An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

[email protected]

An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

[email protected]

An investigational dengue vaccine against all four serotypes appears to be safe and immunogenic in children aged 2-17 years, whether or not they previously have been exposed to the virus, said Xavier Sáez-Llorens, MD, of Hospital del Niño Dr José Renán Esquivel, Panama City, Republic of Panama, and his associates.

Studies show dengue to be the most common mosquito-borne viral disease affecting humans, occurring in 125 countries and causing approximately 100 million symptomatic infections annually. Vector control has not halted the global spread of dengue, necessitating development of vaccines. A vaccine for people aged 9 years and older has been licensed, but there remains the need for a safe and effective vaccine against all four dengue virus serotypes for all ages, said Dr. Sáez-Llorens and his associates.

World Health Organization

[email protected]

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

Cutaneous myoepithelial tumors are rare neoplasms but are being increasingly recognized and reported in the literature.^1-7 Myoepithelial tumors are related to benign mixed tumors of the skin but lack the epithelial ductules that are present in mixed tumors. Cutaneous myoepithelial tumors may show a variety of architectural, cytological, and stromal features. Their immunophenotype usually is characterized by coexpression of an epithelial marker (eg, keratin, epithelial membrane antigen [EMA]) and S-100 protein; they also may express a variety of other myoepithelial markers, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin.⁷ EWS RNA binding protein 1 (EWSR1) and pleomorphic adenoma gene 1 (PLAG1) gene rearrangement has been detected in subsets of these tumors on in situ hybridization.^8-10

Malignant myoepithelial tumors of the skin, also referred to as cutaneous myoepithelial carcinomas, are exceedingly rare. Including the current case, a search of PubMed articles indexed for MEDLINE and Google Scholar using the terms myoepithelial carcinoma and cutaneous revealed 12 cases that have been reported in the literature (Table).^1-7,11-13 These tumors often occur in the head and neck areas and the lower extremities and display a bimodal age distribution, generally occurring in patients younger than 21 years and older than 50 years of age; they also show a slight female predominance. Available follow-up data from the literature have shown local recurrence or metastasis in 3 cases^3,4,6; however, in one case the metastatic focus was not histologically identified.⁴ Cutaneous myoepithelial carcinoma presenting with metastatic disease further limits treatment options. Here, we describe a case of metastatic cutaneous myoepithelial carcinoma in a 47-year-old man, a rare example of cutaneous myoepithelial carcinoma with histologically documented metastatic disease at the initial presentation.

Case Report

A 47-year-old man who underwent a renal transplant 19 years prior presented with a weeping, ulcerated, mildly tender lesion on the scalp of 4 months’ duration with neck and back pain of 3 months’ duration. Physical examination demonstrated a 6-cm area of ulceration on the anterior crown of the scalp with adjacent enlarged keratoacanthomalike craters and satellite nodules (Figure 1). He was previously diagnosed with basal cell carcinoma (BCC) of the scalp at an outside institution 4 years prior and was treated with radiation therapy. The prior scalp biopsy for BCC diagnosis was unavailable for review. The patient had a history of chronic eczematous dermatitis in the waistband area that had been present for 19 years and another BCC with nodular and infiltrative patterns on the left helix. Of note, he also had been taking long-term immunosuppressant medications (ie, cyclosporine, azathioprine) for maintenance following the renal transplant.

Because of the extensive ulceration of the primary lesion, a shave biopsy of the scalp was performed on an adjacent satellite nodule. Histopathologic findings showed an intradermal neoplasm characterized by poorly cohesive cells exhibiting epithelioid to plasmacytoid morphologic features surrounded by abundant chondromyxoid stroma. Ductular differentiation was not identified (Figure 2A). The neoplastic cells displayed hyperchromatic nuclei with marked nuclear pleomorphism and atypical mitotic figures (Figure 2B). On immunohistochemistry the tumor cells stained positive for cytokeratin AE1/AE3 (Figure 3), S-100 protein (Figure 4), and p63, and were negative for calponin, desmin, melan-A, cytokeratin 7, and brachyury (Figure 5).

Radiographic imaging was performed due to the patient’s history of neck and back pain. Magnetic resonance imaging showed innumerable slightly expansile, T1-hypointense, T2-hyperintense, and robustly enhancing lesions involving the cervical, thoracic, lumbar, and sacral spine, as well as the thoracic ribs and bilateral iliac bones. There was no evidence of soft tissue tumor around the bone lesions. Ventral cervical spinal cord compression was detected at the C4 vertebra, causing a symptomatic radiculopathy; however, due to widely metastatic disease, the patient was not considered appropriate for neurosurgical intervention of the compression. Computerized tomography of the chest, abdomen, and pelvis did not identify any visceral source of malignancy, though multiple bilaterally enlarged cervical lymph nodes were identified on magnetic resonance imaging.

Fine needle aspiration of a left iliac bone lesion demonstrated neoplastic cells and chondromyxoid stroma essentially identical to the features shown in the skin biopsy (Figure 6). Given the morphologic features of the tumor and coexpression of cytokeratin and S-100 protein, the findings were interpreted as primary cutaneous myoepithelial carcinoma with disseminated metastatic lesions. The patient began treatment with carboplatin and paclitaxel chemotherapy. To combat the symptomatic bone pain and upper extremity radiculopathy, palliative radiation was administered to the cervical spine, lumbar spine, and right sacrum (30 Gy to each site in 10 fractions at 3 Gy per fraction). Despite the attempted chemotherapy and radiation, the patient continued to decline, and after 2 months, he elected to pursue palliative care. The patient died after 3 months in palliative care (5 months after the initial presentation).

Comment

Myoepithelial cells normally surround ducts in secretory organs, such as the breasts, salivary glands, and cutaneous sweat glands. Myoepithelial neoplasms are well recognized in the salivary glands^14,15; however, myoepithelial neoplasms also can arise in other sites, including the soft tissue^4,5,16-18 and skin.^{1-3,7,11,19,20} Myoepithelioma of soft tissue was first described by Burke et al²¹ in 1995 and later described in the skin by Fernandez-Figueras et al²² in 1998. Since then, diagnostic criteria for cutaneous myoepithelial neoplasms have evolved, suggesting a spectrum of disease rather than a single distinct entity.¹¹ Most often, cutaneous myoepithelial carcinomas arise as soft nodular lesions in the head and neck areas or extremities of adults. The nodules typically are nontender and range in size from 0.5 to 18.0 cm. Our review of the literature revealed 11 additional cases of cutaneous myoepithelial carcinomas have been reported, ranging in size from 0.7 to 7.0 cm (Table). In our case, the main lesion was 6 cm, mildly tender, ulcerated, and accompanied by satellite nodules.

