BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

BOSTON – An investigational agent targeted against tumors carrying mutant forms of the metabolic protein IDH1 has shown clinical activity against advanced solid tumors, including gliomas and chondrosarcomas, investigators reported.

In a phase I trial in 62 patients with advanced IDH1 mutation-positive solid tumors that had recurred or progressed on a median three prior lines of therapy, 7 of 11 patients with chondrosarcomas treated with AG-120 had stable disease, with five of the responses maintained beyond 6 months, and 10 of 20 patients with glioma had stable disease, with 4 having responses longer than 6 months, reported Dr. Howard A. Burris III, chief medical officer and executive director, drug development program, at the Sarah Cannon Research Institute, Nashville, Tenn.

“These tumors don’t respond to any of our systemic therapies, so it’s pretty remarkable that you get patients who don’t have treatment options that do so well for so long. We’ve just not seen that in the past,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who was not involved in the study.

A related compound, AG-221, which inhibits IDH2, has previously been shown to produce durable objective responses in 30%-50% of patients with acute myeloid leukemia. Here at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics, Dr. Burris presented the first clinical results with the IHD1-inhibiting compound in solid tumors.

IDH1 is normally involved in regulation of the Krebs cycle, the central metabolic pathway. IDH1 mutations produce the metabolite 2-hydroxyglutarate (2-HG), which causes genetic and epigenetic dysregulation, leading to oncogenesis via unchecked cell proliferation. AG-120 blocks the accumulation of 2-HG, thereby allowing cells to differentiate and undergo apoptosis as normal, thereby restoring homeostasis.

IDH1 mutations are found in an estimated 68%-74% of gliomas, 11%-24% of intrahepatic cholangiocarcinomas (IHCC), and in 40%-52% of chondrosarcomas, Dr. Burris said.

Early efficacy promising

He reported early safety and clinical data from a single-arm, dose escalation study of single-agent AG-210 dosed orally once or twice daily in 28-day cycles in one of eight dose levels. The dose escalation phase has been completed and a 500-mg q.i.d. dose has been selected.

There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Serious adverse events, occurring in one patient each (18 of 62 patients) were acute kidney injury, acute respiratory failure, anemia, ataxia, brain herniation, confusional state, cystitis, urinary tract infection, headache, hyponatremia, joint effusion, esophageal varices hemorrhage, partial seizures, seizure, bacteremia, superior vena cava syndrome, vertebral fracture, and urosepsis. There were no deaths judged to be treatment related.

Data on 55 patients were available for the efficacy analysis. Among 11 patients with chondrosarcoma, 7 had stable disease, 2 had progressive disease, and 2 had unknown status. Among 20 patients with IHCC, there was 1 partial response, 11 cases of stable disease, 6 of progressive disease, and 2 unknown. Among patients with glioma, 10 had stable disease, and 10 had progressive disease.

Of four remaining patients (with adenocarcinoma and colitis-associated neuroendocrine, small intestine, and ovarian cancers), one had stable disease, and three had progression.

The patient with IHCC who had a partial response was a 65-year-old woman who had previously been treated with multiple lines of chemotherapy, including combinations of cisplatin and gemcitabine, gemcitabine and oxaliplatin, and cisplatin and docetaxel. Following treatment with AG-120, she had a 98.7% reduction in 2-HG level, and an 81% reduction in Ki-67 staining, indicating marked tumor reduction.

“This patient in fact was on the trial for more than 9 months. By protocol criteria, she had to come off study for development of a solitary new, small lesion that was felt to be a new metastatic spot, but had no change – no further regrowth of the tumor that had shrunk,” Dr. Burris said in a briefing following his presentation of the data in a plenary session.

In a 38-year-old man with grade II glioma, investigators saw volumetric changes consistent with 2-HG reduction on magnetic resonance spectroscopy, he added.

For the expansion phase, investigators are currently enrolling four cohorts each of 25 patients with low-grade glioma (with at least 6 months of prior scans), IHCC following progression on first-line therapy, high-grade metastatic chondrosarcoma, and patients with other solid tumors with IDH1 mutations. They are also planning a randomized phase II study in patients with IHCC beginning in 2016.

SAN FRANCISCO – Are policies requiring 6 months of abstinence before liver transplantation in severe alcoholic hepatitis justified, given the potential survival advantage that earlier transplantation offers?

Alcoholic hepatitis has an “exceptionally high mortality rate,” noted Dr. Brian Lee of Johns Hopkins University, Baltimore. But a policy requiring 6 months of abstinence before liver transplantation in patients with severe alcoholic hepatitis “is possibly even causing a precondition that’s death for these patients.”

In an interview at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Lee discussed a study in which early liver transplantation in 40 patients with severe alcoholic hepatitis achieved a 100% survival rate at 1 year, with a 22% alcohol relapse rate.

[email protected]

SAN FRANCISCO – Are policies requiring 6 months of abstinence before liver transplantation in severe alcoholic hepatitis justified, given the potential survival advantage that earlier transplantation offers?

Alcoholic hepatitis has an “exceptionally high mortality rate,” noted Dr. Brian Lee of Johns Hopkins University, Baltimore. But a policy requiring 6 months of abstinence before liver transplantation in patients with severe alcoholic hepatitis “is possibly even causing a precondition that’s death for these patients.”

In an interview at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Lee discussed a study in which early liver transplantation in 40 patients with severe alcoholic hepatitis achieved a 100% survival rate at 1 year, with a 22% alcohol relapse rate.

[email protected]

SAN FRANCISCO – Are policies requiring 6 months of abstinence before liver transplantation in severe alcoholic hepatitis justified, given the potential survival advantage that earlier transplantation offers?

Alcoholic hepatitis has an “exceptionally high mortality rate,” noted Dr. Brian Lee of Johns Hopkins University, Baltimore. But a policy requiring 6 months of abstinence before liver transplantation in patients with severe alcoholic hepatitis “is possibly even causing a precondition that’s death for these patients.”

