachment among tarsal and midtarsal bones, as the involvement was contiguous rather than distinct.

Average delay from symptom onset to diagnosis was reported to be 34 weeks.³ Average physician delay from initial visit to correct diagnosis was reported to be 19 weeks.³ Patients may have erythema, fever, and swelling, suggestive of osteomyelitis.³ Laboratory results may show increased white blood cell count and elevated ESR and CRP level.³ In addition, needle biopsy of the tumor may reveal an appearance grossly similar to that of pus.³ Therefore, physicians may send all the tissue out for microbiological analysis (according to the erroneous diagnosis of infection) and none out for pathologic analysis. The situation can be further complicated when Ewing sarcoma occurs in the foot, an uncommon site. In this special case, multiple-bone involvement can present a misleading clinical picture of infection.¹⁰ In other words, infection is one of the best choices in the differential diagnosis.⁷ Also to be considered are multicentric giant cell tumor, fibrosarcoma,¹¹ and osteosarcoma.¹²

Ewing sarcomas are characterized as primitive malignant round cell tumors.¹ These tumors are diagnosed by neuroectodermal differentiation and by their common histologic and immunohistochemical properties.² Ewing sarcoma is the second most common malignant bone tumor in adolescents and young adults. It is the fourth most common primary malignant tumor, accounting for about 9% of all malignant tumors of bone. The most common primary bone tumors are multiple myeloma, osteosarcoma, and chondrosarcoma.³

The diaphyses of long bones (eg, femur, tibia, humerus) and flat bones (eg, pelvis, scapula) are the most commonly involved sites. Involvement of bones in the hands and feet is uncommon (3%-5% of reported cases).⁴ The foot bones most commonly involved include the calcaneus and the metatarsals, in the series by Casadei and colleagues.⁵

About 90% of Ewing sarcoma cases present before age 20 years (mean age, 13 years).⁶ Typical presentation is that of localized pain at the involved site. Some patients have systemic symptoms, such as fever, malaise, weight loss, leukocytosis, and increased erythrocyte sedimentation rate (ESR) mimicking infection. Radiographically, Ewing sarcoma appears as a permeative destructive bone lesion with a moth-eaten appearance (almost 76% of cases).⁷ This is usually associated with lamellated periosteal new bone formation or an “onion skin” appearance. Less commonly, a sunburst configuration with an associated soft-tissue mass can be seen. Computed tomography (CT) and magnetic resonance imaging (MRI) show the osseous extent of the tumor and the presence or absence of the soft-tissue component of the tumor. Radionuclide bone scans show increased technetium-99m methylene diphosphonate accumulation and are typically hot.⁶

Histopathologically, the tumor is composed of small, uniformly sized cells characterized by an almost clear eosinophilic cytoplasm and very little intercellular matrix. There are lobules and strands divided by prominent septa. Macroscopically, appearance can range from a soft, fleshy solid mass to an almost liquid form, as the lesion does not produce any matrix. At time of surgery, the tumor may have a liquefied component and the appearance of pus.⁶ Prognostic factors are tumor site in foot and treatment according to the series by Casadei and colleagues.⁵ Patients with large central tumors, especially in the pelvis, have worse outcomes than patients with distal tumors.⁸

In this article, we report a case of multifocal Ewing sarcoma involving multiple bones in the foot. Given the multifocal nature of the disease confined to the foot, the initial impression was that of osteomyelitis. We describe the histologic, radiologic, and diagnostic features of the tumor and outline treatment and prognosis. To our knowledge, this is the first report of multifocal Ewing sarcoma involving multiple bones in the foot. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 19-year-old man visited our clinic with the chief complaints of left foot pain and swelling. The pain started 10 months earlier and was followed by swelling. Complaints started after a minor local trauma. The man sought outside medical attention 8 months after pain onset. At his first visit at another institution, an initial radiograph was reported as normal, and all laboratory measures, including complete blood cell count (CBC) differential, ESR, and C-reactive protein (CRP) level, were within normal limits. Under the erroneous diagnosis of infection, the patient was treated with cloxacillin 500 mg 4 times a day for 4 weeks.

The patient’s pain had started 10 months before presentation (2 months after antibiotic therapy was initiated) (Figure 1). Physical examination at our institution revealed a palpable mass on the dorsum of the left foot. Anteroposterior and lateral plain radiographs showed a permeative lytic lesion with cortical destruction in the left calcaneus, navicular, cuboid, and cuneiform bones and in all metatarsal bones except the first (Figure 2). A soft-tissue mass around the involved bones was noted as well. The talus was not involved (Figure 3).

CT showed permeative destruction of left foot bones, including the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first. Invasion through the overlying cortex of the involved bones indicated aggressive biological activity of the tumor (Figure 4). MRI showed a destructive bony lesion of the mentioned bones associated with the soft-tissue mass (Figure 3).

Bone scan showed increased uptake in the involved areas (Figure 5). Chest plain radiographs and CT showed no distant metastasis. An incisional biopsy was performed, and histopathology showed a malignant small round cell tumor, identified as Ewing sarcoma (Figure 6). An immunohistochemistry study demonstrated positive CD99 and negative cytokeratin, leukocyte common antigen, desmin, and synaptophysin.

The patient was started on 4 cycles of adjuvant chemotherapy. Cycles 1 and 3 involved cyclophosphamide 2 g, vincristine 2 g, and doxorubicin 50 mg; cycles 2 and 4 involved ifosfamide 3.5 g and etoposide 200 mg. Tumor shrinkage occurred after chemotherapy. Clinical response to preoperative chemotherapy was documented by a decrease in tumor size at follow-ups. The patient underwent below-knee amputation.

Postoperative histopathology confirmed the diagnosis of Ewing sarcoma of the calcaneus, navicular, cuboid, and cuneiform bones and all metatarsal bones except the first (Figure 7). At 2-year follow-up, the patient had no evidence of local recurrence or distant metastasis based on chest CT and clinical examination of the affected site.

Discussion

Ewing sarcoma is the prototype of round small cell malignancies that arise from the long bones and the flat bones. It seldom involves the hands or feet. To our knowledge, this is the first report of Ewing sarcoma of the foot with multiple-bone involvement. Our literature review found a case of Ewing sarcoma of the first phalanx of the third toe, the second metatarsal bone, the cuneiform, the cuboid, and the talus, with lesser soft-tissue extension compared with our patient’s case.⁹

As this foot tumor is rare, there are few reports on its clinical aspects, appropriate treatment, and long-term outcome. For treatment of nonmetastatic Ewing sarcoma, limb-salvage surgery is advised if response has been good and there is a reasonable expectation of negative margins and good functional results.

Radiation and surgery may be part of the overall treatment plan. Radiation without surgery has a unique role in pelvic Ewing sarcoma, in contrast to extremity Ewing sarcoma. In our opinion, margins and histologic necrosis in the resection specimen are examined after surgery, and, if the margins are widely negative and histologic response is good, no further local control is advised. If the margin is positive, postoperative radiation therapy is recommended.¹ Amputation has gradually become a (rare) choice in the treatment of extremity sarcomas.⁹ In our patient’s case, surgery was preferred over radiation therapy after chemotherapy because of the low risk of local side effects and the expected high efficacy. In addition, radiation at such high doses for Ewing sarcoma in the foot causes functional impairment. Because of the multiple-bone involvement, a salvage procedure was not possible for our patient. Given the calcaneal involvement, however, below-knee amputation was considered safer than ankle disarticulation.

Multiple-bone involvement occurs in the advanced stage of Ewing sarcoma, usually after visceral and pulmonary metastases are detected.⁹ The case reported by Rammal and colleagues⁹ had both multiple-bone involvement in the foot and pulmonary metastasis. The authors indicated that hematogenous spread of the tumor was discerned because the lesions were noncontiguous.⁹ Our patient had no distant metastases. We think his tumor originated in a tarsal or midtarsal bone and extended to adjacent bones. Therefore, it probably spread through its capsular and ligamentous attachment among tarsal and midtarsal bones, as the involvement was contiguous rather than distinct.

Average delay from symptom onset to diagnosis was reported to be 34 weeks.³ Average physician delay from initial visit to correct diagnosis was reported to be 19 weeks.³ Patients may have erythema, fever, and swelling, suggestive of osteomyelitis.³ Laboratory results may show increased white blood cell count and elevated ESR and CRP level.³ In addition, needle biopsy of the tumor may reveal an appearance grossly similar to that of pus.³ Therefore, physicians may send all the tissue out for microbiological analysis (according to the erroneous diagnosis of infection) and none out for pathologic analysis. The situation can be further complicated when Ewing sarcoma occurs in the foot, an uncommon site. In this special case, multiple-bone involvement can present a misleading clinical picture of infection.¹⁰ In other words, infection is one of the best choices in the differential diagnosis.⁷ Also to be considered are multicentric giant cell tumor, fibrosarcoma,¹¹ and osteosarcoma.¹²

Q) When I see a patient for an annual physical or gynecologic exam (or even just to give a flu shot), I try to encourage healthy living. Are there any CKD statistics I can use to “encourage” my hypertensive or overweight patients to follow a better plan of care?

According to a recent study by McMahon et al, risk factors for chronic kidney disease (CKD)—including hypertension, dyslipidemia, and diabetes—may be present up to 30 years prior to diagnosis of CKD.¹ Since these risk factors are modifiable, the researchers concluded that early intervention could lead to a reduction in new CKD cases.¹

Using data from the Framingham Offspring Study, the researchers identified 441 patients with incident CKD and then matched them with a control group of 882 patients who did not develop CKD during the 30-year study period. Subjects who eventually developed CKD were more likely than their counterparts to have hypertension (odds ratio [OR], 1.76), obesity (OR, 1.71), and elevated triglyceride levels (OR, 1.43) 30 years prior to CKD diagnosis. Having diabetes nearly tripled a patient’s likelihood of developing CKD within 20 years (OR, 2.90).¹

Early identification of these risk factors and treatment of affected patients is imperative to help prevent kidney disease. Regular screening of young and middle-aged adult patients, as well as early intervention when risk factors are identified, should slow not only the progression of these detrimental conditions but also the development of CKD.

Joanne Hindlet, ACNP, CNN-NP
Houston Nephrology Group

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

Q) When I see a patient for an annual physical or gynecologic exam (or even just to give a flu shot), I try to encourage healthy living. Are there any CKD statistics I can use to “encourage” my hypertensive or overweight patients to follow a better plan of care?