Histologically, cutaneous myoepithelial tumors typically are well-defined, dermal-based nodules with no connection to the overlying epidermis. Similar to myoepithelial tumors of other sites, they can be diagnostically challenging due to the heterogeneity of both their architectural and cytological features. The presence of a chondromyxoid or hyalinized stroma is common but not always present. Neoplastic myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show growth patterns in clusters, cords, glands, or sheets. Focal epithelial cells can be present. Although benign myoepithelial neoplasms with overt ductal differentiation are consistent with cutaneous mixed tumors (chondroid syringomas), those without ducts are characterized as myoepitheliomas. It is uncertain if cases with only focal ductal differentiation should be classified as mixed tumors or as myoepitheliomas. Malignant myoepithelial tumors show infiltrative borders, nuclear pleomorphism, coarse nuclear chromatin, prominent nucleoli, and increased mitotic activity. A 2003 study by Hornick and Fletcher¹⁶ found that cytologic atypia was the primary predictor of malignant behavior for myoepithelial neoplasms of the soft tissue.

Despite a wide variety of expression patterns, immunohistochemistry is critical in demonstrating myoepithelial differentiation and establishing a diagnosis of a myoepithelial neoplasm. Most cases display coexpression of epithelial markers, including keratins and/or EMA as well as S-100 protein. Myogenic markers also may be variably expressed; however, the absence of myogenic markers does not exclude the diagnosis of a myoepithelial tumor. Commonly expressed epithelial markers are cytokeratin AE1/AE3, cytokeratin 8/18, and EMA, while commonly expressed myogenic markers include muscle specific actin and smooth muscle actin.^5,7,11,19 Myoepithelial tumors also may express calponin, p63, and glial fibrillary acidic protein.¹⁶

Molecular studies also can aid in the diagnosis of myoepithelial tumors. A study by Antonescu et al⁸ demonstrated EWSR1 gene rearrangement in 45% (30/66) of extrasalivary myoepithelial tumors and the absence of EWSR1 gene rearrangement in salivary gland myoepithelial tumors. The authors also showed that EWSR1-negative tumors were more likely to be superficially located, display ductal differentiation, and possess a benign clinical course.⁸ In another study, Bahrami et al²³ suggested that a subset of mixed tumors, specifically those with tubuloductal differentiation, are genetically linked to salivary gland pleomorphic adenomas, which was achieved by the coexpression of the PLAG1 protein and PLAG1 gene rearrangement on immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. Of the 19 cases evaluated, 11 (58%) expressed nuclear staining for PLAG1 immunohistochemistry; 8 of those 11 showed positive gene rearrangement for PLAG1 using FISH. These findings raise the possibility that cutaneous mixed tumors may be more closely related to those of the salivary glands, while deep myoepithelial tumors that lack ductal differentiation may represent a distinct group. Similar to the study by Antonescu et al,⁸ Flucke et al¹⁰ investigated EWSR1 gene rearrangement but limited their sample to cutaneous tumors, including myoepitheliomas, mixed tumors, and myoepithelial carcinoma. The authors found that 44% of cases (7/16) expressed EWSR1; this expression suggests that cutaneous myoepithelial tumors may have a genetic relationship to their soft tissue, bone, and visceral counterparts.¹⁰

Myoepithelial tumors display a broad spectrum of morphologic features; however, one of the most common growth patterns is that of oval to round cells forming cords and chains in a chondromyxoid stroma. As such, the histopathologic differential diagnosis for myoepithelial tumors includes other epithelioid or round-cell neoplasms with similar growth patterns including extraskeletal myxoid chondrosarcoma (EMC), ossifying fibromyxoid tumor of soft parts, and extra-axial soft tissue chordoma. Extraskeletal myxoid chondrosarcoma bears the closest similarity to myoepithelial tumors both histologically and by ancillary studies. It typically possesses cords or chains of small round tumor cells set in a chondromyxoid or myxoid background. In contrast to myoepithelial tumors, which typically have more abundant cytoplasm and can show at least focal areas of spindle cell growth, the cells of EMC are more uniform, small, round cells with relatively scant cytoplasm. Extraskeletal myxoid chondrosarcomas lack the typical myoepithelial coexpression of cytokeratin and S-100 protein, with a minority of EMCs expressing S-100 protein but rarely cytokeratin. Most cases of EMC possess a balanced t(9;22) translocation involving the EWSR1 gene,²⁴ a finding that could lead to confusion with soft tissue myoepithelial tumors, which also may show EWSR1 rearrangement on FISH. Ossifying fibromyxoid tumor of soft parts is also composed of round cells arranged in cords in a myxoid or fibrous stroma; the majority of cases also display a peripheral rim of mature bone, a feature that is not typically seen in myoepithelial tumors. Similar to myoepithelial tumors, ossifying fibromyxoid tumor of soft parts often is positive for S-100 protein; however, it rarely is positive for cytokeratins. Ossifying fibromyxoid tumor of soft parts has been shown to have a rearrangement of the PHD finger protein 1 (PHF1) gene in approximately half of cases, a molecular finding that has not been reported for myoepithelial tumors.²⁵ Finally, extra-axial soft tissue chordomas, though quite rare, may possess striking similarities to myoepithelial tumors both histopathologically and immunohistochemically. Chordomas are composed of epithelioid cells arranged in nests, nodules, and chains with a variably myxoid background. A variable amount of cells with bubbly cytoplasm (known as physaliphorous cells) can be seen. High mitotic activity is not a characteristic feature in chordomas. They classically coexpress cytokeratins and S-100 protein, similar to myoepithelial tumors. A subset of myoepitheliomas with similar histologic features to chordoma was historically referred to as parachordoma.^26,27 The distinction between these 2 entities was challenging until the relatively recent advent of brachyury, a sensitive and specific nuclear marker of chordoma; extra-axial soft tissue chordomas and their central counterparts both express nuclear brachyury, while myoepitheliomas (including those with a parachordoma histologic pattern) do not.²⁸ Our case did not display physaliphorous cells but did demonstrate abundant nuclear pleomorphism and high mitotic activity. In addition, immunohistochemical staining was negative for brachyury.