In an interview at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Lee discussed a study in which early liver transplantation in 40 patients with severe alcoholic hepatitis achieved a 100% survival rate at 1 year, with a 22% alcohol relapse rate.

[email protected]

Andexanet alfa has been found to reverse the anticoagulant effects of factor Xa inhibitors rivaroxaban and apixaban, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 11 issue of the New England Journal of Medicine.

In a two-part randomized, placebo-controlled study involving 145 healthy individuals with a mean age of 58 years, patients treated first with apixaban and then given a bolus of andexanet had a 94% reduction in anti-factor Xa activity, compared with a 21% reduction with placebo. Thrombin generation was restored in 100% of patients within 2-5 minutes.

In the patients treated with rivaroxaban, treatment with andexanet reduced anti-factor Xa activity by 92%, compared with 18% with placebo. Thrombin generation was restored in 96% of participants in the andexanet group, compared with 7% in the placebo group.

Adverse events associated with andexanet were minor, including constipation, feeling hot, or a strange taste in the mouth, and the effects of the andexanet also were sustained over the course of a 2-hour infusion in addition to the bolus (N Engl J Med. 2015 Nov 11. doi: 10.1056/NEJMoa1510991).

“The rapid onset and offset of action of andexanet and the ability to administer it as a bolus or as a bolus plus an infusion may provide flexibility with regard to the restoration of hemostasis when urgent factor Xa inhibitor reversal is required,” Dr. Deborah M. Siegal of McMaster University, Hamilton, Ont., and coauthors wrote.

The study was supported by Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer. Several authors are employees of Portola, one with stock options and related patent. Other authors declared grants and personal fees from the pharmaceutical industry, including the study supporters.

Andexanet alfa has been found to reverse the anticoagulant effects of factor Xa inhibitors rivaroxaban and apixaban, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 11 issue of the New England Journal of Medicine.

In a two-part randomized, placebo-controlled study involving 145 healthy individuals with a mean age of 58 years, patients treated first with apixaban and then given a bolus of andexanet had a 94% reduction in anti-factor Xa activity, compared with a 21% reduction with placebo. Thrombin generation was restored in 100% of patients within 2-5 minutes.

In the patients treated with rivaroxaban, treatment with andexanet reduced anti-factor Xa activity by 92%, compared with 18% with placebo. Thrombin generation was restored in 96% of participants in the andexanet group, compared with 7% in the placebo group.

Adverse events associated with andexanet were minor, including constipation, feeling hot, or a strange taste in the mouth, and the effects of the andexanet also were sustained over the course of a 2-hour infusion in addition to the bolus (N Engl J Med. 2015 Nov 11. doi: 10.1056/NEJMoa1510991).

“The rapid onset and offset of action of andexanet and the ability to administer it as a bolus or as a bolus plus an infusion may provide flexibility with regard to the restoration of hemostasis when urgent factor Xa inhibitor reversal is required,” Dr. Deborah M. Siegal of McMaster University, Hamilton, Ont., and coauthors wrote.

The study was supported by Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer. Several authors are employees of Portola, one with stock options and related patent. Other authors declared grants and personal fees from the pharmaceutical industry, including the study supporters.

Andexanet alfa has been found to reverse the anticoagulant effects of factor Xa inhibitors rivaroxaban and apixaban, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 11 issue of the New England Journal of Medicine.

In a two-part randomized, placebo-controlled study involving 145 healthy individuals with a mean age of 58 years, patients treated first with apixaban and then given a bolus of andexanet had a 94% reduction in anti-factor Xa activity, compared with a 21% reduction with placebo. Thrombin generation was restored in 100% of patients within 2-5 minutes.

In the patients treated with rivaroxaban, treatment with andexanet reduced anti-factor Xa activity by 92%, compared with 18% with placebo. Thrombin generation was restored in 96% of participants in the andexanet group, compared with 7% in the placebo group.

Adverse events associated with andexanet were minor, including constipation, feeling hot, or a strange taste in the mouth, and the effects of the andexanet also were sustained over the course of a 2-hour infusion in addition to the bolus (N Engl J Med. 2015 Nov 11. doi: 10.1056/NEJMoa1510991).

“The rapid onset and offset of action of andexanet and the ability to administer it as a bolus or as a bolus plus an infusion may provide flexibility with regard to the restoration of hemostasis when urgent factor Xa inhibitor reversal is required,” Dr. Deborah M. Siegal of McMaster University, Hamilton, Ont., and coauthors wrote.

The study was supported by Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer. Several authors are employees of Portola, one with stock options and related patent. Other authors declared grants and personal fees from the pharmaceutical industry, including the study supporters.

Four weeks into the 2015-2016 flu season, activity levels of influenza-like illness (ILI) are minimal in all 50 states, the Centers for Disease Control and Prevention reported Nov. 13.

Seven states – Georgia, Hawaii, Illinois, Minnesota, Nevada, Utah, and Virginia – had level 2 activity for the week ending Nov. 7, 2015, which, although still minimal, was higher than the level 1 activity in the other 43 states. There was a moderate level of influenza-like illness activity (level 7) in Puerto Rico, which was up from level 6 the week before, and there were insufficient data to determine flu activity in the District of Columbia, according to the CDC.

ILI is defined as fever (temperature of 100° F or greater) and cough and/or sore throat. Activity level within a state is the proportion of outpatient visits to health care providers for influenza-like illness.

For the country overall, the proportion of outpatient visits for ILI was 1.4%, which is below the national baseline of 2.1% for week 4 of the flu season, the CDC noted.

[email protected]

Four weeks into the 2015-2016 flu season, activity levels of influenza-like illness (ILI) are minimal in all 50 states, the Centers for Disease Control and Prevention reported Nov. 13.