According to a recent study by McMahon et al, risk factors for chronic kidney disease (CKD)—including hypertension, dyslipidemia, and diabetes—may be present up to 30 years prior to diagnosis of CKD.¹ Since these risk factors are modifiable, the researchers concluded that early intervention could lead to a reduction in new CKD cases.¹

Using data from the Framingham Offspring Study, the researchers identified 441 patients with incident CKD and then matched them with a control group of 882 patients who did not develop CKD during the 30-year study period. Subjects who eventually developed CKD were more likely than their counterparts to have hypertension (odds ratio [OR], 1.76), obesity (OR, 1.71), and elevated triglyceride levels (OR, 1.43) 30 years prior to CKD diagnosis. Having diabetes nearly tripled a patient’s likelihood of developing CKD within 20 years (OR, 2.90).¹

Early identification of these risk factors and treatment of affected patients is imperative to help prevent kidney disease. Regular screening of young and middle-aged adult patients, as well as early intervention when risk factors are identified, should slow not only the progression of these detrimental conditions but also the development of CKD.

Joanne Hindlet, ACNP, CNN-NP
Houston Nephrology Group

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

Q) When I see a patient for an annual physical or gynecologic exam (or even just to give a flu shot), I try to encourage healthy living. Are there any CKD statistics I can use to “encourage” my hypertensive or overweight patients to follow a better plan of care?

According to a recent study by McMahon et al, risk factors for chronic kidney disease (CKD)—including hypertension, dyslipidemia, and diabetes—may be present up to 30 years prior to diagnosis of CKD.¹ Since these risk factors are modifiable, the researchers concluded that early intervention could lead to a reduction in new CKD cases.¹

Using data from the Framingham Offspring Study, the researchers identified 441 patients with incident CKD and then matched them with a control group of 882 patients who did not develop CKD during the 30-year study period. Subjects who eventually developed CKD were more likely than their counterparts to have hypertension (odds ratio [OR], 1.76), obesity (OR, 1.71), and elevated triglyceride levels (OR, 1.43) 30 years prior to CKD diagnosis. Having diabetes nearly tripled a patient’s likelihood of developing CKD within 20 years (OR, 2.90).¹

Early identification of these risk factors and treatment of affected patients is imperative to help prevent kidney disease. Regular screening of young and middle-aged adult patients, as well as early intervention when risk factors are identified, should slow not only the progression of these detrimental conditions but also the development of CKD.

Joanne Hindlet, ACNP, CNN-NP
Houston Nephrology Group

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

Q) In my admitting orders for a CKD patient, I wrote for a “renal diet.” However, the nephrology practitioners changed it to a DASH diet. What is the difference? Why would they not want a “renal diet”?

The answer to this question is: It depends—on the patient, his/her comorbidities, and the need for dialysis treatments (and if so, what type he/she is receiving). Renal diet is a general term used to refer to medical nutrition therapy (MNT) given to a patient with CKD. Each of the five stages of CKD has its own specific MNT requirements.

The MNT for CKD patients often involves modification of the following nutrients: protein, sodium, potassium, phosphorus, and sometimes fluid. The complexity of this therapy often confuses health care professionals when a CKD patient is admitted to the hospital. Let’s examine each nutrient modification to understand optimal nutrition for CKD patients.

Protein. As kidneys fail to excrete urea, protein metabolism is compromised. Thus, in CKD stages 1 and 2, the general recommendations for protein intake are 0.8 to 1.4 g/kg/d. As a patient progresses into CKD stages 3 and 4, these recommendations decrease to 0.6 to 0.8 g/kg/d. In addition, the Kidney Disease Outcomes Quality Initiative (KDOQI) and the Academy of Nutrition and Dietetics recommend that at least 50% of that protein intake be of high biological value (eg, foods of animal origin, soy proteins, dairy, legumes, and nuts and nut butters).²

Why the wide range in protein intake? Needs vary depending on the patient’s comorbidities and nutritional status. Patients with greater need (eg, documented malnutrition, infections, or wounds) will require more protein than those without documented catabolic stress. Additionally, protein needs are based on weight, making it crucial to obtain an accurate weight. When managing a very overweight or underweight patient, an appropriate standard body weight must be calculated. This assessment should be done by a registered dietitian (RD).

Also, renal replacement therapies, once introduced, sharply increase protein needs. Hemodialysis (HD) can account for free amino acid losses of 5 to 20 g per treatment. Peritoneal dialysis (PD) can result in albumin losses of 5 to 15 g/d.² As a result, protein needs in HD and PD patients are about 1.2 g/kg/d of standard body weight. It has been reported that 30% to 50% of patients are not consuming these amounts, placing them at risk for malnutrition and a higher incidence of morbidity and mortality.²

Sodium. In CKD stages 1 to 4, dietary sodium intake should be less than 2,400 mg/d. The Dietary Approaches to Stop Hypertension (DASH) diet and a Mediterranean diet have been associated with ­reduced risk for decline in glomerular filtration rate (GFR) and better blood pressure control.³ Both of these diets can be employed, especially in the beginning stages of CKD. But as CKD progresses and urine output declines, recommendations for sodium intake for both HD and PD patients decrease to 2,000 mg/d. In an anuric patient, 2,000 mg/d is the maximum.²

Potassium. As kidney function declines, potassium retention occurs. In CKD stages 1 to 4, potassium restriction is not employed unless the serum level rises above normal.² The addition of an ACE inhibitor or an angiotensin II receptor blocker to the medication regimen necessitates close monitoring of potassium levels. Potassium allowance for HD varies according to the patient’s urine output and can range from 2 to 4 g/d. PD patients generally can tolerate 3 to 4 g/d of potassium without becoming hyperkalemic, as potassium is well cleared with PD.²

Continue for further examinations >>

Phosphorus. Mineral bone abnormalities begin early in the course of CKD and lead to high-turnover bone disease, adynamic bone disease, fractures, and soft-tissue calcification. Careful monitoring of calcium, intact parathyroid hormone, and phosphorus levels is required throughout all stages of CKD, with hyperphosphatemia of particular concern.

In CKD stages 1 and 2, dietary phosphorus should be limited to maintain a normal serum level.² As CKD progresses and phosphorus retention increases, 800 to 1,000 mg/d or 10 to 12 mg of phosphorus per gram of protein should be prescribed.

Even with the limitation of dietary phosphorus, phosphate-binding medications may be ­required to control serum phosphorus in later CKD stages and in HD and PD patients.² Limiting ­dietary phosphorus can be difficult for patients because of inorganic phosphate salt additives widely found in canned and processed foods; they are also added to dark colas and to meats and poultry to act as preservatives and improve flavor and texture. Phosphorus additives are 100% bioavailable and therefore more readily absorbed than organic phosphorus.⁴

Fluid. Lastly, CKD patients need to think about their fluid intake. HD patients with a urine output of > 1,000 mL/24-h period will be allowed up to 2,000 mL/d of fluid. (A 12-oz canned drink is 355 mL.) Those with less than 1,000 mL of urine output will be allowed 1,000 to 1,500 mL/d, with anuric patients capped at 1,000 mL/d. PD patients are allowed 1,000 to 3,000 mL/d depending on urine output and overall status.² Patients should also be reminded that foods such as soup and gelatin are counted in their fluid allowance.

The complexities of the “renal diet” make patient education by an RD critical. However, a recent article suggested that MNT for CKD patients is underutilized, with limited referrals and lack of education for primary care providers and RDs cited as reasons.⁵ This is mystifying considering that Medicare will pay for RD services for CKD patients.

The National Kidney Disease Education Program, in association with the Academy of Nutrition and Dietetics, has developed free professional and patient education materials to address this need; they are available at http://nkdep.nih.gov/.

Luanne DiGuglielmo, MS, RD, CSR
DaVita Summit Renal Center
Mountainside, New Jersey

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

Q) In my admitting orders for a CKD patient, I wrote for a “renal diet.” However, the nephrology practitioners changed it to a DASH diet. What is the difference? Why would they not want a “renal diet”?

The answer to this question is: It depends—on the patient, his/her comorbidities, and the need for dialysis treatments (and if so, what type he/she is receiving). Renal diet is a general term used to refer to medical nutrition therapy (MNT) given to a patient with CKD. Each of the five stages of CKD has its own specific MNT requirements.

The MNT for CKD patients often involves modification of the following nutrients: protein, sodium, potassium, phosphorus, and sometimes fluid. The complexity of this therapy often confuses health care professionals when a CKD patient is admitted to the hospital. Let’s examine each nutrient modification to understand optimal nutrition for CKD patients.

Protein. As kidneys fail to excrete urea, protein metabolism is compromised. Thus, in CKD stages 1 and 2, the general recommendations for protein intake are 0.8 to 1.4 g/kg/d. As a patient progresses into CKD stages 3 and 4, these recommendations decrease to 0.6 to 0.8 g/kg/d. In addition, the Kidney Disease Outcomes Quality Initiative (KDOQI) and the Academy of Nutrition and Dietetics recommend that at least 50% of that protein intake be of high biological value (eg, foods of animal origin, soy proteins, dairy, legumes, and nuts and nut butters).²

Why the wide range in protein intake? Needs vary depending on the patient’s comorbidities and nutritional status. Patients with greater need (eg, documented malnutrition, infections, or wounds) will require more protein than those without documented catabolic stress. Additionally, protein needs are based on weight, making it crucial to obtain an accurate weight. When managing a very overweight or underweight patient, an appropriate standard body weight must be calculated. This assessment should be done by a registered dietitian (RD).

Also, renal replacement therapies, once introduced, sharply increase protein needs. Hemodialysis (HD) can account for free amino acid losses of 5 to 20 g per treatment. Peritoneal dialysis (PD) can result in albumin losses of 5 to 15 g/d.² As a result, protein needs in HD and PD patients are about 1.2 g/kg/d of standard body weight. It has been reported that 30% to 50% of patients are not consuming these amounts, placing them at risk for malnutrition and a higher incidence of morbidity and mortality.²

Sodium. In CKD stages 1 to 4, dietary sodium intake should be less than 2,400 mg/d. The Dietary Approaches to Stop Hypertension (DASH) diet and a Mediterranean diet have been associated with ­reduced risk for decline in glomerular filtration rate (GFR) and better blood pressure control.³ Both of these diets can be employed, especially in the beginning stages of CKD. But as CKD progresses and urine output declines, recommendations for sodium intake for both HD and PD patients decrease to 2,000 mg/d. In an anuric patient, 2,000 mg/d is the maximum.²

Potassium. As kidney function declines, potassium retention occurs. In CKD stages 1 to 4, potassium restriction is not employed unless the serum level rises above normal.² The addition of an ACE inhibitor or an angiotensin II receptor blocker to the medication regimen necessitates close monitoring of potassium levels. Potassium allowance for HD varies according to the patient’s urine output and can range from 2 to 4 g/d. PD patients generally can tolerate 3 to 4 g/d of potassium without becoming hyperkalemic, as potassium is well cleared with PD.²

Continue for further examinations >>

Phosphorus. Mineral bone abnormalities begin early in the course of CKD and lead to high-turnover bone disease, adynamic bone disease, fractures, and soft-tissue calcification. Careful monitoring of calcium, intact parathyroid hormone, and phosphorus levels is required throughout all stages of CKD, with hyperphosphatemia of particular concern.