Because cutaneous myoepithelial tumors are relatively rare, a well-defined standard of care for treatment is lacking. Surgical excision is the primary treatment method in most reported cases in the literature.^17,19 Miller et al²⁹ reported the successful treatment of recurrent cutaneous myoepitheliomas with Mohs micrographic surgery. Chemotherapy may be useful in the setting of metastatic myoepithelial carcinomas in adults, but reported results are inconsistent.^30,31 Radiation treatment of recurrent or metastatic disease has not been shown to be effective. A study of children treated with surgical resection and chemotherapy using ifosfamide, cisplatin, and etoposide followed by radiation therapy showed positive results.³²

Our case highlights several challenges that may arise in establishing a diagnosis of cutaneous myoepithelial carcinoma with disseminated metastases. The diagnostic difficulty in our case was compounded by the advanced nature of the lesion at the time of presentation. Given the rarity of metastatic cutaneous myoepithelial carcinomas and the lack of a prior primary diagnosis of a malignant myoepithelioma, the index of suspicion for this entity was not high. A report of myoepithelial carcinoma of the parotid gland metastatic to the skin has been reported,³³ but in the absence of salivary gland involvement or other visceral lesions, metastasis from any source other than our patient’s cutaneous scalp lesion is unlikely. The histopathologic features in combination with the characteristic immunophenotype, unique clinical setting, and radiographic findings were essential to arriving at the correct diagnosis. Unlike previously reported metastatic lesions, our case is unique in that metastatic lesions were identified at the time of initial clinical presentation.

Conclusion

Cutaneous myoepithelial carcinomas are exceedingly rare tumors with a wide range of histopathologic and immunohistochemical findings. In challenging cases, studies for EWSR1 or PLAG1 gene rearrangement can be helpful. Furthermore, this case illustrates the potential for widespread dissemination of myoepithelial carcinomas requiring clinical evaluation and imaging studies to exclude metastatic lesions.

AT ASCRS 2017

SEATTLE – Postponing surgery for acute ulcerative colitis more than a day increases postoperative complications, lengths of stay, and hospital costs, according to a review by Johns Hopkins University, Baltimore, of almost 2,000 patients.  

It’s not uncommon to wait 5 or even 10 days to give biologics a chance to work when patients are admitted for acute ulcerative colitis (UC). Based on the review, however, “we believe that the need for prolonged medical therapy and resuscitation in this patient population prior to colectomy may be overstated,” and that “the lasting effects of persistent inflammation cascade are underestimated.”

There has to be “a conversation with the gastroenterologist to strike the right balance between medical and surgical therapy. Early surgical intervention” should be considered, lead author and general surgery resident Ira Leeds, MD, said at the American Society of Colon and Rectal Surgeons annual meeting.

The team reviewed 1,953 index UC admissions with emergent non-elective abdominal surgery in the National Inpatient Sample (NIS) database from 2008-13; 546 patients (28%) had early operations - within 24 hours of admission – and the other 1,407 had operations after that time.
Although it’s impossible to say for sure given the limits of administrative data in the NIS, patients who had surgery soon after admission were probably sicker. Even so, they were less likely to have complications than patients in the delayed surgery group (55% versus 43%), and they had shorter hospital stays, with just 8% in the hospital past 21 days, versus 29% of patients who had delayed operations. The findings were similar for both overall length of stay and post-op length of stay.

Renal complications (8% versus 14%), pulmonary complications (20% versus 25%), and thromboembolic events (4% versus 6%) were also less common in the early surgery group. On multivariable analysis, delayed surgery increased the complication rate by 64%.
With fewer complications and shorter hospital stays, early operations were also less expensive, with a mean total hospitalization cost of $19,985 versus $34,258. The findings were all statistically significant.

Dr. Leeds noted the limits of the study; medical management regimes and the reasons for variations in surgical timing are unknown, among other things. “This is not the final answer on what to do with patients like this, but it opens the door to prospective studies that could control” for such variables, he said.

Early surgery patients were more likely to be male (57% versus 51%) and from households with incomes higher than the national median. There were no difference in age, race, comorbidities, region, or hospital type between the two  groups.
Dr. Leeds said he had no disclosures.

[email protected]  

AGA Resource

Visit www.gastro.org/ibd for patient education guides that you can share with your patients to help them understand and manage their ulcerative colitis and IBD.

AT ASCRS 2017

SEATTLE – Postponing surgery for acute ulcerative colitis more than a day increases postoperative complications, lengths of stay, and hospital costs, according to a review by Johns Hopkins University, Baltimore, of almost 2,000 patients.  

It’s not uncommon to wait 5 or even 10 days to give biologics a chance to work when patients are admitted for acute ulcerative colitis (UC). Based on the review, however, “we believe that the need for prolonged medical therapy and resuscitation in this patient population prior to colectomy may be overstated,” and that “the lasting effects of persistent inflammation cascade are underestimated.”

There has to be “a conversation with the gastroenterologist to strike the right balance between medical and surgical therapy. Early surgical intervention” should be considered, lead author and general surgery resident Ira Leeds, MD, said at the American Society of Colon and Rectal Surgeons annual meeting.

The team reviewed 1,953 index UC admissions with emergent non-elective abdominal surgery in the National Inpatient Sample (NIS) database from 2008-13; 546 patients (28%) had early operations - within 24 hours of admission – and the other 1,407 had operations after that time.
Although it’s impossible to say for sure given the limits of administrative data in the NIS, patients who had surgery soon after admission were probably sicker. Even so, they were less likely to have complications than patients in the delayed surgery group (55% versus 43%), and they had shorter hospital stays, with just 8% in the hospital past 21 days, versus 29% of patients who had delayed operations. The findings were similar for both overall length of stay and post-op length of stay.

Renal complications (8% versus 14%), pulmonary complications (20% versus 25%), and thromboembolic events (4% versus 6%) were also less common in the early surgery group. On multivariable analysis, delayed surgery increased the complication rate by 64%.
With fewer complications and shorter hospital stays, early operations were also less expensive, with a mean total hospitalization cost of $19,985 versus $34,258. The findings were all statistically significant.

Dr. Leeds noted the limits of the study; medical management regimes and the reasons for variations in surgical timing are unknown, among other things. “This is not the final answer on what to do with patients like this, but it opens the door to prospective studies that could control” for such variables, he said.

Early surgery patients were more likely to be male (57% versus 51%) and from households with incomes higher than the national median. There were no difference in age, race, comorbidities, region, or hospital type between the two  groups.
Dr. Leeds said he had no disclosures.

[email protected]  

AGA Resource

Visit www.gastro.org/ibd for patient education guides that you can share with your patients to help them understand and manage their ulcerative colitis and IBD.