Seven states – Georgia, Hawaii, Illinois, Minnesota, Nevada, Utah, and Virginia – had level 2 activity for the week ending Nov. 7, 2015, which, although still minimal, was higher than the level 1 activity in the other 43 states. There was a moderate level of influenza-like illness activity (level 7) in Puerto Rico, which was up from level 6 the week before, and there were insufficient data to determine flu activity in the District of Columbia, according to the CDC.

ILI is defined as fever (temperature of 100° F or greater) and cough and/or sore throat. Activity level within a state is the proportion of outpatient visits to health care providers for influenza-like illness.

For the country overall, the proportion of outpatient visits for ILI was 1.4%, which is below the national baseline of 2.1% for week 4 of the flu season, the CDC noted.

[email protected]

Four weeks into the 2015-2016 flu season, activity levels of influenza-like illness (ILI) are minimal in all 50 states, the Centers for Disease Control and Prevention reported Nov. 13.

Seven states – Georgia, Hawaii, Illinois, Minnesota, Nevada, Utah, and Virginia – had level 2 activity for the week ending Nov. 7, 2015, which, although still minimal, was higher than the level 1 activity in the other 43 states. There was a moderate level of influenza-like illness activity (level 7) in Puerto Rico, which was up from level 6 the week before, and there were insufficient data to determine flu activity in the District of Columbia, according to the CDC.

ILI is defined as fever (temperature of 100° F or greater) and cough and/or sore throat. Activity level within a state is the proportion of outpatient visits to health care providers for influenza-like illness.

For the country overall, the proportion of outpatient visits for ILI was 1.4%, which is below the national baseline of 2.1% for week 4 of the flu season, the CDC noted.

[email protected]

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

As I listened to Dr. Jackson T. Wright, one of the investigators of the SPRINT Trial, emphasize the importance of treating systolic blood pressure to the target of 120 mm Hg, I thought about the difficulty in treating blood pressure in the elderly.

Successfully lowering blood pressure even to the current target of 140 mm Hg systolic is one of the most difficult therapeutic tasks that I face. But, to my mind, the worldwide success achieved by hypertension therapy has had the most profound effect on cardiovascular medicine in the last half century. I am no epidemiologist, but the striking decrease in cardiovascular mortality in the United States associated with the introduction of the hypertension therapy is undeniable.

The pharmaceutical companies that developed of these drugs, some of which are still around and some that have merged with other entities, never priced these drugs at the potential benefit of decreasing the cost of hypertension to society. If they had, their price would be so exorbitant that their universal benefit to mankind would never have been seen. They were doing their job and returning significant benefit both to humanity and their investors. They priced the drugs so that we could afford to pay for them. All of these drugs – ACE inhibitors, calcium- and beta-blockers, and diuretics – are now available as generics and as a class have had a lasting and continuing impact on the societal cost and benefit.

Yet somehow, the world has changed. I am not the first to notice it. We now have drugs that can cost thousands of dollars a month and none of us can afford to pay for them. Because we now all share in the cost of drug therapy in one way or another, we all pay the cost. The justification for the high price is not based solely on their development cost, which in many instances were developed decades if not centuries ago, but on the presumed net expense of the untreated disease to society or to the achievement of entrepreneurial profits. Hepatitis C was one of the first in which the cost of new drug therapy was based on the net savings associated with the prevention of the chronic liver disease and its subsequent long-term societal expense. Since I am not a hepatologist, it took me a little leap of faith to accept the potential economic benefit of this therapy, but at least the current data suggest that indeed this therapy works. I remain dubious about the calculations of their societal net benefit cost.

Now move forward. We now have two drugs that can lower cholesterol, potentially to levels beyond our imagination, that are now on the high-expense list. According to recent rumors, evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) will cost someone $12,000-$14,000 a year to lower serum cholesterol almost to immeasurable levels without any evidence of benefit in decreasing cardiovascular disease. (For those of you with short-term memory deficits, we just tried to pump up HDL cholesterol only to find that when successful, it increased mortality.) Now, if these drugs are successful in preventing the development and progression of atherosclerotic disease, as in the example of hepatitis C, I may change my mind and write the script for it.

Meanwhile, drug prices have escalated as a result of speculation in the pharmaceutical market by Wall Street entrepreneurs who buy up the drug patents that have been available for years like isoproterenol and digitalis, for the sole purpose of a creating a monopoly to inflate the price and return large profits to their investors. When questioned about the 20-fold increase in the cost of isoproterenol, a representative of one of the pharmaceutical companies stated, “that the price was based on many factors, including clinical benefits and the value they bring to the patients, physicians, payers, and society” (New York Times 2015 Oct 4 p. BU1, “Side Effects of Hijacking Drug Prices”). The audacity of drug company executives to presume that they are in a position to make that judgment is outrageous. And yet the U.S. Congress makes it illegal for Medicare and Medicaid to bargain for the best drug prices, while European and Asian pay a fraction of what we pay here.

These ruminations only suggest that madness in the pharmaceutical world is not limited to Wall Street but reaches even the higher levels of government. Get your checkbooks out everyone; the best is yet to come.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

As I listened to Dr. Jackson T. Wright, one of the investigators of the SPRINT Trial, emphasize the importance of treating systolic blood pressure to the target of 120 mm Hg, I thought about the difficulty in treating blood pressure in the elderly.

Successfully lowering blood pressure even to the current target of 140 mm Hg systolic is one of the most difficult therapeutic tasks that I face. But, to my mind, the worldwide success achieved by hypertension therapy has had the most profound effect on cardiovascular medicine in the last half century. I am no epidemiologist, but the striking decrease in cardiovascular mortality in the United States associated with the introduction of the hypertension therapy is undeniable.