In CKD stages 1 and 2, dietary phosphorus should be limited to maintain a normal serum level.² As CKD progresses and phosphorus retention increases, 800 to 1,000 mg/d or 10 to 12 mg of phosphorus per gram of protein should be prescribed.

Even with the limitation of dietary phosphorus, phosphate-binding medications may be ­required to control serum phosphorus in later CKD stages and in HD and PD patients.² Limiting ­dietary phosphorus can be difficult for patients because of inorganic phosphate salt additives widely found in canned and processed foods; they are also added to dark colas and to meats and poultry to act as preservatives and improve flavor and texture. Phosphorus additives are 100% bioavailable and therefore more readily absorbed than organic phosphorus.⁴

Fluid. Lastly, CKD patients need to think about their fluid intake. HD patients with a urine output of > 1,000 mL/24-h period will be allowed up to 2,000 mL/d of fluid. (A 12-oz canned drink is 355 mL.) Those with less than 1,000 mL of urine output will be allowed 1,000 to 1,500 mL/d, with anuric patients capped at 1,000 mL/d. PD patients are allowed 1,000 to 3,000 mL/d depending on urine output and overall status.² Patients should also be reminded that foods such as soup and gelatin are counted in their fluid allowance.

The complexities of the “renal diet” make patient education by an RD critical. However, a recent article suggested that MNT for CKD patients is underutilized, with limited referrals and lack of education for primary care providers and RDs cited as reasons.⁵ This is mystifying considering that Medicare will pay for RD services for CKD patients.

The National Kidney Disease Education Program, in association with the Academy of Nutrition and Dietetics, has developed free professional and patient education materials to address this need; they are available at http://nkdep.nih.gov/.

Luanne DiGuglielmo, MS, RD, CSR
DaVita Summit Renal Center
Mountainside, New Jersey

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

Q) In my admitting orders for a CKD patient, I wrote for a “renal diet.” However, the nephrology practitioners changed it to a DASH diet. What is the difference? Why would they not want a “renal diet”?

The answer to this question is: It depends—on the patient, his/her comorbidities, and the need for dialysis treatments (and if so, what type he/she is receiving). Renal diet is a general term used to refer to medical nutrition therapy (MNT) given to a patient with CKD. Each of the five stages of CKD has its own specific MNT requirements.

The MNT for CKD patients often involves modification of the following nutrients: protein, sodium, potassium, phosphorus, and sometimes fluid. The complexity of this therapy often confuses health care professionals when a CKD patient is admitted to the hospital. Let’s examine each nutrient modification to understand optimal nutrition for CKD patients.

Protein. As kidneys fail to excrete urea, protein metabolism is compromised. Thus, in CKD stages 1 and 2, the general recommendations for protein intake are 0.8 to 1.4 g/kg/d. As a patient progresses into CKD stages 3 and 4, these recommendations decrease to 0.6 to 0.8 g/kg/d. In addition, the Kidney Disease Outcomes Quality Initiative (KDOQI) and the Academy of Nutrition and Dietetics recommend that at least 50% of that protein intake be of high biological value (eg, foods of animal origin, soy proteins, dairy, legumes, and nuts and nut butters).²

Why the wide range in protein intake? Needs vary depending on the patient’s comorbidities and nutritional status. Patients with greater need (eg, documented malnutrition, infections, or wounds) will require more protein than those without documented catabolic stress. Additionally, protein needs are based on weight, making it crucial to obtain an accurate weight. When managing a very overweight or underweight patient, an appropriate standard body weight must be calculated. This assessment should be done by a registered dietitian (RD).

Also, renal replacement therapies, once introduced, sharply increase protein needs. Hemodialysis (HD) can account for free amino acid losses of 5 to 20 g per treatment. Peritoneal dialysis (PD) can result in albumin losses of 5 to 15 g/d.² As a result, protein needs in HD and PD patients are about 1.2 g/kg/d of standard body weight. It has been reported that 30% to 50% of patients are not consuming these amounts, placing them at risk for malnutrition and a higher incidence of morbidity and mortality.²

Sodium. In CKD stages 1 to 4, dietary sodium intake should be less than 2,400 mg/d. The Dietary Approaches to Stop Hypertension (DASH) diet and a Mediterranean diet have been associated with ­reduced risk for decline in glomerular filtration rate (GFR) and better blood pressure control.³ Both of these diets can be employed, especially in the beginning stages of CKD. But as CKD progresses and urine output declines, recommendations for sodium intake for both HD and PD patients decrease to 2,000 mg/d. In an anuric patient, 2,000 mg/d is the maximum.²

Potassium. As kidney function declines, potassium retention occurs. In CKD stages 1 to 4, potassium restriction is not employed unless the serum level rises above normal.² The addition of an ACE inhibitor or an angiotensin II receptor blocker to the medication regimen necessitates close monitoring of potassium levels. Potassium allowance for HD varies according to the patient’s urine output and can range from 2 to 4 g/d. PD patients generally can tolerate 3 to 4 g/d of potassium without becoming hyperkalemic, as potassium is well cleared with PD.²

Continue for further examinations >>

Phosphorus. Mineral bone abnormalities begin early in the course of CKD and lead to high-turnover bone disease, adynamic bone disease, fractures, and soft-tissue calcification. Careful monitoring of calcium, intact parathyroid hormone, and phosphorus levels is required throughout all stages of CKD, with hyperphosphatemia of particular concern.

In CKD stages 1 and 2, dietary phosphorus should be limited to maintain a normal serum level.² As CKD progresses and phosphorus retention increases, 800 to 1,000 mg/d or 10 to 12 mg of phosphorus per gram of protein should be prescribed.

Even with the limitation of dietary phosphorus, phosphate-binding medications may be ­required to control serum phosphorus in later CKD stages and in HD and PD patients.² Limiting ­dietary phosphorus can be difficult for patients because of inorganic phosphate salt additives widely found in canned and processed foods; they are also added to dark colas and to meats and poultry to act as preservatives and improve flavor and texture. Phosphorus additives are 100% bioavailable and therefore more readily absorbed than organic phosphorus.⁴

Fluid. Lastly, CKD patients need to think about their fluid intake. HD patients with a urine output of > 1,000 mL/24-h period will be allowed up to 2,000 mL/d of fluid. (A 12-oz canned drink is 355 mL.) Those with less than 1,000 mL of urine output will be allowed 1,000 to 1,500 mL/d, with anuric patients capped at 1,000 mL/d. PD patients are allowed 1,000 to 3,000 mL/d depending on urine output and overall status.² Patients should also be reminded that foods such as soup and gelatin are counted in their fluid allowance.

The complexities of the “renal diet” make patient education by an RD critical. However, a recent article suggested that MNT for CKD patients is underutilized, with limited referrals and lack of education for primary care providers and RDs cited as reasons.⁵ This is mystifying considering that Medicare will pay for RD services for CKD patients.

The National Kidney Disease Education Program, in association with the Academy of Nutrition and Dietetics, has developed free professional and patient education materials to address this need; they are available at http://nkdep.nih.gov/.

Luanne DiGuglielmo, MS, RD, CSR
DaVita Summit Renal Center
Mountainside, New Jersey

REFERENCES
1. McMahon GM, Preis SR, Hwang S-J, Fox CS. Mid-adulthood risk factor profiles for CKD. J Am Soc Nephrol. 2014 Jun 26; [Epub ahead of print].
2. Byham-Gray L, Stover J, Wiesen K. A Clinical Guide to Nutrition Care in Kidney Disease. 2nd ed. The Academy of Nutrition and Dietetics; 2013.
3. Crews DC. Chronic kidney disease and access to healthful foods. ASN Kidney News. 2014;6(5):11.
4. Moe SM. Phosphate additives in food: you are what you eat—but shouldn’t you know that? ASN Kidney News. 2014;6(5):8.
5. Narva A, Norton J. Medical nutrition therapy for CKD. ASN Kidney News. 2014;6(5):7.

PRACTICE CHANGER
Prescribe a high-dose statin before any patient with acute coronary syndrome (ACS) undergoes percutaneous coronary intervention (PCI); it may be reasonable to extend this to patients being evaluated for ACS.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis¹

ILLUSTRATIVE CASE
A 48-year-old man comes to the emergency department with chest pain and is diagnosed with ACS. He is scheduled to have PCI within the next 24 hours. When should you start him on a statin?

Statins are the mainstay pharmaceutical treatment for hyperlipidemia and are used for primary and secondary prevention of coronary artery disease and stroke.^2,3 Well known for their cholesterol-lowering effect, they also offer benefits independent of lipids, including improving endothelial function, decreasing oxidative stress, and decreasing vascular inflammation.^4-6

Compared to patients with stable angina, those with ACS experience markedly higher rates of coronary events, especially immediately before and after PCI and during the subsequent 30 days.¹ American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST elevation myocardial infarction (NSTEMI) advocate starting statins before patients are discharged from the hospital, but they don’t specify precisely when.⁷

Considering the higher risk for coronary events before and after PCI and statins’ pleiotropic effects, it is reasonable to investigate the optimal time to start statins in patients with ACS.

Continue for study summary >>

STUDY SUMMARY
Meta-analysis shows statins before PCI cut risk for MI
Navarese et al¹ performed a systematic review and meta-analysis of studies comparing the clinical outcomes of patients with ACS who received statins before or after PCI (statins group) with those who received low-dose or no statins (control group). The authors searched PubMed, Cochrane, Google Scholar, and ­CINAHL databases as well as key conference proceedings for studies published before November 2013. Using reasonable inclusion and exclusion criteria and appropriate statistical methods, they analyzed the results of 20 randomized controlled trials that included 8,750 patients. Four studies enrolled only patients with ST elevation MI (STEMI), eight were restricted to NSTEMI, and the remaining eight studies enrolled patients with any type of MI or unstable angina.

For patients who were started on a statin before PCI, the mean timing of administration was 0.53 days before. For those started after PCI, the average time to administration was 3.18 days after.

Administering statins before PCI resulted in a greater reduction in the odds of MI than did starting them afterward. Whether administered before or after PCI, statins reduced the incidence of MIs. The overall 30-day incidence of MIs was 3.4% (123 of 3,621) in the statins group and 5% (179 of 3,577) in the control group. This resulted in an absolute risk reduction of 1.6% (number needed to treat = 62.5) and a 33% reduction of the odds of MI (odds ratio [OR] = 0.67). There was also a trend toward reduced mortality in the statin group (OR = 0.66).