AT ASCRS 2017

SEATTLE – Postponing surgery for acute ulcerative colitis more than a day increases postoperative complications, lengths of stay, and hospital costs, according to a review by Johns Hopkins University, Baltimore, of almost 2,000 patients.  

It’s not uncommon to wait 5 or even 10 days to give biologics a chance to work when patients are admitted for acute ulcerative colitis (UC). Based on the review, however, “we believe that the need for prolonged medical therapy and resuscitation in this patient population prior to colectomy may be overstated,” and that “the lasting effects of persistent inflammation cascade are underestimated.”

There has to be “a conversation with the gastroenterologist to strike the right balance between medical and surgical therapy. Early surgical intervention” should be considered, lead author and general surgery resident Ira Leeds, MD, said at the American Society of Colon and Rectal Surgeons annual meeting.

The team reviewed 1,953 index UC admissions with emergent non-elective abdominal surgery in the National Inpatient Sample (NIS) database from 2008-13; 546 patients (28%) had early operations - within 24 hours of admission – and the other 1,407 had operations after that time.
Although it’s impossible to say for sure given the limits of administrative data in the NIS, patients who had surgery soon after admission were probably sicker. Even so, they were less likely to have complications than patients in the delayed surgery group (55% versus 43%), and they had shorter hospital stays, with just 8% in the hospital past 21 days, versus 29% of patients who had delayed operations. The findings were similar for both overall length of stay and post-op length of stay.

Renal complications (8% versus 14%), pulmonary complications (20% versus 25%), and thromboembolic events (4% versus 6%) were also less common in the early surgery group. On multivariable analysis, delayed surgery increased the complication rate by 64%.
With fewer complications and shorter hospital stays, early operations were also less expensive, with a mean total hospitalization cost of $19,985 versus $34,258. The findings were all statistically significant.

Dr. Leeds noted the limits of the study; medical management regimes and the reasons for variations in surgical timing are unknown, among other things. “This is not the final answer on what to do with patients like this, but it opens the door to prospective studies that could control” for such variables, he said.

Early surgery patients were more likely to be male (57% versus 51%) and from households with incomes higher than the national median. There were no difference in age, race, comorbidities, region, or hospital type between the two  groups.
Dr. Leeds said he had no disclosures.

[email protected]  

AGA Resource

Visit www.gastro.org/ibd for patient education guides that you can share with your patients to help them understand and manage their ulcerative colitis and IBD.

BOSTON—Effectiveness and tolerability were the key factors influencing patients’ satisfaction with prophylactic migraine medications, according to a study presented at the 59th Annual Scientific Meeting of the American Headache Society. “There is an unmet need for treatments that have better efficacy and tolerability profiles than existing prophylactic migraine medications,” said lead author Marci Clark, PharmD, Director of Patient-Centered Outcomes Assessment at RTI Health Solutions in Ann Arbor, Michigan, on behalf of her study collaborators.

To gain insight into reasons for patient satisfaction or dissatisfaction with prophylactic migraine medications and identify medication characteristics that would increase patient satisfaction with future prophylactic migraine medications, the researchers recruited study participants from research facilities in Charlotte, North Carolina; St. Louis, Missouri; Southfield, Michigan; and Tampa, Florida. Individuals were eligible to participate if they met the following self-reported criteria: age 18 to 55, physician diagnosis of migraine for 12 or more months, current or prior experience taking one or more prescription prophylactic migraine medication in the past six months, experiencing four or more migraine headache days per month, and further classification as having episodic or chronic migraine (based on the headache/migraine days reported). Individual discussions with all participants were conducted by two experienced interviewers.

Forty participants were recruited and interviewed; 36 met all eligibility criteria. Twenty-one participants met the criteria for episodic migraine, 15 met the criteria for chronic migraine, and four participants, who were current migraineurs, were unable to be classified as episodic or chronic migraine. Participants provided feedback on 20 prescription prophylactic migraine medications. The most commonly used current or prior migraine prophylactics were topiramate (n = 27), amitriptyline (n = 6), propranolol (n = 6), onabotulinumtoxinA (n = 5), and zonisamide (n = 3).

In general, medication effectiveness and tolerability were the most influential factors on patient satisfaction or dissatisfaction with their prophylactic migraine medications. Lack of efficacy, cited by 56% of respondents, was the most frequently reported reason for participants’ dissatisfaction with their medications. Regarding tolerability, 51% of participants reported that a particular side effect was the most dissatisfying characteristic of their medication. The most bothersome side effects reported by participants were memory loss (n = 6), dizziness or light-headedness (n = 5), tiredness/drowsiness/grogginess/sluggishness (n = 5), nausea (n = 3), and dry mouth (n = 2).

Among those who were satisfied with their prophylactic migraine medications, decreased migraine frequency was the most common reason for their satisfaction (65%), followed by decreased migraine severity or intensity, which was reported by 28% of participants.

The most frequently reported desirable characteristics of a new prophylactic migraine medication that would increase participants’ satisfaction were related to the medication’s ability to decrease the frequency and severity or intensity of migraines. Nausea (36%), weight gain (26%), dizziness/light-headedness (23%), drowsiness/grogginess (15%), and memory loss, including the ability to remember words and speak clearly (13%), are side effects that patients reported that they do not want to see in a new or future prophylactic migraine medication.

BOSTON—Effectiveness and tolerability were the key factors influencing patients’ satisfaction with prophylactic migraine medications, according to a study presented at the 59th Annual Scientific Meeting of the American Headache Society. “There is an unmet need for treatments that have better efficacy and tolerability profiles than existing prophylactic migraine medications,” said lead author Marci Clark, PharmD, Director of Patient-Centered Outcomes Assessment at RTI Health Solutions in Ann Arbor, Michigan, on behalf of her study collaborators.

To gain insight into reasons for patient satisfaction or dissatisfaction with prophylactic migraine medications and identify medication characteristics that would increase patient satisfaction with future prophylactic migraine medications, the researchers recruited study participants from research facilities in Charlotte, North Carolina; St. Louis, Missouri; Southfield, Michigan; and Tampa, Florida. Individuals were eligible to participate if they met the following self-reported criteria: age 18 to 55, physician diagnosis of migraine for 12 or more months, current or prior experience taking one or more prescription prophylactic migraine medication in the past six months, experiencing four or more migraine headache days per month, and further classification as having episodic or chronic migraine (based on the headache/migraine days reported). Individual discussions with all participants were conducted by two experienced interviewers.