The pharmaceutical companies that developed of these drugs, some of which are still around and some that have merged with other entities, never priced these drugs at the potential benefit of decreasing the cost of hypertension to society. If they had, their price would be so exorbitant that their universal benefit to mankind would never have been seen. They were doing their job and returning significant benefit both to humanity and their investors. They priced the drugs so that we could afford to pay for them. All of these drugs – ACE inhibitors, calcium- and beta-blockers, and diuretics – are now available as generics and as a class have had a lasting and continuing impact on the societal cost and benefit.

Yet somehow, the world has changed. I am not the first to notice it. We now have drugs that can cost thousands of dollars a month and none of us can afford to pay for them. Because we now all share in the cost of drug therapy in one way or another, we all pay the cost. The justification for the high price is not based solely on their development cost, which in many instances were developed decades if not centuries ago, but on the presumed net expense of the untreated disease to society or to the achievement of entrepreneurial profits. Hepatitis C was one of the first in which the cost of new drug therapy was based on the net savings associated with the prevention of the chronic liver disease and its subsequent long-term societal expense. Since I am not a hepatologist, it took me a little leap of faith to accept the potential economic benefit of this therapy, but at least the current data suggest that indeed this therapy works. I remain dubious about the calculations of their societal net benefit cost.

Now move forward. We now have two drugs that can lower cholesterol, potentially to levels beyond our imagination, that are now on the high-expense list. According to recent rumors, evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) will cost someone $12,000-$14,000 a year to lower serum cholesterol almost to immeasurable levels without any evidence of benefit in decreasing cardiovascular disease. (For those of you with short-term memory deficits, we just tried to pump up HDL cholesterol only to find that when successful, it increased mortality.) Now, if these drugs are successful in preventing the development and progression of atherosclerotic disease, as in the example of hepatitis C, I may change my mind and write the script for it.

Meanwhile, drug prices have escalated as a result of speculation in the pharmaceutical market by Wall Street entrepreneurs who buy up the drug patents that have been available for years like isoproterenol and digitalis, for the sole purpose of a creating a monopoly to inflate the price and return large profits to their investors. When questioned about the 20-fold increase in the cost of isoproterenol, a representative of one of the pharmaceutical companies stated, “that the price was based on many factors, including clinical benefits and the value they bring to the patients, physicians, payers, and society” (New York Times 2015 Oct 4 p. BU1, “Side Effects of Hijacking Drug Prices”). The audacity of drug company executives to presume that they are in a position to make that judgment is outrageous. And yet the U.S. Congress makes it illegal for Medicare and Medicaid to bargain for the best drug prices, while European and Asian pay a fraction of what we pay here.

These ruminations only suggest that madness in the pharmaceutical world is not limited to Wall Street but reaches even the higher levels of government. Get your checkbooks out everyone; the best is yet to come.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

As I listened to Dr. Jackson T. Wright, one of the investigators of the SPRINT Trial, emphasize the importance of treating systolic blood pressure to the target of 120 mm Hg, I thought about the difficulty in treating blood pressure in the elderly.

Successfully lowering blood pressure even to the current target of 140 mm Hg systolic is one of the most difficult therapeutic tasks that I face. But, to my mind, the worldwide success achieved by hypertension therapy has had the most profound effect on cardiovascular medicine in the last half century. I am no epidemiologist, but the striking decrease in cardiovascular mortality in the United States associated with the introduction of the hypertension therapy is undeniable.

The pharmaceutical companies that developed of these drugs, some of which are still around and some that have merged with other entities, never priced these drugs at the potential benefit of decreasing the cost of hypertension to society. If they had, their price would be so exorbitant that their universal benefit to mankind would never have been seen. They were doing their job and returning significant benefit both to humanity and their investors. They priced the drugs so that we could afford to pay for them. All of these drugs – ACE inhibitors, calcium- and beta-blockers, and diuretics – are now available as generics and as a class have had a lasting and continuing impact on the societal cost and benefit.

Yet somehow, the world has changed. I am not the first to notice it. We now have drugs that can cost thousands of dollars a month and none of us can afford to pay for them. Because we now all share in the cost of drug therapy in one way or another, we all pay the cost. The justification for the high price is not based solely on their development cost, which in many instances were developed decades if not centuries ago, but on the presumed net expense of the untreated disease to society or to the achievement of entrepreneurial profits. Hepatitis C was one of the first in which the cost of new drug therapy was based on the net savings associated with the prevention of the chronic liver disease and its subsequent long-term societal expense. Since I am not a hepatologist, it took me a little leap of faith to accept the potential economic benefit of this therapy, but at least the current data suggest that indeed this therapy works. I remain dubious about the calculations of their societal net benefit cost.

Now move forward. We now have two drugs that can lower cholesterol, potentially to levels beyond our imagination, that are now on the high-expense list. According to recent rumors, evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) will cost someone $12,000-$14,000 a year to lower serum cholesterol almost to immeasurable levels without any evidence of benefit in decreasing cardiovascular disease. (For those of you with short-term memory deficits, we just tried to pump up HDL cholesterol only to find that when successful, it increased mortality.) Now, if these drugs are successful in preventing the development and progression of atherosclerotic disease, as in the example of hepatitis C, I may change my mind and write the script for it.

Meanwhile, drug prices have escalated as a result of speculation in the pharmaceutical market by Wall Street entrepreneurs who buy up the drug patents that have been available for years like isoproterenol and digitalis, for the sole purpose of a creating a monopoly to inflate the price and return large profits to their investors. When questioned about the 20-fold increase in the cost of isoproterenol, a representative of one of the pharmaceutical companies stated, “that the price was based on many factors, including clinical benefits and the value they bring to the patients, physicians, payers, and society” (New York Times 2015 Oct 4 p. BU1, “Side Effects of Hijacking Drug Prices”). The audacity of drug company executives to presume that they are in a position to make that judgment is outrageous. And yet the U.S. Congress makes it illegal for Medicare and Medicaid to bargain for the best drug prices, while European and Asian pay a fraction of what we pay here.