In addition, administering statins before PCI resulted in a greater reduction in the odds of MI at 30 days (OR = 0.38) than starting them post-PCI (OR = 0.85) when compared to the controls. The difference between the pre-PCI OR and the post-PCI OR was statistically significant; these findings persisted past 30 days.

WHAT’S NEW
Early statin administration is most effective
According to ACC/AHA guidelines, all patients with ACS should be receiving a statin by the time they are discharged. However, when to start the statin is not specified. This meta-analysis is the first report to show that administering a statin before PCI can significantly reduce the risk for subsequent MI.

Next page: Caveats and challenges >>

CAVEATS
Benefits might vary with ­different statins
The studies evaluated in this ­meta-analysis used various statins and dosing regimens, which could have affected the results. However, sensitivity analyses found similar benefits across different types of statins. In addition, most of the included trials used high doses of statins, which minimized the potential discrepancy in outcomes from various dosing regimens. And while the included studies were not perfect, Navarese et al¹ used reasonable methods to identify potential biases.

CHALLENGES TO IMPLEMENTATION
No barriers to earlier start
Implementing this intervention may be as simple as editing a standard order. This meta-analysis also suggests that the earlier the intervention, the greater the benefit, which may be an argument for starting a statin when a patient first presents for evaluation for ACS, since the associated risks are quite low. We believe it would be beneficial if the next update of the ACC/AHA guidelines⁷ included this recommendation.

REFERENCES
1. Navarese EP, Kowalewski M, Andreotti F, et al. Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol. 2014;113:1753-1764.
2. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000;321:983-986.
3. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
4. Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002;86:5-18.
5. Li J, Li JJ, He JG, et al. Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. 2010;28:8-14.
6. Tandon V, Bano G, Khajuria V, et al. Pleiotropic effects of statins. Indian J Pharmacol. 2005; 37:77-85.
7. Wright RS, Anderson JL, Adams CD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57: e215-e367.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(12):735, 738.

PRACTICE CHANGER
Prescribe a high-dose statin before any patient with acute coronary syndrome (ACS) undergoes percutaneous coronary intervention (PCI); it may be reasonable to extend this to patients being evaluated for ACS.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis¹

ILLUSTRATIVE CASE
A 48-year-old man comes to the emergency department with chest pain and is diagnosed with ACS. He is scheduled to have PCI within the next 24 hours. When should you start him on a statin?

Statins are the mainstay pharmaceutical treatment for hyperlipidemia and are used for primary and secondary prevention of coronary artery disease and stroke.^2,3 Well known for their cholesterol-lowering effect, they also offer benefits independent of lipids, including improving endothelial function, decreasing oxidative stress, and decreasing vascular inflammation.^4-6

Compared to patients with stable angina, those with ACS experience markedly higher rates of coronary events, especially immediately before and after PCI and during the subsequent 30 days.¹ American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST elevation myocardial infarction (NSTEMI) advocate starting statins before patients are discharged from the hospital, but they don’t specify precisely when.⁷

Considering the higher risk for coronary events before and after PCI and statins’ pleiotropic effects, it is reasonable to investigate the optimal time to start statins in patients with ACS.

Continue for study summary >>

STUDY SUMMARY
Meta-analysis shows statins before PCI cut risk for MI
Navarese et al¹ performed a systematic review and meta-analysis of studies comparing the clinical outcomes of patients with ACS who received statins before or after PCI (statins group) with those who received low-dose or no statins (control group). The authors searched PubMed, Cochrane, Google Scholar, and ­CINAHL databases as well as key conference proceedings for studies published before November 2013. Using reasonable inclusion and exclusion criteria and appropriate statistical methods, they analyzed the results of 20 randomized controlled trials that included 8,750 patients. Four studies enrolled only patients with ST elevation MI (STEMI), eight were restricted to NSTEMI, and the remaining eight studies enrolled patients with any type of MI or unstable angina.

For patients who were started on a statin before PCI, the mean timing of administration was 0.53 days before. For those started after PCI, the average time to administration was 3.18 days after.

Administering statins before PCI resulted in a greater reduction in the odds of MI than did starting them afterward. Whether administered before or after PCI, statins reduced the incidence of MIs. The overall 30-day incidence of MIs was 3.4% (123 of 3,621) in the statins group and 5% (179 of 3,577) in the control group. This resulted in an absolute risk reduction of 1.6% (number needed to treat = 62.5) and a 33% reduction of the odds of MI (odds ratio [OR] = 0.67). There was also a trend toward reduced mortality in the statin group (OR = 0.66).

In addition, administering statins before PCI resulted in a greater reduction in the odds of MI at 30 days (OR = 0.38) than starting them post-PCI (OR = 0.85) when compared to the controls. The difference between the pre-PCI OR and the post-PCI OR was statistically significant; these findings persisted past 30 days.

WHAT’S NEW
Early statin administration is most effective
According to ACC/AHA guidelines, all patients with ACS should be receiving a statin by the time they are discharged. However, when to start the statin is not specified. This meta-analysis is the first report to show that administering a statin before PCI can significantly reduce the risk for subsequent MI.

Next page: Caveats and challenges >>

CAVEATS
Benefits might vary with ­different statins
The studies evaluated in this ­meta-analysis used various statins and dosing regimens, which could have affected the results. However, sensitivity analyses found similar benefits across different types of statins. In addition, most of the included trials used high doses of statins, which minimized the potential discrepancy in outcomes from various dosing regimens. And while the included studies were not perfect, Navarese et al¹ used reasonable methods to identify potential biases.

CHALLENGES TO IMPLEMENTATION
No barriers to earlier start
Implementing this intervention may be as simple as editing a standard order. This meta-analysis also suggests that the earlier the intervention, the greater the benefit, which may be an argument for starting a statin when a patient first presents for evaluation for ACS, since the associated risks are quite low. We believe it would be beneficial if the next update of the ACC/AHA guidelines⁷ included this recommendation.

REFERENCES
1. Navarese EP, Kowalewski M, Andreotti F, et al. Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol. 2014;113:1753-1764.
2. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000;321:983-986.
3. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
4. Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002;86:5-18.
5. Li J, Li JJ, He JG, et al. Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. 2010;28:8-14.
6. Tandon V, Bano G, Khajuria V, et al. Pleiotropic effects of statins. Indian J Pharmacol. 2005; 37:77-85.
7. Wright RS, Anderson JL, Adams CD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57: e215-e367.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(12):735, 738.

PRACTICE CHANGER
Prescribe a high-dose statin before any patient with acute coronary syndrome (ACS) undergoes percutaneous coronary intervention (PCI); it may be reasonable to extend this to patients being evaluated for ACS.¹

STRENGTH OF RECOMMENDATION
A: Based on a meta-analysis¹

ILLUSTRATIVE CASE
A 48-year-old man comes to the emergency department with chest pain and is diagnosed with ACS. He is scheduled to have PCI within the next 24 hours. When should you start him on a statin?

Statins are the mainstay pharmaceutical treatment for hyperlipidemia and are used for primary and secondary prevention of coronary artery disease and stroke.^2,3 Well known for their cholesterol-lowering effect, they also offer benefits independent of lipids, including improving endothelial function, decreasing oxidative stress, and decreasing vascular inflammation.^4-6

Compared to patients with stable angina, those with ACS experience markedly higher rates of coronary events, especially immediately before and after PCI and during the subsequent 30 days.¹ American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST elevation myocardial infarction (NSTEMI) advocate starting statins before patients are discharged from the hospital, but they don’t specify precisely when.⁷

Considering the higher risk for coronary events before and after PCI and statins’ pleiotropic effects, it is reasonable to investigate the optimal time to start statins in patients with ACS.

Continue for study summary >>

STUDY SUMMARY
Meta-analysis shows statins before PCI cut risk for MI
Navarese et al¹ performed a systematic review and meta-analysis of studies comparing the clinical outcomes of patients with ACS who received statins before or after PCI (statins group) with those who received low-dose or no statins (control group). The authors searched PubMed, Cochrane, Google Scholar, and ­CINAHL databases as well as key conference proceedings for studies published before November 2013. Using reasonable inclusion and exclusion criteria and appropriate statistical methods, they analyzed the results of 20 randomized controlled trials that included 8,750 patients. Four studies enrolled only patients with ST elevation MI (STEMI), eight were restricted to NSTEMI, and the remaining eight studies enrolled patients with any type of MI or unstable angina.

For patients who were started on a statin before PCI, the mean timing of administration was 0.53 days before. For those started after PCI, the average time to administration was 3.18 days after.

Administering statins before PCI resulted in a greater reduction in the odds of MI than did starting them afterward. Whether administered before or after PCI, statins reduced the incidence of MIs. The overall 30-day incidence of MIs was 3.4% (123 of 3,621) in the statins group and 5% (179 of 3,577) in the control group. This resulted in an absolute risk reduction of 1.6% (number needed to treat = 62.5) and a 33% reduction of the odds of MI (odds ratio [OR] = 0.67). There was also a trend toward reduced mortality in the statin group (OR = 0.66).

In addition, administering statins before PCI resulted in a greater reduction in the odds of MI at 30 days (OR = 0.38) than starting them post-PCI (OR = 0.85) when compared to the controls. The difference between the pre-PCI OR and the post-PCI OR was statistically significant; these findings persisted past 30 days.

WHAT’S NEW
Early statin administration is most effective
According to ACC/AHA guidelines, all patients with ACS should be receiving a statin by the time they are discharged. However, when to start the statin is not specified. This meta-analysis is the first report to show that administering a statin before PCI can significantly reduce the risk for subsequent MI.

Next page: Caveats and challenges >>

CAVEATS
Benefits might vary with ­different statins
The studies evaluated in this ­meta-analysis used various statins and dosing regimens, which could have affected the results. However, sensitivity analyses found similar benefits across different types of statins. In addition, most of the included trials used high doses of statins, which minimized the potential discrepancy in outcomes from various dosing regimens. And while the included studies were not perfect, Navarese et al¹ used reasonable methods to identify potential biases.

CHALLENGES TO IMPLEMENTATION
No barriers to earlier start
Implementing this intervention may be as simple as editing a standard order. This meta-analysis also suggests that the earlier the intervention, the greater the benefit, which may be an argument for starting a statin when a patient first presents for evaluation for ACS, since the associated risks are quite low. We believe it would be beneficial if the next update of the ACC/AHA guidelines⁷ included this recommendation.

REFERENCES
1. Navarese EP, Kowalewski M, Andreotti F, et al. Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol. 2014;113:1753-1764.
2. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000;321:983-986.
3. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
4. Liao JK. Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol. 2002;86:5-18.
5. Li J, Li JJ, He JG, et al. Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther. 2010;28:8-14.
6. Tandon V, Bano G, Khajuria V, et al. Pleiotropic effects of statins. Indian J Pharmacol. 2005; 37:77-85.
7. Wright RS, Anderson JL, Adams CD, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57: e215-e367.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(12):735, 738.