Forty participants were recruited and interviewed; 36 met all eligibility criteria. Twenty-one participants met the criteria for episodic migraine, 15 met the criteria for chronic migraine, and four participants, who were current migraineurs, were unable to be classified as episodic or chronic migraine. Participants provided feedback on 20 prescription prophylactic migraine medications. The most commonly used current or prior migraine prophylactics were topiramate (n = 27), amitriptyline (n = 6), propranolol (n = 6), onabotulinumtoxinA (n = 5), and zonisamide (n = 3).

In general, medication effectiveness and tolerability were the most influential factors on patient satisfaction or dissatisfaction with their prophylactic migraine medications. Lack of efficacy, cited by 56% of respondents, was the most frequently reported reason for participants’ dissatisfaction with their medications. Regarding tolerability, 51% of participants reported that a particular side effect was the most dissatisfying characteristic of their medication. The most bothersome side effects reported by participants were memory loss (n = 6), dizziness or light-headedness (n = 5), tiredness/drowsiness/grogginess/sluggishness (n = 5), nausea (n = 3), and dry mouth (n = 2).

Among those who were satisfied with their prophylactic migraine medications, decreased migraine frequency was the most common reason for their satisfaction (65%), followed by decreased migraine severity or intensity, which was reported by 28% of participants.

The most frequently reported desirable characteristics of a new prophylactic migraine medication that would increase participants’ satisfaction were related to the medication’s ability to decrease the frequency and severity or intensity of migraines. Nausea (36%), weight gain (26%), dizziness/light-headedness (23%), drowsiness/grogginess (15%), and memory loss, including the ability to remember words and speak clearly (13%), are side effects that patients reported that they do not want to see in a new or future prophylactic migraine medication.

BOSTON—Effectiveness and tolerability were the key factors influencing patients’ satisfaction with prophylactic migraine medications, according to a study presented at the 59th Annual Scientific Meeting of the American Headache Society. “There is an unmet need for treatments that have better efficacy and tolerability profiles than existing prophylactic migraine medications,” said lead author Marci Clark, PharmD, Director of Patient-Centered Outcomes Assessment at RTI Health Solutions in Ann Arbor, Michigan, on behalf of her study collaborators.

To gain insight into reasons for patient satisfaction or dissatisfaction with prophylactic migraine medications and identify medication characteristics that would increase patient satisfaction with future prophylactic migraine medications, the researchers recruited study participants from research facilities in Charlotte, North Carolina; St. Louis, Missouri; Southfield, Michigan; and Tampa, Florida. Individuals were eligible to participate if they met the following self-reported criteria: age 18 to 55, physician diagnosis of migraine for 12 or more months, current or prior experience taking one or more prescription prophylactic migraine medication in the past six months, experiencing four or more migraine headache days per month, and further classification as having episodic or chronic migraine (based on the headache/migraine days reported). Individual discussions with all participants were conducted by two experienced interviewers.

Forty participants were recruited and interviewed; 36 met all eligibility criteria. Twenty-one participants met the criteria for episodic migraine, 15 met the criteria for chronic migraine, and four participants, who were current migraineurs, were unable to be classified as episodic or chronic migraine. Participants provided feedback on 20 prescription prophylactic migraine medications. The most commonly used current or prior migraine prophylactics were topiramate (n = 27), amitriptyline (n = 6), propranolol (n = 6), onabotulinumtoxinA (n = 5), and zonisamide (n = 3).

In general, medication effectiveness and tolerability were the most influential factors on patient satisfaction or dissatisfaction with their prophylactic migraine medications. Lack of efficacy, cited by 56% of respondents, was the most frequently reported reason for participants’ dissatisfaction with their medications. Regarding tolerability, 51% of participants reported that a particular side effect was the most dissatisfying characteristic of their medication. The most bothersome side effects reported by participants were memory loss (n = 6), dizziness or light-headedness (n = 5), tiredness/drowsiness/grogginess/sluggishness (n = 5), nausea (n = 3), and dry mouth (n = 2).

Among those who were satisfied with their prophylactic migraine medications, decreased migraine frequency was the most common reason for their satisfaction (65%), followed by decreased migraine severity or intensity, which was reported by 28% of participants.

The most frequently reported desirable characteristics of a new prophylactic migraine medication that would increase participants’ satisfaction were related to the medication’s ability to decrease the frequency and severity or intensity of migraines. Nausea (36%), weight gain (26%), dizziness/light-headedness (23%), drowsiness/grogginess (15%), and memory loss, including the ability to remember words and speak clearly (13%), are side effects that patients reported that they do not want to see in a new or future prophylactic migraine medication.

LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.

Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.

“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.

LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.

Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.

“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.

LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.

Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.

“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

MADRID – In Sweden, less than 7% of those who experience an osteoporotic fracture receive osteoporosis treatment within the first year, when the risk of a second fracture is the highest.

Women are more likely than are men to get a prescription, but people older than 80 years, and those with dementia or low socioeconomic status, are less likely to receive one, Anna Spångeus, MD, PhD, said at the European Congress of Rheumatology.

[email protected]

On Twitter @alz_gal

MADRID – In Sweden, less than 7% of those who experience an osteoporotic fracture receive osteoporosis treatment within the first year, when the risk of a second fracture is the highest.

Women are more likely than are men to get a prescription, but people older than 80 years, and those with dementia or low socioeconomic status, are less likely to receive one, Anna Spångeus, MD, PhD, said at the European Congress of Rheumatology.

[email protected]

On Twitter @alz_gal

MADRID – In Sweden, less than 7% of those who experience an osteoporotic fracture receive osteoporosis treatment within the first year, when the risk of a second fracture is the highest.

Women are more likely than are men to get a prescription, but people older than 80 years, and those with dementia or low socioeconomic status, are less likely to receive one, Anna Spångeus, MD, PhD, said at the European Congress of Rheumatology.

[email protected]

On Twitter @alz_gal

The presence of bone marrow lesions and cartilage defects on baseline MRI scans of knee osteoarthritis (OA) patients may help to predict moderate to severe pain trajectories, based on data from a population-based study presented here at the European Congress of Rheumatology.

Three pain trajectories were identified: 52% of the patients reported stable mild pain over time, 33% reported moderate pain over time, and 15% reported fluctuating or severe pain over time.

The presence of bone marrow lesions and cartilage defects on baseline MRI scans of knee osteoarthritis (OA) patients may help to predict moderate to severe pain trajectories, based on data from a population-based study presented here at the European Congress of Rheumatology.

