CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

CHICAGO – A combination of an immunostimulatory IL-15-based agent, ALT-803, with a therapeutic monoclonal antibody (mAb) against CD20, was well tolerated and had clinical activity in patients with indolent non-Hodgkin lymphoma (iNHL), according to preliminary findings from a phase 1 study.

“The cancer immunotherapy breakthrough that happened several years ago continues year after year, with a plethora of different modalities of immunotherapy at our disposal,” Todd A. Fehniger, MD, PhD, said at the annual meeting of the American Association for Cancer Research.

Immunotherapy with anti-CD20 mAbs, alone or in combination with chemotherapy, is a standard therapy for iNHL patients. Since iNHL cells express CD20, targeting it with mAbs triggers antitumor responses via cell surface receptors resulting in a potent antibody-dependent cellular toxicity. However, response in patients is highly heterogeneous, with relapse within a few months in a subset of patients. In addition, chemotherapeutic combinations can be toxic and result in serious and long-term complications.

“Relapsed or refractory iNHL is not curable and treatment strategies without long-term complications are needed,” said Dr. Fehniger, associate professor of medicine at Washington University, St. Louis.

In an attempt to address this, Dr. Fehniger and his colleagues combined rituximab, an anti-CD20 antibody, with a relatively new IL-15 agonist immunostimulatory agent called ALT-803.

In the phase 1 trial, the researchers enrolled patients with indolent non-Hodgkin lymphoma who had relapsed after at least 1 prior to CD20 antibody containing therapy. The study was a standard 3+3 dose escalation design with rituximab administered by intravenous infusion, 375 mg/m² in four weekly doses, followed by a rest and four consolidation doses every 8 weeks for four cycles.

ALT-803 was administered concurrently at dose levels of 1 mcg/kg, 3 mcg/kg, and 6 mcg/kg IV followed by 6 mcg/kg, 10 mcg/kg, 15 mcg/kg, and 20 mcg/kg subcutaneously.

SOURCE: Fehniger TA et al. AACR Annual Meeting, Abstract CT146.

Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).^1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).^1,3

The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation⁴; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.⁴

Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.

Methods

A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.

Results

Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years. Twelve (42.86%) patients were 70 years of age or older, 11 (39.29%) were between 50 and 69 years, and 5 (17.85%) were younger than 50 years. Fifteen (53.57%) of the lesions were localized to the fingers, and 13 (46.43%) were localized to the toes; 18 (64.3%) of the lesions were distal and 10 (35.7%) were proximal to the distal interphalangeal joint. The most common pathologic diagnosis was squamous cell carcinoma (SCC) in situ (12/28 [42.86%]), followed by melanoma in situ (6/28 [21.42%]), severely dysplastic nevus (4/28 [14.29%]), SCC (4/28 [14.29%]), acrospiroma (1/28 [3.57%]), and melanoma (1/28 [3.57%]).

Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.

Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.

Comment

Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.^1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.^1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).^3-5

The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.⁶ More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.^4,6 Moehrle et al⁷ found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,⁸ no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al⁵ reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively. Based on a review of PubMed articles indexed for MEDLINE using the search terms surgical treatment of digital melanoma and nonmelanoma skin cancers, Mohs micrographic surgery for melanoma and nonmelanoma skin cancer, and surgical treatment of subungual skin cancer, conservative functional surgical approaches have been found to be cosmetically favorable, whereas local recurrence and survival rates have been shown to be unaffected by the level and degree of amputation.^4,5

In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.⁹ The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al⁹ revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.¹⁰

The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.^9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.^11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.^11,12

Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.

Surgical grafts can be categorized based on the origin of the graft.^2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.^2,13Xenografts (eg, porcine grafts) can be used to repair defects involving the mucosa and those with a large wound depth, exposed cartilage, and/or bony defects, as well as wounds with indeterminate tumor margins and in patients with medical comorbidities that might prevent or delay plans for immediate wound reconstruction (eg, diabetes, cardiovascular disease, autoimmune connective tissue disease).^13,14

A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.¹⁵ Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.¹⁴ The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.² Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.¹⁵ The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.

Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.

In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.¹⁶ The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.