A 57-year-old woman sustained an injury to her left shoulder during a fall down stairs. She presented to the emergency department, where a physician ordered x-rays that a radiologist interpreted as depicting a simple fracture.

The patient claimed that the radiologist misread the x-rays and that the emergency medicine (EM) physician failed to realize her pain was out of proportion to a fracture. She said the EM physician should have ordered additional tests and sought a radiologic consult. The patient contended that she had actually dislocated her shoulder and that the delay in treatment caused her condition to worsen, leaving her unable to use her left hand.

In addition to the radiologist and the EM physician, two nurses were named as defendants. The plaintiff maintained that they had failed to notify the physician when her condition deteriorated.

OUTCOME
A $2.75 million settlement was reached. The hospital, the EM physician, and the nurses were responsible for $1.5 million and the radiologist, $1.25 million.

Continue for David M. Lang's comments >>

COMMENT
Although complex regional pain syndrome (CRPS, formerly known as reflex sympathetic dystrophy) is not specifically mentioned in this case synopsis, the size of the settlement suggests that it was likely claimed as the resulting injury. CRPS is frequently a source of litigation.

Relatively minor trauma can lead to CRPS; why only certain patients subsequently develop the syndrome, however, is a mystery. What is certain is that CRPS is recognized as one of the most painful conditions known to humankind. Once it develops, the syndrome can result in constant, debilitating pain, the loss of a limb, and near-total decay of a patient’s quality of life.

Plaintiffs’ attorneys are quick to claim negligence and substantial damages for these patients, with their sad, compelling stories. Because the underlying pathophysiology of CRPS is unclear, liability is often hotly debated, with cases difficult to defend.

Malpractice cases generally involve two elements: liability (the presence and magnitude of the error) and damages (the severity of the injury and impact on life). CRPS cases are often considered “damages” cases, because while liability may be uncertain, the patient’s damages are very clear. An understandingly sympathetic jury panel sees the unfortunate patient’s red, swollen, misshapen limb, hears the story of the patient’s ever-present, exquisite pain, and (based largely on human emotion) infers negligence based on the magnitude of the patient’s suffering.

In this case, the patient sustained a shoulder injury in a fall that was initially treated as a fracture (presumptively proximal) but later determined to be a dislocation. Management of the injury was not described, but we can assume that if a fracture was diagnosed, the shoulder joint was immobilized. The plaintiff did not claim that there were any diminished neurovascular findings at the time of injury. We are not told whether follow-up was arranged for the patient, what the final, full diagnosis was (eg, fracture/anterior dislocation of the proximal humerus), or when/if the shoulder was actively reduced.

Under these circumstances, what could a bedside clinician have done differently? The most prominent element is the report of “pain out of proportion to the diagnosis.” When confronted with pain that seems out of proportion to a limb injury, stop and review the case. Be sure to consider occult or evolving neurovascular injury (eg, compartment syndrome, brachial plexus injury). Seek consultation and a second opinion in cases involving pain that seems intractable and out of proportion.

One quick word about pain and drug-seeking behavior. Many of us are all too familiar with patients who overstate their symptoms to obtain narcotic pain medications. Will you encounter drug seekers who embellish their level of pain to obtain narcotics? You know the answer to that question.

But it is necessary to take an injured patient’s claim of pain as stated. Don’t view yourself as “wrong” or “fooled” if patients misstate their level of pain and you respond accordingly. In many cases, there is no way to differentiate between genuine manifestations of pain and gamesmanship. To attempt to do so is dangerous because it may lead you to dismiss a patient with genuine pain for fear of being “fooled.” Don’t. Few situations will irritate a jury more than a patient with genuine pathology who is wrongly considered a “drug seeker.” Take patients at face value and act appropriately if substance misuse is later discovered.

In this case, recognition of ­out-of-control pain may have resulted in an orthopedic consultation. At minimum, that would demonstrate that the patient’s pain was taken seriously and the clinicians acted with due concern for her.  —DML

A 57-year-old woman sustained an injury to her left shoulder during a fall down stairs. She presented to the emergency department, where a physician ordered x-rays that a radiologist interpreted as depicting a simple fracture.

The patient claimed that the radiologist misread the x-rays and that the emergency medicine (EM) physician failed to realize her pain was out of proportion to a fracture. She said the EM physician should have ordered additional tests and sought a radiologic consult. The patient contended that she had actually dislocated her shoulder and that the delay in treatment caused her condition to worsen, leaving her unable to use her left hand.

In addition to the radiologist and the EM physician, two nurses were named as defendants. The plaintiff maintained that they had failed to notify the physician when her condition deteriorated.

OUTCOME
A $2.75 million settlement was reached. The hospital, the EM physician, and the nurses were responsible for $1.5 million and the radiologist, $1.25 million.

Continue for David M. Lang's comments >>

COMMENT
Although complex regional pain syndrome (CRPS, formerly known as reflex sympathetic dystrophy) is not specifically mentioned in this case synopsis, the size of the settlement suggests that it was likely claimed as the resulting injury. CRPS is frequently a source of litigation.

Relatively minor trauma can lead to CRPS; why only certain patients subsequently develop the syndrome, however, is a mystery. What is certain is that CRPS is recognized as one of the most painful conditions known to humankind. Once it develops, the syndrome can result in constant, debilitating pain, the loss of a limb, and near-total decay of a patient’s quality of life.

Plaintiffs’ attorneys are quick to claim negligence and substantial damages for these patients, with their sad, compelling stories. Because the underlying pathophysiology of CRPS is unclear, liability is often hotly debated, with cases difficult to defend.

Malpractice cases generally involve two elements: liability (the presence and magnitude of the error) and damages (the severity of the injury and impact on life). CRPS cases are often considered “damages” cases, because while liability may be uncertain, the patient’s damages are very clear. An understandingly sympathetic jury panel sees the unfortunate patient’s red, swollen, misshapen limb, hears the story of the patient’s ever-present, exquisite pain, and (based largely on human emotion) infers negligence based on the magnitude of the patient’s suffering.

In this case, the patient sustained a shoulder injury in a fall that was initially treated as a fracture (presumptively proximal) but later determined to be a dislocation. Management of the injury was not described, but we can assume that if a fracture was diagnosed, the shoulder joint was immobilized. The plaintiff did not claim that there were any diminished neurovascular findings at the time of injury. We are not told whether follow-up was arranged for the patient, what the final, full diagnosis was (eg, fracture/anterior dislocation of the proximal humerus), or when/if the shoulder was actively reduced.

Under these circumstances, what could a bedside clinician have done differently? The most prominent element is the report of “pain out of proportion to the diagnosis.” When confronted with pain that seems out of proportion to a limb injury, stop and review the case. Be sure to consider occult or evolving neurovascular injury (eg, compartment syndrome, brachial plexus injury). Seek consultation and a second opinion in cases involving pain that seems intractable and out of proportion.

One quick word about pain and drug-seeking behavior. Many of us are all too familiar with patients who overstate their symptoms to obtain narcotic pain medications. Will you encounter drug seekers who embellish their level of pain to obtain narcotics? You know the answer to that question.

But it is necessary to take an injured patient’s claim of pain as stated. Don’t view yourself as “wrong” or “fooled” if patients misstate their level of pain and you respond accordingly. In many cases, there is no way to differentiate between genuine manifestations of pain and gamesmanship. To attempt to do so is dangerous because it may lead you to dismiss a patient with genuine pain for fear of being “fooled.” Don’t. Few situations will irritate a jury more than a patient with genuine pathology who is wrongly considered a “drug seeker.” Take patients at face value and act appropriately if substance misuse is later discovered.

In this case, recognition of ­out-of-control pain may have resulted in an orthopedic consultation. At minimum, that would demonstrate that the patient’s pain was taken seriously and the clinicians acted with due concern for her.  —DML

A 57-year-old woman sustained an injury to her left shoulder during a fall down stairs. She presented to the emergency department, where a physician ordered x-rays that a radiologist interpreted as depicting a simple fracture.

The patient claimed that the radiologist misread the x-rays and that the emergency medicine (EM) physician failed to realize her pain was out of proportion to a fracture. She said the EM physician should have ordered additional tests and sought a radiologic consult. The patient contended that she had actually dislocated her shoulder and that the delay in treatment caused her condition to worsen, leaving her unable to use her left hand.

In addition to the radiologist and the EM physician, two nurses were named as defendants. The plaintiff maintained that they had failed to notify the physician when her condition deteriorated.

OUTCOME
A $2.75 million settlement was reached. The hospital, the EM physician, and the nurses were responsible for $1.5 million and the radiologist, $1.25 million.

Continue for David M. Lang's comments >>

COMMENT
Although complex regional pain syndrome (CRPS, formerly known as reflex sympathetic dystrophy) is not specifically mentioned in this case synopsis, the size of the settlement suggests that it was likely claimed as the resulting injury. CRPS is frequently a source of litigation.

Relatively minor trauma can lead to CRPS; why only certain patients subsequently develop the syndrome, however, is a mystery. What is certain is that CRPS is recognized as one of the most painful conditions known to humankind. Once it develops, the syndrome can result in constant, debilitating pain, the loss of a limb, and near-total decay of a patient’s quality of life.

Plaintiffs’ attorneys are quick to claim negligence and substantial damages for these patients, with their sad, compelling stories. Because the underlying pathophysiology of CRPS is unclear, liability is often hotly debated, with cases difficult to defend.

Malpractice cases generally involve two elements: liability (the presence and magnitude of the error) and damages (the severity of the injury and impact on life). CRPS cases are often considered “damages” cases, because while liability may be uncertain, the patient’s damages are very clear. An understandingly sympathetic jury panel sees the unfortunate patient’s red, swollen, misshapen limb, hears the story of the patient’s ever-present, exquisite pain, and (based largely on human emotion) infers negligence based on the magnitude of the patient’s suffering.

In this case, the patient sustained a shoulder injury in a fall that was initially treated as a fracture (presumptively proximal) but later determined to be a dislocation. Management of the injury was not described, but we can assume that if a fracture was diagnosed, the shoulder joint was immobilized. The plaintiff did not claim that there were any diminished neurovascular findings at the time of injury. We are not told whether follow-up was arranged for the patient, what the final, full diagnosis was (eg, fracture/anterior dislocation of the proximal humerus), or when/if the shoulder was actively reduced.

Under these circumstances, what could a bedside clinician have done differently? The most prominent element is the report of “pain out of proportion to the diagnosis.” When confronted with pain that seems out of proportion to a limb injury, stop and review the case. Be sure to consider occult or evolving neurovascular injury (eg, compartment syndrome, brachial plexus injury). Seek consultation and a second opinion in cases involving pain that seems intractable and out of proportion.