These ruminations only suggest that madness in the pharmaceutical world is not limited to Wall Street but reaches even the higher levels of government. Get your checkbooks out everyone; the best is yet to come.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

NEW YORK - Hospital resources, and not necessarily patient characteristics, may be causing safety-net hospitals to deliver inferior surgical outcomes at increased cost in elective surgical procedures, according to a new study.

"Analysis of Medicare Hospital Compare data revealed that safety-net hospitals perform worse on Surgical Care Improvement Project (SCIP) measures and have less efficient emergency departments throughput," first author Dr. Richard S. Hoehn from the University of Cincinnati, Ohio, said by email. "This last category indicates that these hospitals have insufficient staffing and/or resources to handle their patient burden."

"Safety-net hospitals care for a vulnerable population and maintain an open door to all patients, regardless of their ability to pay. Our study of nine major surgical procedures at academic medical centers in the United States found that hospitals with the highest safety net burden have the most patients of low socioeconomic status, extreme severity of illness, and in need of urgent surgery," Dr. Hoehn said.

"These hospitals also had the worst mortality and readmission rates and highest costs for most procedures. After controlling for patient age, race, severity of illness, and socioeconomic status, safety-net hospitals still had worse outcomes. Their inferior mortality and readmission rates were somewhat reduced, but the increased costs observed at these centers persisted, implying that other characteristics intrinsic to safety-net hospitals are associated with increased costs," he added.

Dr. Hoehn and colleagues analyzed outcomes for nine surgical procedures at 231 hospitals in the University HealthSystem Consortium over a four-year period ending in 2012, accounting for more than 12.6 million patient encounters. They sorted the hospitals into high safety-net burden (HBH) versus hospitals with low (LBH) or medium (MBH) safety-net burden.

They found the HBHs overall to have the most patients likely to be young, black, have the lowest socioeconomic status, and have the highest severity of illness and the highest cost for surgical care (p<0.01 for all). They also had the highest proportion of patient-emergent cases and the longest lengths of stay (p<0.01 for all).

After the researchers adjusted for patient characteristics and hospital volume, the HBHs still had higher odds ratios of mortality for three procedures (OR, 1.81 to 2.08, p<0.05), readmission for two procedures (OR, 1.19 to 1.30, p<0.05), and the highest cost of care for seven procedures (risk ratios, 1.23 to 1.35, p<0.05).

Postoperative mortality was worse for colectomy, esophagectomy, pancreaticoduodenectomy, and ventral hernia repair. Readmission odds were higher for coronary artery bypass, colectomy, kidney transplant, and ventral hernia repair.

"[W]hen assessing markers of emergency department throughput, HBHs were inferior to LBHs in all measures, including time from arrival to evaluation, admission decision time, times from arrival to departure for discharged and admitted patients, time for pain medicine administration to patients with long-bone fractures, and patients who left without being seen (p <= 0.002 for all)," the researchers write in JAMA Surgery, online October 14.

In an accompanying editorial, Dr. Larry R. Kaiser of Temple University School of Medicine, Philadelphia, and colleagues note, "At best, emergency department throughput as a surrogate for staffing adequacy and systems efficiency is an indirect estimate of these important hospital factors. Deficiencies in documentation and coding may or may not be influenced by overall hospital performance but could have a significant influence on expected rates of death and complications."

Dr. Kaiser said by email, "Physicians and surgeons should be very careful in drawing substantive conclusions from the study because of factors we don't know about these patients. Let the message be greater resources should be provided to those hospitals bearing the burden of caring for this underserved population of patients who, if anything, are more complex than commercially insured patients with similar problems."

"It's important to acknowledge that this study is not trying to criticize safety-net hospitals," Dr. Hoehn emphasized. "We are trying to highlight the unique situation these providers face, and also show that current policy changes that financially penalize these hospitals may adversely impact surgical care and further exacerbate the disparities in health care that already exist in our country. Safety-net hospitals in America have always been important institutions that train doctors and care for indigent patients, and our goal is to find a way to preserve this model in the face of changing healthcare policy."

Dr. Hoehn continued, "There are two options to improve the care at these centers: either close these hospitals and send their patients elsewhere or invest in initiatives that will allow these hospitals to improve not only their outcomes but also their efficiency. To do this, we must better understand their needs."

Dr. Kaiser said, "Continued scrutiny of outcomes with transparency and sharing of data with all those involved in the care of patients will result in continued quality improvement. Participation in [universal health care] that allows institutions to benchmark their data with similar institutions will tend to push those who need improvement to continue to improve."

"There must be a concerted effort among all involved in caring for patients at an institution to continue to improve quality. The designation of a chief quality officer working in concert with the chief medical officer also is critically important in working toward improved quality. But all of this depends on accurate recording and reporting of quality metrics," he concluded.

NEW YORK - Hospital resources, and not necessarily patient characteristics, may be causing safety-net hospitals to deliver inferior surgical outcomes at increased cost in elective surgical procedures, according to a new study.

"Analysis of Medicare Hospital Compare data revealed that safety-net hospitals perform worse on Surgical Care Improvement Project (SCIP) measures and have less efficient emergency departments throughput," first author Dr. Richard S. Hoehn from the University of Cincinnati, Ohio, said by email. "This last category indicates that these hospitals have insufficient staffing and/or resources to handle their patient burden."

"Safety-net hospitals care for a vulnerable population and maintain an open door to all patients, regardless of their ability to pay. Our study of nine major surgical procedures at academic medical centers in the United States found that hospitals with the highest safety net burden have the most patients of low socioeconomic status, extreme severity of illness, and in need of urgent surgery," Dr. Hoehn said.