Three pain trajectories were identified: 52% of the patients reported stable mild pain over time, 33% reported moderate pain over time, and 15% reported fluctuating or severe pain over time.

The presence of bone marrow lesions and cartilage defects on baseline MRI scans of knee osteoarthritis (OA) patients may help to predict moderate to severe pain trajectories, based on data from a population-based study presented here at the European Congress of Rheumatology.

Three pain trajectories were identified: 52% of the patients reported stable mild pain over time, 33% reported moderate pain over time, and 15% reported fluctuating or severe pain over time.

Dermatologists looking for a way to participate in an advanced alternative payment model under Medicare’s new Quality Payment Program will likely need to develop their own and get it approved.

Advanced alternative payment models (APMs) involve physicians taking on two-sided risk along with Medicare in exchange for the potential for higher bonus payments for delivering higher-value care to patients. Officials at the Centers for Medicare & Medicaid Services have created seven APMs (some primary care and some specialty focused), but they do not appeal to everyone.

“The likelihood that a private practice dermatologist is going to participate in a risk-bearing APM is, I think, possible but challenging,” said Kathryn Schwarzenberger, MD, chair of the American Academy of Dermatology’s Workgroup on Innovation in Payment and Delivery. “To have a fully qualified, double-sided risk APM for most private practitioners is going to be difficult. The advanced APMs, unless you are in a group, we have figured most dermatologists wouldn’t be interested.”

A physician-created APM might be a different story, however.

Getting approval for this type of APM – technically known as physician-focused payment models (PFPMs) – is tough. Of the first three PFPMs reviewed by Medicare’s Physician-Focused Payment Model Technical Advisory Committee (PTAC), two were recommended for limited trial periods only. A third proposal was not recommended. None of these early proposals were dermatology focused.

Not jumping into the process early was a prudent move, according to Dr. Schwarzenberger.

“We learned that it is probably good to sit back at this point and watch and see what is happening,” she said. “I think the rules have become much more clear. I think now that PTAC has provided us with some better guidelines for how to develop a successful APM, we have a much better chance of doing so.”

In this earliest review, each proposed APM was assigned to three commissioners, including at least one physician, for review against 10 criteria:

• Scope of proposed PFPM (high priority).

• Quality and cost (high priority).

• Payment methodology (high priority).

• Value over volume.

• Flexibility.

• Ability to be evaluated.

• Integration and care coordination.

• Patient choice.

• Patient safety.

• Health information technology.

While each proposal met a few of the criteria, none met all three high-priority criteria, and none was recommended for approval by its preliminary reviewers; however, after committee deliberation, two received provisional recommendation.

“We recommended the two models for small-scale testing,” PTAC Vice-Chairman Elizabeth Mitchell said in an interview. “Even though we think they are very good ideas, we know that more experience and evidence are required before they may be ready.”

The two models that got the limited recommendation were:

• Project Sonar, submitted by the Illinois Gastroenterology Group and SonarMD, a Web-based platform that queries patients with inflammatory bowel disease monthly to determine which are in need of more hands-on care.

• American College of Surgeons–Brandeis APM, submitted by the American College of Surgeons, an episode-based payment model that uses claims data but expands on existing CMS value-based models by not requiring hospitalizations. It creates an episodic payment using outpatient settings, including acute and chronic care.

The COPD [chronic obstructive pulmonary disease] and Asthma Monitoring Project (CAMP), a smartphone app to remotely monitor and guide treatment of patients with asthma and chronic obstructive pulmonary disease, was not recommended. It was submitted by Pulmonary Medicine, Infectious Disease and Critical Care Consultants Medical Group of Sacramento.

PTAC has received more than 20 letters of intent from physicians and aims to hold another round of public hearings in September to determine their usefulness.

“I think it is very safe to say that our whole committee has been really gratified with the level of interest and engagement,” said Ms. Mitchell, president and CEO of Network for Regional Healthcare Improvement in Portland, Maine. The volume of applications “underscores the level of interest from the field. The entire reason PTAC was established was to get those good ideas from practicing physicians and others who are identifying better ways to deliver care but are facing barriers in the current payment system.”

She offered advice to those who are contemplating submission of a payment model: “Really understand the criteria and review the request for proposals. I think the committee lays out what we are looking for in terms of information, and we are hoping that it is really straightforward.”

She also stressed that successful models need to work broadly. “We are not talking about something that works for a single practice,” she said. “We are talking about models that are ready for inclusion in the whole CMS portfolio. It is helpful if there is experience to draw from that informs our deliberations, but we recognize that, in some cases, there has not been the opportunity to test these models broadly.”

Most of all, the highest priority when it comes to the models is related to quality of care and cost.

“We are not soliciting models that are essentially tweaks to fee for service. We are looking for changes that cannot be made without a new method of payment,” she said, adding that the models “have to either reduce cost while maintaining quality or improve quality without raising cost.”

Meeting transcripts and video are posted online and can help potential applicants see how the committee came to its recommendations.

“The committee does not deliberate on the proposals except in public,” Ms. Mitchell said. “So, those public meetings were the first time we had deliberated on any of the proposals we have considered. The preliminary review teams have discussed it [in depth], but the full committee can only deliberate in public.”

Dr. Schwarzenberger said that while the AAD working group is looking at some dermatology-specific conditions that might be good for a PFPM a broader approach may be better. Perhaps the focus should be “where dermatology’s involvement with other physicians, where we might be able to help them practice medicine better or save money,” she said. “Maybe where we can make our biggest financial and potentially quality impacts.”
 

[email protected]

Dermatologists looking for a way to participate in an advanced alternative payment model under Medicare’s new Quality Payment Program will likely need to develop their own and get it approved.

Advanced alternative payment models (APMs) involve physicians taking on two-sided risk along with Medicare in exchange for the potential for higher bonus payments for delivering higher-value care to patients. Officials at the Centers for Medicare & Medicaid Services have created seven APMs (some primary care and some specialty focused), but they do not appeal to everyone.

“The likelihood that a private practice dermatologist is going to participate in a risk-bearing APM is, I think, possible but challenging,” said Kathryn Schwarzenberger, MD, chair of the American Academy of Dermatology’s Workgroup on Innovation in Payment and Delivery. “To have a fully qualified, double-sided risk APM for most private practitioners is going to be difficult. The advanced APMs, unless you are in a group, we have figured most dermatologists wouldn’t be interested.”

A physician-created APM might be a different story, however.

Getting approval for this type of APM – technically known as physician-focused payment models (PFPMs) – is tough. Of the first three PFPMs reviewed by Medicare’s Physician-Focused Payment Model Technical Advisory Committee (PTAC), two were recommended for limited trial periods only. A third proposal was not recommended. None of these early proposals were dermatology focused.