One quick word about pain and drug-seeking behavior. Many of us are all too familiar with patients who overstate their symptoms to obtain narcotic pain medications. Will you encounter drug seekers who embellish their level of pain to obtain narcotics? You know the answer to that question.

But it is necessary to take an injured patient’s claim of pain as stated. Don’t view yourself as “wrong” or “fooled” if patients misstate their level of pain and you respond accordingly. In many cases, there is no way to differentiate between genuine manifestations of pain and gamesmanship. To attempt to do so is dangerous because it may lead you to dismiss a patient with genuine pain for fear of being “fooled.” Don’t. Few situations will irritate a jury more than a patient with genuine pathology who is wrongly considered a “drug seeker.” Take patients at face value and act appropriately if substance misuse is later discovered.

In this case, recognition of ­out-of-control pain may have resulted in an orthopedic consultation. At minimum, that would demonstrate that the patient’s pain was taken seriously and the clinicians acted with due concern for her.  —DML

Efforts to reach agreement on how vitamin D deficiency is defined are complicated by the fact that the cutoff points used in reports from clinical laboratories vary widely.

“I think reporting is a great problem because primary care physicians are very hurried,” Dr. John F. Aloia said at a public conference on vitamin D sponsored by the National Institutes of Health. “When you look at the laboratory report, what you get is a column that’s normal and another column that’s low or high. The choice of the laboratories to choose their own cutpoints is really a problem. The other part of that reporting is using the low level of normal in a range at the RDA [recommended daily allowance].”

In its recently updated recommendations on vitamin D screening, the U.S. Preventive Services Task Force noted that variability between serum vitamin D assay methods “and between laboratories using the same methods may range from 10% to 20%, and classification of samples as ‘deficient’ or ‘nondeficient’ may vary by 4% to 32%, depending on which assay is used. Another factor that may complicate interpretation is that 25-(OH)D may act as a negative acute-phase reactant and its levels may decrease in response to inflammation. Lastly, whether common laboratory reference ranges are appropriate for all ethnic groups is unclear.”

Trying to exert influence on what ranges of serum vitamin D laboratories are using in reporting data “is an issue,” said Dr. Aloia, director of the Bone Mineral Research Center at Winthrop University Hospital, Mineola, N.Y., and professor of medicine at Stony Brook (N.Y.) University. “A laboratory can report anything it chooses to. For instance, the American College of Pathology and other [professional organizations] don’t have the responsibility for [the cut-offs in] those reports.”

Dr. Aloia favors translating the reporting of vitamin D levels based on something like Z scores, “so when you see lab reports, some of them will have a paragraph of explanation to guide the physician,” he explained. “We’re going to need that. We have to move away from just [a] cutpoint range and the lower level of the range being the RDA.”

Dr. Roger Bouillon, professor emeritus of internal medicine at the University of Leuven (Belgium), supports a threshold of 20 ng/mL serum vitamin D in adults. “I don’t like a range [of vitamin D]; they just need to have a level above 20 ng/mL. For me, a threshold is the best strategy on a population basis.”

During an open comment session, attendee Dr. Neil C. Binkley expressed concern over applying Z-score principles to the vitamin D field. “I love bone density measurement,” said Dr. Binkley, codirector of the Osteoporosis Clinical Center & Research Program at the University of Wisconsin, Madison, and past president of the International Society for Clinical Densitometry. “The T-score was in fact an advance in the field. But I can’t tell you how strongly I would urge you to not consider T-scores or Z-scores or something like that in the vitamin D field. Rather, I would urge that we do a better job at measuring 25-hydroxyvitamin D so our laboratories agree and have concise guidance for primary care. If you choose to go into the probability realm and the Z-scores, it is going to be a disaster.”

The presenters reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

Efforts to reach agreement on how vitamin D deficiency is defined are complicated by the fact that the cutoff points used in reports from clinical laboratories vary widely.

“I think reporting is a great problem because primary care physicians are very hurried,” Dr. John F. Aloia said at a public conference on vitamin D sponsored by the National Institutes of Health. “When you look at the laboratory report, what you get is a column that’s normal and another column that’s low or high. The choice of the laboratories to choose their own cutpoints is really a problem. The other part of that reporting is using the low level of normal in a range at the RDA [recommended daily allowance].”

In its recently updated recommendations on vitamin D screening, the U.S. Preventive Services Task Force noted that variability between serum vitamin D assay methods “and between laboratories using the same methods may range from 10% to 20%, and classification of samples as ‘deficient’ or ‘nondeficient’ may vary by 4% to 32%, depending on which assay is used. Another factor that may complicate interpretation is that 25-(OH)D may act as a negative acute-phase reactant and its levels may decrease in response to inflammation. Lastly, whether common laboratory reference ranges are appropriate for all ethnic groups is unclear.”

Trying to exert influence on what ranges of serum vitamin D laboratories are using in reporting data “is an issue,” said Dr. Aloia, director of the Bone Mineral Research Center at Winthrop University Hospital, Mineola, N.Y., and professor of medicine at Stony Brook (N.Y.) University. “A laboratory can report anything it chooses to. For instance, the American College of Pathology and other [professional organizations] don’t have the responsibility for [the cut-offs in] those reports.”

Dr. Aloia favors translating the reporting of vitamin D levels based on something like Z scores, “so when you see lab reports, some of them will have a paragraph of explanation to guide the physician,” he explained. “We’re going to need that. We have to move away from just [a] cutpoint range and the lower level of the range being the RDA.”

Dr. Roger Bouillon, professor emeritus of internal medicine at the University of Leuven (Belgium), supports a threshold of 20 ng/mL serum vitamin D in adults. “I don’t like a range [of vitamin D]; they just need to have a level above 20 ng/mL. For me, a threshold is the best strategy on a population basis.”

During an open comment session, attendee Dr. Neil C. Binkley expressed concern over applying Z-score principles to the vitamin D field. “I love bone density measurement,” said Dr. Binkley, codirector of the Osteoporosis Clinical Center & Research Program at the University of Wisconsin, Madison, and past president of the International Society for Clinical Densitometry. “The T-score was in fact an advance in the field. But I can’t tell you how strongly I would urge you to not consider T-scores or Z-scores or something like that in the vitamin D field. Rather, I would urge that we do a better job at measuring 25-hydroxyvitamin D so our laboratories agree and have concise guidance for primary care. If you choose to go into the probability realm and the Z-scores, it is going to be a disaster.”

The presenters reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

Efforts to reach agreement on how vitamin D deficiency is defined are complicated by the fact that the cutoff points used in reports from clinical laboratories vary widely.

“I think reporting is a great problem because primary care physicians are very hurried,” Dr. John F. Aloia said at a public conference on vitamin D sponsored by the National Institutes of Health. “When you look at the laboratory report, what you get is a column that’s normal and another column that’s low or high. The choice of the laboratories to choose their own cutpoints is really a problem. The other part of that reporting is using the low level of normal in a range at the RDA [recommended daily allowance].”

In its recently updated recommendations on vitamin D screening, the U.S. Preventive Services Task Force noted that variability between serum vitamin D assay methods “and between laboratories using the same methods may range from 10% to 20%, and classification of samples as ‘deficient’ or ‘nondeficient’ may vary by 4% to 32%, depending on which assay is used. Another factor that may complicate interpretation is that 25-(OH)D may act as a negative acute-phase reactant and its levels may decrease in response to inflammation. Lastly, whether common laboratory reference ranges are appropriate for all ethnic groups is unclear.”

Trying to exert influence on what ranges of serum vitamin D laboratories are using in reporting data “is an issue,” said Dr. Aloia, director of the Bone Mineral Research Center at Winthrop University Hospital, Mineola, N.Y., and professor of medicine at Stony Brook (N.Y.) University. “A laboratory can report anything it chooses to. For instance, the American College of Pathology and other [professional organizations] don’t have the responsibility for [the cut-offs in] those reports.”

Dr. Aloia favors translating the reporting of vitamin D levels based on something like Z scores, “so when you see lab reports, some of them will have a paragraph of explanation to guide the physician,” he explained. “We’re going to need that. We have to move away from just [a] cutpoint range and the lower level of the range being the RDA.”

Dr. Roger Bouillon, professor emeritus of internal medicine at the University of Leuven (Belgium), supports a threshold of 20 ng/mL serum vitamin D in adults. “I don’t like a range [of vitamin D]; they just need to have a level above 20 ng/mL. For me, a threshold is the best strategy on a population basis.”

During an open comment session, attendee Dr. Neil C. Binkley expressed concern over applying Z-score principles to the vitamin D field. “I love bone density measurement,” said Dr. Binkley, codirector of the Osteoporosis Clinical Center & Research Program at the University of Wisconsin, Madison, and past president of the International Society for Clinical Densitometry. “The T-score was in fact an advance in the field. But I can’t tell you how strongly I would urge you to not consider T-scores or Z-scores or something like that in the vitamin D field. Rather, I would urge that we do a better job at measuring 25-hydroxyvitamin D so our laboratories agree and have concise guidance for primary care. If you choose to go into the probability realm and the Z-scores, it is going to be a disaster.”

The presenters reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

The common practice of immediate cord clamping, which generally means clamping within 15-20 seconds after birth, was fueled by efforts to reduce the risk of postpartum hemorrhage, a leading cause of maternal death worldwide. Immediate clamping was part of a full active management intervention recommended in 2007 by the World Health Organization, along with the use of uterotonics (generally oxytocin) immediately after birth and controlled cord traction to quickly deliver the placenta.

Adoption of the WHO-recommended “active management during the third stage of labor” (AMTSL) worked, leading to a 70% reduction in postpartum hemorrhage and a 60% reduction in blood transfusion over passive management. However, it appears that immediate cord clamping has not played an important role in these reductions. Several randomized controlled trials have shown that early clamping does not impact the risk of postpartum hemorrhage (> 1000 cc or > 500 cc), nor does it impact the need for manual removal of the placenta or the need for blood transfusion.

Instead, the critical component of the AMTSL package appears to be administration of a uterotonic, as reported in a large WHO-directed multicenter clinical trial published in 2012. The study also found that women who received controlled cord traction bled an average of 11 cc less – an insignificant difference – than did women who delivered their placentas by their own effort. Moreover, they had a third stage of labor that was an average of 6 minutes shorter (Lancet 2012;379:1721-7).

With assurance that the timing of umbilical cord clamping does not impact maternal outcomes, investigators have begun to look more at the impact of immediate versus delayed cord clamping on the health of the baby.

Thus far, the issues in this arena are a bit more complicated than on the maternal side. There are indications, however, that slight delays in umbilical cord clamping may be beneficial for the newborn – particularly for preterm infants, who appear in systemic reviews to have a nearly 50% reduction in intraventricular hemorrhage when clamping is delayed.