There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits. In our study, patients treated with MMS were evaluated for recurrence of the primary lesion during postoperative follow-up appointments at the office or with the patient’s referring dermatologist. Follow-up data evaluating tumor recurrence were obtained for 25 of the patients, demonstrating no recurrence (mean follow-up, 35.4 months). Longer follow-up data would be more informative, but our findings nonetheless demonstrate that MMS is an effective treatment option for cutaneous malignancies of the digits.

Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.

Conclusion

This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.

Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).^1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).^1,3

The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation⁴; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.⁴

Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.

Methods

A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.

Results

Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years. Twelve (42.86%) patients were 70 years of age or older, 11 (39.29%) were between 50 and 69 years, and 5 (17.85%) were younger than 50 years. Fifteen (53.57%) of the lesions were localized to the fingers, and 13 (46.43%) were localized to the toes; 18 (64.3%) of the lesions were distal and 10 (35.7%) were proximal to the distal interphalangeal joint. The most common pathologic diagnosis was squamous cell carcinoma (SCC) in situ (12/28 [42.86%]), followed by melanoma in situ (6/28 [21.42%]), severely dysplastic nevus (4/28 [14.29%]), SCC (4/28 [14.29%]), acrospiroma (1/28 [3.57%]), and melanoma (1/28 [3.57%]).

Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.

Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.

Comment

Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.^1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.^1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).^3-5

The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.⁶ More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.^4,6 Moehrle et al⁷ found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,⁸ no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al⁵ reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively. Based on a review of PubMed articles indexed for MEDLINE using the search terms surgical treatment of digital melanoma and nonmelanoma skin cancers, Mohs micrographic surgery for melanoma and nonmelanoma skin cancer, and surgical treatment of subungual skin cancer, conservative functional surgical approaches have been found to be cosmetically favorable, whereas local recurrence and survival rates have been shown to be unaffected by the level and degree of amputation.^4,5

In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.⁹ The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al⁹ revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.¹⁰

The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.^9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.^11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.^11,12

Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.

Surgical grafts can be categorized based on the origin of the graft.^2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.^2,13Xenografts (eg, porcine grafts) can be used to repair defects involving the mucosa and those with a large wound depth, exposed cartilage, and/or bony defects, as well as wounds with indeterminate tumor margins and in patients with medical comorbidities that might prevent or delay plans for immediate wound reconstruction (eg, diabetes, cardiovascular disease, autoimmune connective tissue disease).^13,14

A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.¹⁵ Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.¹⁴ The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.² Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.¹⁵ The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.

Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.

In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.¹⁶ The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.

There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits. In our study, patients treated with MMS were evaluated for recurrence of the primary lesion during postoperative follow-up appointments at the office or with the patient’s referring dermatologist. Follow-up data evaluating tumor recurrence were obtained for 25 of the patients, demonstrating no recurrence (mean follow-up, 35.4 months). Longer follow-up data would be more informative, but our findings nonetheless demonstrate that MMS is an effective treatment option for cutaneous malignancies of the digits.

Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.

Conclusion

This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.

Mohs micrographic surgery (MMS) is a specialized surgical technique for the treatment of melanoma and nonmelanoma skin cancers (NMSCs).^1-3 The procedure involves surgical excision, histopathologic examination, precise mapping of malignant tissue, and wound management. Indications for MMS in skin cancer patients include recurring lesions, lesions in high-risk anatomic locations, aggressive histologic subtypes (ie, morpheaform, micronodular, infiltrative, high-grade, poorly differentiated), perineural invasion, large lesion size (>2 cm in diameter), poorly defined lateral or vertical clinical borders, rapid growth of the lesion, immunocompromised status, and sites of positive margins on prior excision. The therapeutic advantages of MMS include tissue conservation and optimal margin control in cosmetically or functionally sensitive areas, such as acral sites (eg, hands, feet, digits).^1,3

The intricacies of the nail apparatus complicate diagnostic biopsy and precise delineation of peripheral margins in digital skin cancers; thus, early diagnosis and intraoperative histologic examination of the margins are essential. Traditionally, the surgical approach to subungual cutaneous tumors such as melanoma has included digital amputation⁴; however, a study of the treatment of subungual melanoma revealed no difference in survival based on the level of amputation, therefore advocating for less radical treatment.⁴

Interestingly, MMS for cutaneous tumors localized to the digits is not frequently reviewed in the dermatologic literature. We present a retrospective case series evaluating the clinical outcomes of digital melanoma and NMSCs treated with MMS.