Not jumping into the process early was a prudent move, according to Dr. Schwarzenberger.

“We learned that it is probably good to sit back at this point and watch and see what is happening,” she said. “I think the rules have become much more clear. I think now that PTAC has provided us with some better guidelines for how to develop a successful APM, we have a much better chance of doing so.”

In this earliest review, each proposed APM was assigned to three commissioners, including at least one physician, for review against 10 criteria:

• Scope of proposed PFPM (high priority).

• Quality and cost (high priority).

• Payment methodology (high priority).

• Value over volume.

• Flexibility.

• Ability to be evaluated.

• Integration and care coordination.

• Patient choice.

• Patient safety.

• Health information technology.

While each proposal met a few of the criteria, none met all three high-priority criteria, and none was recommended for approval by its preliminary reviewers; however, after committee deliberation, two received provisional recommendation.

“We recommended the two models for small-scale testing,” PTAC Vice-Chairman Elizabeth Mitchell said in an interview. “Even though we think they are very good ideas, we know that more experience and evidence are required before they may be ready.”

The two models that got the limited recommendation were:

• Project Sonar, submitted by the Illinois Gastroenterology Group and SonarMD, a Web-based platform that queries patients with inflammatory bowel disease monthly to determine which are in need of more hands-on care.

• American College of Surgeons–Brandeis APM, submitted by the American College of Surgeons, an episode-based payment model that uses claims data but expands on existing CMS value-based models by not requiring hospitalizations. It creates an episodic payment using outpatient settings, including acute and chronic care.

The COPD [chronic obstructive pulmonary disease] and Asthma Monitoring Project (CAMP), a smartphone app to remotely monitor and guide treatment of patients with asthma and chronic obstructive pulmonary disease, was not recommended. It was submitted by Pulmonary Medicine, Infectious Disease and Critical Care Consultants Medical Group of Sacramento.

PTAC has received more than 20 letters of intent from physicians and aims to hold another round of public hearings in September to determine their usefulness.

“I think it is very safe to say that our whole committee has been really gratified with the level of interest and engagement,” said Ms. Mitchell, president and CEO of Network for Regional Healthcare Improvement in Portland, Maine. The volume of applications “underscores the level of interest from the field. The entire reason PTAC was established was to get those good ideas from practicing physicians and others who are identifying better ways to deliver care but are facing barriers in the current payment system.”

She offered advice to those who are contemplating submission of a payment model: “Really understand the criteria and review the request for proposals. I think the committee lays out what we are looking for in terms of information, and we are hoping that it is really straightforward.”

She also stressed that successful models need to work broadly. “We are not talking about something that works for a single practice,” she said. “We are talking about models that are ready for inclusion in the whole CMS portfolio. It is helpful if there is experience to draw from that informs our deliberations, but we recognize that, in some cases, there has not been the opportunity to test these models broadly.”

Most of all, the highest priority when it comes to the models is related to quality of care and cost.

“We are not soliciting models that are essentially tweaks to fee for service. We are looking for changes that cannot be made without a new method of payment,” she said, adding that the models “have to either reduce cost while maintaining quality or improve quality without raising cost.”

Meeting transcripts and video are posted online and can help potential applicants see how the committee came to its recommendations.

“The committee does not deliberate on the proposals except in public,” Ms. Mitchell said. “So, those public meetings were the first time we had deliberated on any of the proposals we have considered. The preliminary review teams have discussed it [in depth], but the full committee can only deliberate in public.”

Dr. Schwarzenberger said that while the AAD working group is looking at some dermatology-specific conditions that might be good for a PFPM a broader approach may be better. Perhaps the focus should be “where dermatology’s involvement with other physicians, where we might be able to help them practice medicine better or save money,” she said. “Maybe where we can make our biggest financial and potentially quality impacts.”
 

[email protected]

Dermatologists looking for a way to participate in an advanced alternative payment model under Medicare’s new Quality Payment Program will likely need to develop their own and get it approved.

Advanced alternative payment models (APMs) involve physicians taking on two-sided risk along with Medicare in exchange for the potential for higher bonus payments for delivering higher-value care to patients. Officials at the Centers for Medicare & Medicaid Services have created seven APMs (some primary care and some specialty focused), but they do not appeal to everyone.

“The likelihood that a private practice dermatologist is going to participate in a risk-bearing APM is, I think, possible but challenging,” said Kathryn Schwarzenberger, MD, chair of the American Academy of Dermatology’s Workgroup on Innovation in Payment and Delivery. “To have a fully qualified, double-sided risk APM for most private practitioners is going to be difficult. The advanced APMs, unless you are in a group, we have figured most dermatologists wouldn’t be interested.”

A physician-created APM might be a different story, however.

Getting approval for this type of APM – technically known as physician-focused payment models (PFPMs) – is tough. Of the first three PFPMs reviewed by Medicare’s Physician-Focused Payment Model Technical Advisory Committee (PTAC), two were recommended for limited trial periods only. A third proposal was not recommended. None of these early proposals were dermatology focused.

Not jumping into the process early was a prudent move, according to Dr. Schwarzenberger.

“We learned that it is probably good to sit back at this point and watch and see what is happening,” she said. “I think the rules have become much more clear. I think now that PTAC has provided us with some better guidelines for how to develop a successful APM, we have a much better chance of doing so.”

In this earliest review, each proposed APM was assigned to three commissioners, including at least one physician, for review against 10 criteria:

• Scope of proposed PFPM (high priority).

• Quality and cost (high priority).

• Payment methodology (high priority).

• Value over volume.

• Flexibility.

• Ability to be evaluated.

• Integration and care coordination.

• Patient choice.

• Patient safety.

• Health information technology.

While each proposal met a few of the criteria, none met all three high-priority criteria, and none was recommended for approval by its preliminary reviewers; however, after committee deliberation, two received provisional recommendation.

“We recommended the two models for small-scale testing,” PTAC Vice-Chairman Elizabeth Mitchell said in an interview. “Even though we think they are very good ideas, we know that more experience and evidence are required before they may be ready.”

The two models that got the limited recommendation were:

• Project Sonar, submitted by the Illinois Gastroenterology Group and SonarMD, a Web-based platform that queries patients with inflammatory bowel disease monthly to determine which are in need of more hands-on care.