Timing in term infants

The theoretical benefits of delayed cord clamping include increased neonatal blood volume (improved perfusion and decreased organ injury), more time for spontaneous breathing (reduced risks of resuscitation and a smoother transition of cardiopulmonary and cerebral circulation), and increased stem cells for the infant (anti-inflammatory, neurotropic, and neuroprotective effects).

Theoretically, delayed clamping will increase the infant’s iron stores and lower the incidence of iron deficiency anemia during infancy. This is particularly relevant in developing countries, where up to 50% of infants have anemia by 1 year of age. Anemia is consistently associated with abnormal neurodevelopment, and treatment may not always reverse developmental issues.

On the negative side, delayed clamping is associated with theoretical concerns about hyperbilirubinemia and jaundice, hypothermia, polycythemia, and delays in the bonding of infants and mothers.

For term infants, our best reading on the benefits and risks of delayed umbilical cord clamping comes from a 2013 Cochrane systematic review that assessed results from 15 randomized controlled trials involving 3,911 women and infant pairs. Early cord clamping was generally carried out within 60 seconds of birth, whereas delayed cord clamping involved clamping the umbilical cord more than 1 minute after birth or when cord pulsation has ceased.

The review found that delayed clamping was associated with a significantly higher neonatal hemoglobin concentration at 24-48 hours postpartum (a weighted mean difference of 2 g/dL) and increased iron reserves up to 6 months after birth. Infants in the early clamping group were more than twice as likely to be iron deficient at 3-6 months compared with infants whose cord clamping was delayed (Cochrane Database Syst. Rev. 2013;7:CD004074)

There were no significant differences between early and late clamping in neonatal mortality or for most other neonatal morbidity outcomes. Delayed clamping also did not increase the risk of severe postpartum hemorrhage, blood loss, or reduced hemoglobin levels in mothers.

The downside to delayed cord clamping was an increased risk of jaundice requiring phototherapy. Infants in the later cord clamping group were 40% more likely to need phototherapy – a difference that equates to 3% of infants in the early clamping group and 5% of infants in the late clamping group.

Data were insufficient in the Cochrane review to draw reliable conclusions about the comparative effects on other short-term outcomes such as symptomatic polycythemia, respiratory problems, hypothermia, and infection, as data were limited on long-term outcomes.

In practice, this means that the risk of jaundice must be weighed against the risk of iron deficiency. In developed countries we have the resources both to increase iron stores of infants and to provide phototherapy. While the WHO recommends umbilical cord clamping after 1-3 minutes to improve an infant’s iron status, I do not believe the evidence is strong enough to universally adopt such delayed cord clamping in the United States.

Considering the risks of jaundice and the relative infrequency of iron deficiency in the United States, we should not routinely delay clamping for term infants at this point.

A recent committee opinion developed by the American College of Obstetricians and Gynecologists and endorsed by the American Academy of Pediatrics (No. 543, December 2012) captures this view by concluding that “insufficient evidence exists to support or to refute the benefits from delayed umbilical cord clamping for term infants that are born in settings with rich resources.” Although the ACOG opinion preceded the Cochrane review, the committee, of which I was a member, reviewed much of the same literature.

Timing in preterm infants

Preterm neonates are at increased risk of temperature dysregulation, hypotension, and the need for rapid initial pediatric care and blood transfusion. The increased risk of intraventricular hemorrhage and necrotizing enterocolitis in preterm infants is possibly related to the increased risk of hypotension.

As with term infants, a 2012 Cochrane systematic review offers good insight on our current knowledge. This review of umbilical cord clamping at preterm birth covers 15 studies that included 738 infants delivered between 24 and 36 weeks of gestation. The timing of umbilical cord clamping ranged from 25 seconds to a maximum of 180 seconds (Cochrane Database Syst. Rev. 2012;8:CD003248).

Delayed cord clamping was associated with fewer transfusions for anemia or low blood pressure, less intraventricular hemorrhage of all grades (relative risk 0.59), and a lower risk for necrotizing enterocolitis (relative risk 0.62), compared with immediate clamping.

While there were no clear differences with respect to severe intraventricular hemorrhage (grades 3-4), the nearly 50% reduction in intraventricular hemorrhage overall among deliveries with delayed clamping was significant enough to prompt ACOG to conclude that delayed cord clamping should be considered for preterm infants. This reduction in intraventricular hemorrhage appears to be the single most important benefit, based on current findings.

The data on cord clamping in preterm infants are suggestive of benefit, but are not robust. The studies published thus far have been small, and many of them, as the 2012 Cochrane review points out, involved incomplete reporting and wide confidence intervals. Moreover, just as with the studies on term infants, there has been a lack of long-term follow-up in most of the published trials.

When considering delayed cord clamping in preterm infants, as the ACOG Committee Opinion recommends, I urge focusing on earlier gestational ages. Allowing more placental transfusion at births that occur at or after 36 weeks of gestation may not make much sense because by that point the risk of intraventricular hemorrhage is almost nonexistent.

Our practice and the future

At our institution, births that occur at less than 32 weeks of gestation are eligible for delayed umbilical cord clamping, usually at 30-45 seconds after birth. The main contraindications are placental abruption and multiples.

We do not perform any milking or stripping of the umbilical cord, as the risks are unknown and it is not yet clear whether such practices are equivalent to delayed cord clamping. Compared with delayed cord clamping, which is a natural passive transfusion of placental blood to the infant, milking and stripping are not physiologic.

Additional data from an ongoing large international multicenter study, the Australian Placental Transfusion Study, may resolve some of the current controversy. This study is evaluating the cord clamping in neonates < 30 weeks’ gestation. Another study ongoing in Europe should also provide more information.

These studies – and other trials that are larger and longer than the trials published thus far – are necessary to evaluate long-term outcomes and to establish the ideal timing for umbilical cord clamping. Research is also needed to evaluate the management of the third stage of labor relative to umbilical cord clamping as well as the timing in relation to the initiation of voluntary or assisted ventilation.

Dr. Macones said he had no relevant financial disclosures.

Dr. Macones is the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis.

The common practice of immediate cord clamping, which generally means clamping within 15-20 seconds after birth, was fueled by efforts to reduce the risk of postpartum hemorrhage, a leading cause of maternal death worldwide. Immediate clamping was part of a full active management intervention recommended in 2007 by the World Health Organization, along with the use of uterotonics (generally oxytocin) immediately after birth and controlled cord traction to quickly deliver the placenta.

Adoption of the WHO-recommended “active management during the third stage of labor” (AMTSL) worked, leading to a 70% reduction in postpartum hemorrhage and a 60% reduction in blood transfusion over passive management. However, it appears that immediate cord clamping has not played an important role in these reductions. Several randomized controlled trials have shown that early clamping does not impact the risk of postpartum hemorrhage (> 1000 cc or > 500 cc), nor does it impact the need for manual removal of the placenta or the need for blood transfusion.

Instead, the critical component of the AMTSL package appears to be administration of a uterotonic, as reported in a large WHO-directed multicenter clinical trial published in 2012. The study also found that women who received controlled cord traction bled an average of 11 cc less – an insignificant difference – than did women who delivered their placentas by their own effort. Moreover, they had a third stage of labor that was an average of 6 minutes shorter (Lancet 2012;379:1721-7).

With assurance that the timing of umbilical cord clamping does not impact maternal outcomes, investigators have begun to look more at the impact of immediate versus delayed cord clamping on the health of the baby.

Thus far, the issues in this arena are a bit more complicated than on the maternal side. There are indications, however, that slight delays in umbilical cord clamping may be beneficial for the newborn – particularly for preterm infants, who appear in systemic reviews to have a nearly 50% reduction in intraventricular hemorrhage when clamping is delayed.

Timing in term infants

The theoretical benefits of delayed cord clamping include increased neonatal blood volume (improved perfusion and decreased organ injury), more time for spontaneous breathing (reduced risks of resuscitation and a smoother transition of cardiopulmonary and cerebral circulation), and increased stem cells for the infant (anti-inflammatory, neurotropic, and neuroprotective effects).

Theoretically, delayed clamping will increase the infant’s iron stores and lower the incidence of iron deficiency anemia during infancy. This is particularly relevant in developing countries, where up to 50% of infants have anemia by 1 year of age. Anemia is consistently associated with abnormal neurodevelopment, and treatment may not always reverse developmental issues.

On the negative side, delayed clamping is associated with theoretical concerns about hyperbilirubinemia and jaundice, hypothermia, polycythemia, and delays in the bonding of infants and mothers.

For term infants, our best reading on the benefits and risks of delayed umbilical cord clamping comes from a 2013 Cochrane systematic review that assessed results from 15 randomized controlled trials involving 3,911 women and infant pairs. Early cord clamping was generally carried out within 60 seconds of birth, whereas delayed cord clamping involved clamping the umbilical cord more than 1 minute after birth or when cord pulsation has ceased.

The review found that delayed clamping was associated with a significantly higher neonatal hemoglobin concentration at 24-48 hours postpartum (a weighted mean difference of 2 g/dL) and increased iron reserves up to 6 months after birth. Infants in the early clamping group were more than twice as likely to be iron deficient at 3-6 months compared with infants whose cord clamping was delayed (Cochrane Database Syst. Rev. 2013;7:CD004074)

There were no significant differences between early and late clamping in neonatal mortality or for most other neonatal morbidity outcomes. Delayed clamping also did not increase the risk of severe postpartum hemorrhage, blood loss, or reduced hemoglobin levels in mothers.

The downside to delayed cord clamping was an increased risk of jaundice requiring phototherapy. Infants in the later cord clamping group were 40% more likely to need phototherapy – a difference that equates to 3% of infants in the early clamping group and 5% of infants in the late clamping group.

Data were insufficient in the Cochrane review to draw reliable conclusions about the comparative effects on other short-term outcomes such as symptomatic polycythemia, respiratory problems, hypothermia, and infection, as data were limited on long-term outcomes.

In practice, this means that the risk of jaundice must be weighed against the risk of iron deficiency. In developed countries we have the resources both to increase iron stores of infants and to provide phototherapy. While the WHO recommends umbilical cord clamping after 1-3 minutes to improve an infant’s iron status, I do not believe the evidence is strong enough to universally adopt such delayed cord clamping in the United States.

Considering the risks of jaundice and the relative infrequency of iron deficiency in the United States, we should not routinely delay clamping for term infants at this point.

A recent committee opinion developed by the American College of Obstetricians and Gynecologists and endorsed by the American Academy of Pediatrics (No. 543, December 2012) captures this view by concluding that “insufficient evidence exists to support or to refute the benefits from delayed umbilical cord clamping for term infants that are born in settings with rich resources.” Although the ACOG opinion preceded the Cochrane review, the committee, of which I was a member, reviewed much of the same literature.