Methods

A retrospective chart review was performed at a private dermatology practice to identify patients who underwent MMS for melanoma or NMSC localized to the digits from January 2009 to December 2014. All patients were treated in the office by 1 Mohs surgeon (A.H.) and were evaluated before and after MMS. Data were collected from the electronic medical record of the practice, including patient demographics, histopathologic diagnosis, tumor status (primary or recurrent lesion), anatomic site of the tumor, preoperative and postoperative size of the lesion, number of MMS stages, surgical repair technique, postoperative complications, and follow-up period.

Results

Twenty-seven patients (13 male, 14 female) with a total of 28 lesions (malignant melanoma or NMSC) localized to the digits were identified (Table). The mean age at the time of MMS was 64.07 years. Twelve (42.86%) patients were 70 years of age or older, 11 (39.29%) were between 50 and 69 years, and 5 (17.85%) were younger than 50 years. Fifteen (53.57%) of the lesions were localized to the fingers, and 13 (46.43%) were localized to the toes; 18 (64.3%) of the lesions were distal and 10 (35.7%) were proximal to the distal interphalangeal joint. The most common pathologic diagnosis was squamous cell carcinoma (SCC) in situ (12/28 [42.86%]), followed by melanoma in situ (6/28 [21.42%]), severely dysplastic nevus (4/28 [14.29%]), SCC (4/28 [14.29%]), acrospiroma (1/28 [3.57%]), and melanoma (1/28 [3.57%]).

Surgical techniques used for repair following MMS included xenograft (10/28 [35.71%]); split-thickness skin graft (7/28 [25.0%]); secondary intention (4/28 [14.29%]); flap (4/28 [14.29%]); full-thickness skin graft (2/28 [7.14%]); and complex closure (1/28 [3.57%]). Clinical preoperative, operative, and postoperative photos from Patient 21 in this series are shown here (Figure). Two patients required bony phalanx resection due to invasion of the tumor into the periosteum: 1 had a malignant melanoma (Breslow depth, 2.52 mm); the other had an SCC. In addition, following removal of a severely dysplastic nevus, debulked tissue revealed melanoma in 1 patient.

Postoperative complications were noted in 4 (14.29%) of 28 MMS procedures, including bacterial wound infection (3.57%), excess granulation tissue that required wound debridement (7.14%), and delay in wound healing (3.57%). Follow-up data were available for 25 of the 28 MMS procedures (mean follow-up, 35.4 months), during which no recurrences were observed.

Comment

Mohs micrographic surgery is a specialized technique used in the treatment of cutaneous tumors, including basal cell carcinoma, SCC, melanoma in situ, atypical fibroxanthoma, dermatofibrosarcoma protuberans, sebaceous carcinoma, microcystic adnexal carcinoma, and Merkel cell carcinoma, among other cutaneous tumors.^1-3 Mohs micrographic surgery provides the advantage of tissue conservation as well as optimal margin control in cosmetically or functionally sensitive areas while providing a higher cure rate than surgical excision. During the procedure, the surgical margin is examined histologically, thus ensuring definitive removal of the tumor but minimal loss of surrounding normal tissue.^1-3 Mohs micrographic surgery is particularly useful for treating lesions on acral sites (eg, hands, feet, and digits).^3-5