• American College of Surgeons–Brandeis APM, submitted by the American College of Surgeons, an episode-based payment model that uses claims data but expands on existing CMS value-based models by not requiring hospitalizations. It creates an episodic payment using outpatient settings, including acute and chronic care.

The COPD [chronic obstructive pulmonary disease] and Asthma Monitoring Project (CAMP), a smartphone app to remotely monitor and guide treatment of patients with asthma and chronic obstructive pulmonary disease, was not recommended. It was submitted by Pulmonary Medicine, Infectious Disease and Critical Care Consultants Medical Group of Sacramento.

PTAC has received more than 20 letters of intent from physicians and aims to hold another round of public hearings in September to determine their usefulness.

“I think it is very safe to say that our whole committee has been really gratified with the level of interest and engagement,” said Ms. Mitchell, president and CEO of Network for Regional Healthcare Improvement in Portland, Maine. The volume of applications “underscores the level of interest from the field. The entire reason PTAC was established was to get those good ideas from practicing physicians and others who are identifying better ways to deliver care but are facing barriers in the current payment system.”

She offered advice to those who are contemplating submission of a payment model: “Really understand the criteria and review the request for proposals. I think the committee lays out what we are looking for in terms of information, and we are hoping that it is really straightforward.”

She also stressed that successful models need to work broadly. “We are not talking about something that works for a single practice,” she said. “We are talking about models that are ready for inclusion in the whole CMS portfolio. It is helpful if there is experience to draw from that informs our deliberations, but we recognize that, in some cases, there has not been the opportunity to test these models broadly.”

Most of all, the highest priority when it comes to the models is related to quality of care and cost.

“We are not soliciting models that are essentially tweaks to fee for service. We are looking for changes that cannot be made without a new method of payment,” she said, adding that the models “have to either reduce cost while maintaining quality or improve quality without raising cost.”

Meeting transcripts and video are posted online and can help potential applicants see how the committee came to its recommendations.

“The committee does not deliberate on the proposals except in public,” Ms. Mitchell said. “So, those public meetings were the first time we had deliberated on any of the proposals we have considered. The preliminary review teams have discussed it [in depth], but the full committee can only deliberate in public.”

Dr. Schwarzenberger said that while the AAD working group is looking at some dermatology-specific conditions that might be good for a PFPM a broader approach may be better. Perhaps the focus should be “where dermatology’s involvement with other physicians, where we might be able to help them practice medicine better or save money,” she said. “Maybe where we can make our biggest financial and potentially quality impacts.”
 

[email protected]

American Indians and Alaska Natives (AI/ANs) have a high risk of diabetes-related vision loss, in part because only half get the annual eye exam needed for timely diagnosis and treatment. But using an innovative telemedicine program, IHS increased the number of AI/ANs who receive an annual retina exam by 20% from 2007 to 2015.

The IHS teleophthalmology program, established in 2000, provides high-quality retinal exams in primary care clinics. More than 70,000 retinal exams have been done for AI/AN patients, IHS says. The exam can be done during a regular office visit without dilation. The retinal photographs are sent electronically to a central reading center where they’re interpreted by trained and certified IHS eye doctors.

The program, available at about 100 sites in 25 states, has not only increased access, IHS says, but also reduced the overall cost of care by preventing complications resulting from delayed or missed care. Screening and treating eye disease in patients with diabetes mellitus costs $3,190 per quality-adjusted life-year saved, IHS says; $840,000 would be saved annually in detecting high-risk diabetic retinopathy (DR). Another $1,090,000 would be saved by reducing the need for additional surgery for complications resulting from delayed identification of patients with high-risk DR.

The program has been validated to American Telemedicine Association Category 3, meaning its clinical outcome is equal to or better than a conventional eye examination for DR. As one of the few and largest programs validated and operating at this level, IHS says the teleophthalmology program has brought high-quality point-of-care specialty service to more than 150,000 AI/AN patients.

American Indians and Alaska Natives (AI/ANs) have a high risk of diabetes-related vision loss, in part because only half get the annual eye exam needed for timely diagnosis and treatment. But using an innovative telemedicine program, IHS increased the number of AI/ANs who receive an annual retina exam by 20% from 2007 to 2015.

The IHS teleophthalmology program, established in 2000, provides high-quality retinal exams in primary care clinics. More than 70,000 retinal exams have been done for AI/AN patients, IHS says. The exam can be done during a regular office visit without dilation. The retinal photographs are sent electronically to a central reading center where they’re interpreted by trained and certified IHS eye doctors.

The program, available at about 100 sites in 25 states, has not only increased access, IHS says, but also reduced the overall cost of care by preventing complications resulting from delayed or missed care. Screening and treating eye disease in patients with diabetes mellitus costs $3,190 per quality-adjusted life-year saved, IHS says; $840,000 would be saved annually in detecting high-risk diabetic retinopathy (DR). Another $1,090,000 would be saved by reducing the need for additional surgery for complications resulting from delayed identification of patients with high-risk DR.

The program has been validated to American Telemedicine Association Category 3, meaning its clinical outcome is equal to or better than a conventional eye examination for DR. As one of the few and largest programs validated and operating at this level, IHS says the teleophthalmology program has brought high-quality point-of-care specialty service to more than 150,000 AI/AN patients.

American Indians and Alaska Natives (AI/ANs) have a high risk of diabetes-related vision loss, in part because only half get the annual eye exam needed for timely diagnosis and treatment. But using an innovative telemedicine program, IHS increased the number of AI/ANs who receive an annual retina exam by 20% from 2007 to 2015.

The IHS teleophthalmology program, established in 2000, provides high-quality retinal exams in primary care clinics. More than 70,000 retinal exams have been done for AI/AN patients, IHS says. The exam can be done during a regular office visit without dilation. The retinal photographs are sent electronically to a central reading center where they’re interpreted by trained and certified IHS eye doctors.

The program, available at about 100 sites in 25 states, has not only increased access, IHS says, but also reduced the overall cost of care by preventing complications resulting from delayed or missed care. Screening and treating eye disease in patients with diabetes mellitus costs $3,190 per quality-adjusted life-year saved, IHS says; $840,000 would be saved annually in detecting high-risk diabetic retinopathy (DR). Another $1,090,000 would be saved by reducing the need for additional surgery for complications resulting from delayed identification of patients with high-risk DR.

The program has been validated to American Telemedicine Association Category 3, meaning its clinical outcome is equal to or better than a conventional eye examination for DR. As one of the few and largest programs validated and operating at this level, IHS says the teleophthalmology program has brought high-quality point-of-care specialty service to more than 150,000 AI/AN patients.