"These hospitals also had the worst mortality and readmission rates and highest costs for most procedures. After controlling for patient age, race, severity of illness, and socioeconomic status, safety-net hospitals still had worse outcomes. Their inferior mortality and readmission rates were somewhat reduced, but the increased costs observed at these centers persisted, implying that other characteristics intrinsic to safety-net hospitals are associated with increased costs," he added.

Dr. Hoehn and colleagues analyzed outcomes for nine surgical procedures at 231 hospitals in the University HealthSystem Consortium over a four-year period ending in 2012, accounting for more than 12.6 million patient encounters. They sorted the hospitals into high safety-net burden (HBH) versus hospitals with low (LBH) or medium (MBH) safety-net burden.

They found the HBHs overall to have the most patients likely to be young, black, have the lowest socioeconomic status, and have the highest severity of illness and the highest cost for surgical care (p<0.01 for all). They also had the highest proportion of patient-emergent cases and the longest lengths of stay (p<0.01 for all).

After the researchers adjusted for patient characteristics and hospital volume, the HBHs still had higher odds ratios of mortality for three procedures (OR, 1.81 to 2.08, p<0.05), readmission for two procedures (OR, 1.19 to 1.30, p<0.05), and the highest cost of care for seven procedures (risk ratios, 1.23 to 1.35, p<0.05).

Postoperative mortality was worse for colectomy, esophagectomy, pancreaticoduodenectomy, and ventral hernia repair. Readmission odds were higher for coronary artery bypass, colectomy, kidney transplant, and ventral hernia repair.

"[W]hen assessing markers of emergency department throughput, HBHs were inferior to LBHs in all measures, including time from arrival to evaluation, admission decision time, times from arrival to departure for discharged and admitted patients, time for pain medicine administration to patients with long-bone fractures, and patients who left without being seen (p <= 0.002 for all)," the researchers write in JAMA Surgery, online October 14.

In an accompanying editorial, Dr. Larry R. Kaiser of Temple University School of Medicine, Philadelphia, and colleagues note, "At best, emergency department throughput as a surrogate for staffing adequacy and systems efficiency is an indirect estimate of these important hospital factors. Deficiencies in documentation and coding may or may not be influenced by overall hospital performance but could have a significant influence on expected rates of death and complications."

Dr. Kaiser said by email, "Physicians and surgeons should be very careful in drawing substantive conclusions from the study because of factors we don't know about these patients. Let the message be greater resources should be provided to those hospitals bearing the burden of caring for this underserved population of patients who, if anything, are more complex than commercially insured patients with similar problems."

"It's important to acknowledge that this study is not trying to criticize safety-net hospitals," Dr. Hoehn emphasized. "We are trying to highlight the unique situation these providers face, and also show that current policy changes that financially penalize these hospitals may adversely impact surgical care and further exacerbate the disparities in health care that already exist in our country. Safety-net hospitals in America have always been important institutions that train doctors and care for indigent patients, and our goal is to find a way to preserve this model in the face of changing healthcare policy."

Dr. Hoehn continued, "There are two options to improve the care at these centers: either close these hospitals and send their patients elsewhere or invest in initiatives that will allow these hospitals to improve not only their outcomes but also their efficiency. To do this, we must better understand their needs."

Dr. Kaiser said, "Continued scrutiny of outcomes with transparency and sharing of data with all those involved in the care of patients will result in continued quality improvement. Participation in [universal health care] that allows institutions to benchmark their data with similar institutions will tend to push those who need improvement to continue to improve."

"There must be a concerted effort among all involved in caring for patients at an institution to continue to improve quality. The designation of a chief quality officer working in concert with the chief medical officer also is critically important in working toward improved quality. But all of this depends on accurate recording and reporting of quality metrics," he concluded.

NEW YORK - Hospital resources, and not necessarily patient characteristics, may be causing safety-net hospitals to deliver inferior surgical outcomes at increased cost in elective surgical procedures, according to a new study.

"Analysis of Medicare Hospital Compare data revealed that safety-net hospitals perform worse on Surgical Care Improvement Project (SCIP) measures and have less efficient emergency departments throughput," first author Dr. Richard S. Hoehn from the University of Cincinnati, Ohio, said by email. "This last category indicates that these hospitals have insufficient staffing and/or resources to handle their patient burden."

"Safety-net hospitals care for a vulnerable population and maintain an open door to all patients, regardless of their ability to pay. Our study of nine major surgical procedures at academic medical centers in the United States found that hospitals with the highest safety net burden have the most patients of low socioeconomic status, extreme severity of illness, and in need of urgent surgery," Dr. Hoehn said.

"These hospitals also had the worst mortality and readmission rates and highest costs for most procedures. After controlling for patient age, race, severity of illness, and socioeconomic status, safety-net hospitals still had worse outcomes. Their inferior mortality and readmission rates were somewhat reduced, but the increased costs observed at these centers persisted, implying that other characteristics intrinsic to safety-net hospitals are associated with increased costs," he added.

Dr. Hoehn and colleagues analyzed outcomes for nine surgical procedures at 231 hospitals in the University HealthSystem Consortium over a four-year period ending in 2012, accounting for more than 12.6 million patient encounters. They sorted the hospitals into high safety-net burden (HBH) versus hospitals with low (LBH) or medium (MBH) safety-net burden.

They found the HBHs overall to have the most patients likely to be young, black, have the lowest socioeconomic status, and have the highest severity of illness and the highest cost for surgical care (p<0.01 for all). They also had the highest proportion of patient-emergent cases and the longest lengths of stay (p<0.01 for all).

After the researchers adjusted for patient characteristics and hospital volume, the HBHs still had higher odds ratios of mortality for three procedures (OR, 1.81 to 2.08, p<0.05), readmission for two procedures (OR, 1.19 to 1.30, p<0.05), and the highest cost of care for seven procedures (risk ratios, 1.23 to 1.35, p<0.05).