Timing in preterm infants

Preterm neonates are at increased risk of temperature dysregulation, hypotension, and the need for rapid initial pediatric care and blood transfusion. The increased risk of intraventricular hemorrhage and necrotizing enterocolitis in preterm infants is possibly related to the increased risk of hypotension.

As with term infants, a 2012 Cochrane systematic review offers good insight on our current knowledge. This review of umbilical cord clamping at preterm birth covers 15 studies that included 738 infants delivered between 24 and 36 weeks of gestation. The timing of umbilical cord clamping ranged from 25 seconds to a maximum of 180 seconds (Cochrane Database Syst. Rev. 2012;8:CD003248).

Delayed cord clamping was associated with fewer transfusions for anemia or low blood pressure, less intraventricular hemorrhage of all grades (relative risk 0.59), and a lower risk for necrotizing enterocolitis (relative risk 0.62), compared with immediate clamping.

While there were no clear differences with respect to severe intraventricular hemorrhage (grades 3-4), the nearly 50% reduction in intraventricular hemorrhage overall among deliveries with delayed clamping was significant enough to prompt ACOG to conclude that delayed cord clamping should be considered for preterm infants. This reduction in intraventricular hemorrhage appears to be the single most important benefit, based on current findings.

The data on cord clamping in preterm infants are suggestive of benefit, but are not robust. The studies published thus far have been small, and many of them, as the 2012 Cochrane review points out, involved incomplete reporting and wide confidence intervals. Moreover, just as with the studies on term infants, there has been a lack of long-term follow-up in most of the published trials.

When considering delayed cord clamping in preterm infants, as the ACOG Committee Opinion recommends, I urge focusing on earlier gestational ages. Allowing more placental transfusion at births that occur at or after 36 weeks of gestation may not make much sense because by that point the risk of intraventricular hemorrhage is almost nonexistent.

Our practice and the future

At our institution, births that occur at less than 32 weeks of gestation are eligible for delayed umbilical cord clamping, usually at 30-45 seconds after birth. The main contraindications are placental abruption and multiples.

We do not perform any milking or stripping of the umbilical cord, as the risks are unknown and it is not yet clear whether such practices are equivalent to delayed cord clamping. Compared with delayed cord clamping, which is a natural passive transfusion of placental blood to the infant, milking and stripping are not physiologic.

Additional data from an ongoing large international multicenter study, the Australian Placental Transfusion Study, may resolve some of the current controversy. This study is evaluating the cord clamping in neonates < 30 weeks’ gestation. Another study ongoing in Europe should also provide more information.

These studies – and other trials that are larger and longer than the trials published thus far – are necessary to evaluate long-term outcomes and to establish the ideal timing for umbilical cord clamping. Research is also needed to evaluate the management of the third stage of labor relative to umbilical cord clamping as well as the timing in relation to the initiation of voluntary or assisted ventilation.

Dr. Macones said he had no relevant financial disclosures.

Dr. Macones is the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis.

The common practice of immediate cord clamping, which generally means clamping within 15-20 seconds after birth, was fueled by efforts to reduce the risk of postpartum hemorrhage, a leading cause of maternal death worldwide. Immediate clamping was part of a full active management intervention recommended in 2007 by the World Health Organization, along with the use of uterotonics (generally oxytocin) immediately after birth and controlled cord traction to quickly deliver the placenta.

Adoption of the WHO-recommended “active management during the third stage of labor” (AMTSL) worked, leading to a 70% reduction in postpartum hemorrhage and a 60% reduction in blood transfusion over passive management. However, it appears that immediate cord clamping has not played an important role in these reductions. Several randomized controlled trials have shown that early clamping does not impact the risk of postpartum hemorrhage (> 1000 cc or > 500 cc), nor does it impact the need for manual removal of the placenta or the need for blood transfusion.

Instead, the critical component of the AMTSL package appears to be administration of a uterotonic, as reported in a large WHO-directed multicenter clinical trial published in 2012. The study also found that women who received controlled cord traction bled an average of 11 cc less – an insignificant difference – than did women who delivered their placentas by their own effort. Moreover, they had a third stage of labor that was an average of 6 minutes shorter (Lancet 2012;379:1721-7).

With assurance that the timing of umbilical cord clamping does not impact maternal outcomes, investigators have begun to look more at the impact of immediate versus delayed cord clamping on the health of the baby.

Thus far, the issues in this arena are a bit more complicated than on the maternal side. There are indications, however, that slight delays in umbilical cord clamping may be beneficial for the newborn – particularly for preterm infants, who appear in systemic reviews to have a nearly 50% reduction in intraventricular hemorrhage when clamping is delayed.

Timing in term infants

The theoretical benefits of delayed cord clamping include increased neonatal blood volume (improved perfusion and decreased organ injury), more time for spontaneous breathing (reduced risks of resuscitation and a smoother transition of cardiopulmonary and cerebral circulation), and increased stem cells for the infant (anti-inflammatory, neurotropic, and neuroprotective effects).

Theoretically, delayed clamping will increase the infant’s iron stores and lower the incidence of iron deficiency anemia during infancy. This is particularly relevant in developing countries, where up to 50% of infants have anemia by 1 year of age. Anemia is consistently associated with abnormal neurodevelopment, and treatment may not always reverse developmental issues.

On the negative side, delayed clamping is associated with theoretical concerns about hyperbilirubinemia and jaundice, hypothermia, polycythemia, and delays in the bonding of infants and mothers.

For term infants, our best reading on the benefits and risks of delayed umbilical cord clamping comes from a 2013 Cochrane systematic review that assessed results from 15 randomized controlled trials involving 3,911 women and infant pairs. Early cord clamping was generally carried out within 60 seconds of birth, whereas delayed cord clamping involved clamping the umbilical cord more than 1 minute after birth or when cord pulsation has ceased.

The review found that delayed clamping was associated with a significantly higher neonatal hemoglobin concentration at 24-48 hours postpartum (a weighted mean difference of 2 g/dL) and increased iron reserves up to 6 months after birth. Infants in the early clamping group were more than twice as likely to be iron deficient at 3-6 months compared with infants whose cord clamping was delayed (Cochrane Database Syst. Rev. 2013;7:CD004074)

There were no significant differences between early and late clamping in neonatal mortality or for most other neonatal morbidity outcomes. Delayed clamping also did not increase the risk of severe postpartum hemorrhage, blood loss, or reduced hemoglobin levels in mothers.

The downside to delayed cord clamping was an increased risk of jaundice requiring phototherapy. Infants in the later cord clamping group were 40% more likely to need phototherapy – a difference that equates to 3% of infants in the early clamping group and 5% of infants in the late clamping group.

Data were insufficient in the Cochrane review to draw reliable conclusions about the comparative effects on other short-term outcomes such as symptomatic polycythemia, respiratory problems, hypothermia, and infection, as data were limited on long-term outcomes.

In practice, this means that the risk of jaundice must be weighed against the risk of iron deficiency. In developed countries we have the resources both to increase iron stores of infants and to provide phototherapy. While the WHO recommends umbilical cord clamping after 1-3 minutes to improve an infant’s iron status, I do not believe the evidence is strong enough to universally adopt such delayed cord clamping in the United States.

Considering the risks of jaundice and the relative infrequency of iron deficiency in the United States, we should not routinely delay clamping for term infants at this point.

A recent committee opinion developed by the American College of Obstetricians and Gynecologists and endorsed by the American Academy of Pediatrics (No. 543, December 2012) captures this view by concluding that “insufficient evidence exists to support or to refute the benefits from delayed umbilical cord clamping for term infants that are born in settings with rich resources.” Although the ACOG opinion preceded the Cochrane review, the committee, of which I was a member, reviewed much of the same literature.

Timing in preterm infants

Preterm neonates are at increased risk of temperature dysregulation, hypotension, and the need for rapid initial pediatric care and blood transfusion. The increased risk of intraventricular hemorrhage and necrotizing enterocolitis in preterm infants is possibly related to the increased risk of hypotension.

As with term infants, a 2012 Cochrane systematic review offers good insight on our current knowledge. This review of umbilical cord clamping at preterm birth covers 15 studies that included 738 infants delivered between 24 and 36 weeks of gestation. The timing of umbilical cord clamping ranged from 25 seconds to a maximum of 180 seconds (Cochrane Database Syst. Rev. 2012;8:CD003248).

Delayed cord clamping was associated with fewer transfusions for anemia or low blood pressure, less intraventricular hemorrhage of all grades (relative risk 0.59), and a lower risk for necrotizing enterocolitis (relative risk 0.62), compared with immediate clamping.

While there were no clear differences with respect to severe intraventricular hemorrhage (grades 3-4), the nearly 50% reduction in intraventricular hemorrhage overall among deliveries with delayed clamping was significant enough to prompt ACOG to conclude that delayed cord clamping should be considered for preterm infants. This reduction in intraventricular hemorrhage appears to be the single most important benefit, based on current findings.

The data on cord clamping in preterm infants are suggestive of benefit, but are not robust. The studies published thus far have been small, and many of them, as the 2012 Cochrane review points out, involved incomplete reporting and wide confidence intervals. Moreover, just as with the studies on term infants, there has been a lack of long-term follow-up in most of the published trials.

When considering delayed cord clamping in preterm infants, as the ACOG Committee Opinion recommends, I urge focusing on earlier gestational ages. Allowing more placental transfusion at births that occur at or after 36 weeks of gestation may not make much sense because by that point the risk of intraventricular hemorrhage is almost nonexistent.

Our practice and the future

At our institution, births that occur at less than 32 weeks of gestation are eligible for delayed umbilical cord clamping, usually at 30-45 seconds after birth. The main contraindications are placental abruption and multiples.

We do not perform any milking or stripping of the umbilical cord, as the risks are unknown and it is not yet clear whether such practices are equivalent to delayed cord clamping. Compared with delayed cord clamping, which is a natural passive transfusion of placental blood to the infant, milking and stripping are not physiologic.

Additional data from an ongoing large international multicenter study, the Australian Placental Transfusion Study, may resolve some of the current controversy. This study is evaluating the cord clamping in neonates < 30 weeks’ gestation. Another study ongoing in Europe should also provide more information.

These studies – and other trials that are larger and longer than the trials published thus far – are necessary to evaluate long-term outcomes and to establish the ideal timing for umbilical cord clamping. Research is also needed to evaluate the management of the third stage of labor relative to umbilical cord clamping as well as the timing in relation to the initiation of voluntary or assisted ventilation.

Dr. Macones said he had no relevant financial disclosures.

Dr. Macones is the Mitchell and Elaine Yanow Professor and Chair, and director of the division of maternal-fetal medicine and ultrasound in the department of obstetrics and gynecology at Washington University, St. Louis.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.