Postoperative mortality was worse for colectomy, esophagectomy, pancreaticoduodenectomy, and ventral hernia repair. Readmission odds were higher for coronary artery bypass, colectomy, kidney transplant, and ventral hernia repair.

"[W]hen assessing markers of emergency department throughput, HBHs were inferior to LBHs in all measures, including time from arrival to evaluation, admission decision time, times from arrival to departure for discharged and admitted patients, time for pain medicine administration to patients with long-bone fractures, and patients who left without being seen (p <= 0.002 for all)," the researchers write in JAMA Surgery, online October 14.

In an accompanying editorial, Dr. Larry R. Kaiser of Temple University School of Medicine, Philadelphia, and colleagues note, "At best, emergency department throughput as a surrogate for staffing adequacy and systems efficiency is an indirect estimate of these important hospital factors. Deficiencies in documentation and coding may or may not be influenced by overall hospital performance but could have a significant influence on expected rates of death and complications."

Dr. Kaiser said by email, "Physicians and surgeons should be very careful in drawing substantive conclusions from the study because of factors we don't know about these patients. Let the message be greater resources should be provided to those hospitals bearing the burden of caring for this underserved population of patients who, if anything, are more complex than commercially insured patients with similar problems."

"It's important to acknowledge that this study is not trying to criticize safety-net hospitals," Dr. Hoehn emphasized. "We are trying to highlight the unique situation these providers face, and also show that current policy changes that financially penalize these hospitals may adversely impact surgical care and further exacerbate the disparities in health care that already exist in our country. Safety-net hospitals in America have always been important institutions that train doctors and care for indigent patients, and our goal is to find a way to preserve this model in the face of changing healthcare policy."

Dr. Hoehn continued, "There are two options to improve the care at these centers: either close these hospitals and send their patients elsewhere or invest in initiatives that will allow these hospitals to improve not only their outcomes but also their efficiency. To do this, we must better understand their needs."

Dr. Kaiser said, "Continued scrutiny of outcomes with transparency and sharing of data with all those involved in the care of patients will result in continued quality improvement. Participation in [universal health care] that allows institutions to benchmark their data with similar institutions will tend to push those who need improvement to continue to improve."

"There must be a concerted effort among all involved in caring for patients at an institution to continue to improve quality. The designation of a chief quality officer working in concert with the chief medical officer also is critically important in working toward improved quality. But all of this depends on accurate recording and reporting of quality metrics," he concluded.

The Diagnosis: Tinea Corporis

Although contact dermatitis from the metal on the back of the watch was suspected, many modern wrist watches are made with stainless steel rather than nickel, which is a common contact allergen; therefore, other diagnoses were considered in the differential including irritant contact dermatitis, psoriasis, and tinea infection. A potassium hydroxide (KOH) preparation was performed to rule out tinea infection. Unexpectedly, the KOH preparation was positive for fungal hyphae, confirming a diagnosis of tinea corporis. The patient was treated with clotrimazole cream 1% twice daily for 3 weeks during which time the rash completely resolved.

We present this case to stress the importance of performing KOH preparations even when the likelihood of tinea infection seems remote. At our institution, we teach our residents, “If it’s scaly, scrape it.” This adage has served us well. Tinea corporis may be mistaken for many other skin diseases, including eczema, psoriasis, and seborrheic dermatitis.¹ A KOH preparation often is a helpful tool in confirming the diagnosis and should be performed when a dermatophyte infection is suspected. The KOH preparation is the most sensitive diagnostic test used to confirm dermatophyte infection, with 90% of infections showing positive results.^2,3

Tinea infections may occur anywhere on the body, but areas that are prone to excessive heat and/or moisture are particularly susceptible.⁴ Dermatophyte infections typically present as annular, scaly, pruritic patches or plaques often with central clearing and an active border.¹ In our patient, the lesion showed characteristics that were suggestive of a dermatophyte infection but was somewhat atypical in appearance, as it lacked central clearing (Figure). The 3 genera of dermatophytes—Trichophyton, Microsporum, and Epidermophyton—are common causes of fungal infections.² The pathogenesis of dermatophytosis is the synthesis of keratinases that digest keratin and sustain the presence of the fungi. Local factors such as sweating and occlusion facilitate the activity of these organisms.² In our case, the pathogenesis was believed to be due to the entrapment of moisture behind the patient’s watch, creating a favorable environment for fungal growth.

The Diagnosis: Tinea Corporis

Although contact dermatitis from the metal on the back of the watch was suspected, many modern wrist watches are made with stainless steel rather than nickel, which is a common contact allergen; therefore, other diagnoses were considered in the differential including irritant contact dermatitis, psoriasis, and tinea infection. A potassium hydroxide (KOH) preparation was performed to rule out tinea infection. Unexpectedly, the KOH preparation was positive for fungal hyphae, confirming a diagnosis of tinea corporis. The patient was treated with clotrimazole cream 1% twice daily for 3 weeks during which time the rash completely resolved.

We present this case to stress the importance of performing KOH preparations even when the likelihood of tinea infection seems remote. At our institution, we teach our residents, “If it’s scaly, scrape it.” This adage has served us well. Tinea corporis may be mistaken for many other skin diseases, including eczema, psoriasis, and seborrheic dermatitis.¹ A KOH preparation often is a helpful tool in confirming the diagnosis and should be performed when a dermatophyte infection is suspected. The KOH preparation is the most sensitive diagnostic test used to confirm dermatophyte infection, with 90% of infections showing positive results.^2,3

Tinea infections may occur anywhere on the body, but areas that are prone to excessive heat and/or moisture are particularly susceptible.⁴ Dermatophyte infections typically present as annular, scaly, pruritic patches or plaques often with central clearing and an active border.¹ In our patient, the lesion showed characteristics that were suggestive of a dermatophyte infection but was somewhat atypical in appearance, as it lacked central clearing (Figure). The 3 genera of dermatophytes—Trichophyton, Microsporum, and Epidermophyton—are common causes of fungal infections.² The pathogenesis of dermatophytosis is the synthesis of keratinases that digest keratin and sustain the presence of the fungi. Local factors such as sweating and occlusion facilitate the activity of these organisms.² In our case, the pathogenesis was believed to be due to the entrapment of moisture behind the patient’s watch, creating a favorable environment for fungal growth.

The Diagnosis: Tinea Corporis

Although contact dermatitis from the metal on the back of the watch was suspected, many modern wrist watches are made with stainless steel rather than nickel, which is a common contact allergen; therefore, other diagnoses were considered in the differential including irritant contact dermatitis, psoriasis, and tinea infection. A potassium hydroxide (KOH) preparation was performed to rule out tinea infection. Unexpectedly, the KOH preparation was positive for fungal hyphae, confirming a diagnosis of tinea corporis. The patient was treated with clotrimazole cream 1% twice daily for 3 weeks during which time the rash completely resolved.

We present this case to stress the importance of performing KOH preparations even when the likelihood of tinea infection seems remote. At our institution, we teach our residents, “If it’s scaly, scrape it.” This adage has served us well. Tinea corporis may be mistaken for many other skin diseases, including eczema, psoriasis, and seborrheic dermatitis.¹ A KOH preparation often is a helpful tool in confirming the diagnosis and should be performed when a dermatophyte infection is suspected. The KOH preparation is the most sensitive diagnostic test used to confirm dermatophyte infection, with 90% of infections showing positive results.^2,3

Tinea infections may occur anywhere on the body, but areas that are prone to excessive heat and/or moisture are particularly susceptible.⁴ Dermatophyte infections typically present as annular, scaly, pruritic patches or plaques often with central clearing and an active border.¹ In our patient, the lesion showed characteristics that were suggestive of a dermatophyte infection but was somewhat atypical in appearance, as it lacked central clearing (Figure). The 3 genera of dermatophytes—Trichophyton, Microsporum, and Epidermophyton—are common causes of fungal infections.² The pathogenesis of dermatophytosis is the synthesis of keratinases that digest keratin and sustain the presence of the fungi. Local factors such as sweating and occlusion facilitate the activity of these organisms.² In our case, the pathogenesis was believed to be due to the entrapment of moisture behind the patient’s watch, creating a favorable environment for fungal growth.

In his November podcast for The Journal of Community and Supportive Oncology, Dr David Henry discusses an article and accompanying commentary on the US Food and Drug Administration’s re-approval of gefitinib for the treatment of patients with EGFR-mutated lung cancer. (The drug’s original 2003 approval had been withdrawn in 2011 after subsequent findings failed to show a survival advantage.) He also comments on a line-up of clinical and supportive oncology articles reporting on a modified olanzapine regimen for the prevention of chemotherapy-induced nausea and vomiting; caregivers’ attitudes about their roles in promoting exercise among patients with late-stage lung cancer; the impact of inpatient radiation on length of stay and health care costs; and a study of patients with incurable cancer by Japanese investigators who examined differences in the timing of palliative chemotherapy cessation between patients in a local hospital and patients who transitioned to a local hospital from a tertiary medical center. The final item details a case of treatment-related MDS/AML in a patient after receiving therapy for large-cell neuroendocrine lung cancer.

Click on the download icon at the top of this introduction to listen to the podcast.

In his November podcast for The Journal of Community and Supportive Oncology, Dr David Henry discusses an article and accompanying commentary on the US Food and Drug Administration’s re-approval of gefitinib for the treatment of patients with EGFR-mutated lung cancer. (The drug’s original 2003 approval had been withdrawn in 2011 after subsequent findings failed to show a survival advantage.) He also comments on a line-up of clinical and supportive oncology articles reporting on a modified olanzapine regimen for the prevention of chemotherapy-induced nausea and vomiting; caregivers’ attitudes about their roles in promoting exercise among patients with late-stage lung cancer; the impact of inpatient radiation on length of stay and health care costs; and a study of patients with incurable cancer by Japanese investigators who examined differences in the timing of palliative chemotherapy cessation between patients in a local hospital and patients who transitioned to a local hospital from a tertiary medical center. The final item details a case of treatment-related MDS/AML in a patient after receiving therapy for large-cell neuroendocrine lung cancer.

Click on the download icon at the top of this introduction to listen to the podcast.

In his November podcast for The Journal of Community and Supportive Oncology, Dr David Henry discusses an article and accompanying commentary on the US Food and Drug Administration’s re-approval of gefitinib for the treatment of patients with EGFR-mutated lung cancer. (The drug’s original 2003 approval had been withdrawn in 2011 after subsequent findings failed to show a survival advantage.) He also comments on a line-up of clinical and supportive oncology articles reporting on a modified olanzapine regimen for the prevention of chemotherapy-induced nausea and vomiting; caregivers’ attitudes about their roles in promoting exercise among patients with late-stage lung cancer; the impact of inpatient radiation on length of stay and health care costs; and a study of patients with incurable cancer by Japanese investigators who examined differences in the timing of palliative chemotherapy cessation between patients in a local hospital and patients who transitioned to a local hospital from a tertiary medical center. The final item details a case of treatment-related MDS/AML in a patient after receiving therapy for large-cell neuroendocrine lung cancer.

Click on the download icon at the top of this introduction to listen to the podcast.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.

The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.

Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.

Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.

Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.

So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.

“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.

The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.

Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.

Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.

Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.

None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.

There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.

Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.

The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.

The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.

Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.

Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.

Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.

So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.

“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.

The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.

Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.

Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.

Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.

None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.

There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.

Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.

The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.

The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.

Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.

Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.

Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.

So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.

“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.

The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.

Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.

Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.

Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.

None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.

There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.

Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.

The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.