The treatment of digital skin cancers has evolved over the past 50 years with advancements resulting in more precise, tissue-sparing methods, in contrast to previous treatments such as amputation and wide local excision.⁶ More specifically, traditional digital amputation for the treatment of subungual melanoma has been reevaluated in multiple studies, which did not demonstrate a statistically significant difference in survival based on the level of amputation, thereby favoring less radical treatment.^4,6 Moehrle et al⁷ found no statistical difference in recurrence rate when comparing patients with digital melanomas treated with partial amputation and those treated with digit-sparing surgery with limited excision and histologic evaluation of margins. Additionally, in a study conducted by Lazar et al,⁸ no recurrence of 13 subungual malignancies treated with MMS that utilized a full-thickness graft was reported at 4-year follow-up. In a large retrospective series of digital melanomas treated with MMS, Terushkin et al⁵ reported that 96.5% (55/57) of patients with primary melanomas that were treated with MMS avoided amputation, and the 5- and 10-year melanoma-specific survival rates for all patients treated with MMS were 95.0% and 82.6%, respectively. Based on a review of PubMed articles indexed for MEDLINE using the search terms surgical treatment of digital melanoma and nonmelanoma skin cancers, Mohs micrographic surgery for melanoma and nonmelanoma skin cancer, and surgical treatment of subungual skin cancer, conservative functional surgical approaches have been found to be cosmetically favorable, whereas local recurrence and survival rates have been shown to be unaffected by the level and degree of amputation.^4,5

In our study, cutaneous malignancies were located most often on the fingers, and the most common skin cancer identified was SCC in situ. The literature has shown that SCC in situ and SCC are the most common cutaneous neoplasms of the digits and nail unit.⁹ The most common specific anatomic site of cutaneous malignancy in our study was the great toe, followed by the fourth finger. A study conducted by Tan et al⁹ revealed that the great toe was the most common location of melanoma of the nail bed and subungual region, followed by the thumb. In contrast, primary subungual SCCs occur most frequently on the finger, with rare cases involving the toes.¹⁰

The etiology of digital SCC may involve extensive sun exposure, chronic trauma and wounds, and viral infection.^9,11 More specifically, the dermatologic literature provides evidence of human papillomavirus (HPV) type 16 involvement in the pathogenesis of digital and periungual SCC. A genital-digital mechanism of spread has been implicated.^11,12 An increased recurrence rate of HPV-associated digital SCCs has been reported following MMS, likely secondary to residual postsurgical HPV infection.^11,12

Maintaining function and cosmesis of the hands, feet, and digits following MMS can be challenging, sometimes requiring skin grafts and flaps to close the defect. In the 28 MMS procedures evaluated in our study, 19 (67.9%) surgical defects were repaired with a graft (ie, split-thickness skin graft, full-thickness skin graft, xenograft), 4 (14.3%) with a flap (advancement and rotation), 4 (14.3%) by secondary intention, and 1 (3.6%) with primary complex closure.

Surgical grafts can be categorized based on the origin of the graft.^2,13 Autografts, derived from the patient’s skin, are the most frequently used dermatologic graft and can be further categorized as full-thickness skin grafts, which include the epidermis and the entire dermis, thus preserving adnexal structures, and split-thickness skin grafts, which include the epidermis and partial dermis.^2,13Xenografts (eg, porcine grafts) can be used to repair defects involving the mucosa and those with a large wound depth, exposed cartilage, and/or bony defects, as well as wounds with indeterminate tumor margins and in patients with medical comorbidities that might prevent or delay plans for immediate wound reconstruction (eg, diabetes, cardiovascular disease, autoimmune connective tissue disease).^13,14

A cross-sectional survey of fellowship-trained Mohs surgeons revealed that more than two-thirds of repairs for cutaneous acral cancers were performed using a primary closure technique, and one-fourth of closures were performed using secondary intention.¹⁵ Of the less frequently utilized skin-graft repairs, more were for acral lesions on the legs than on the arms.¹⁴ The type of procedure and graft used is dependent on multiple variables, including the anatomic location of the lesion and final size of the defect following MMS.² Similarly, the use of specific types of sutures depends on the anatomic location of the lesion, relative thickness of the skin, degree of tension, and desired cosmetic result.¹⁵ The expertise of a hand surgeon may be required, particularly in cases in which the extensor tendon of the distal interphalangeal joint is compromised, manifested by a droopy fingertip when the hand is held horizontally. Additionally, special attention should be paid to removing the entire nail matrix before skin grafting for subungual tumors to avoid nail growth under the skin graft.

Evaluation of debulked tissue from digital skin cancers proved to be important in our study. In Patient 21, debulked tissue revealed melanoma following removal of a severely dysplastic nevus. This finding emphasizes the importance of complete excision of such lesions, as remaining underlying portions of the lesion can reveal residual tumor of the same or different histopathology.

In a prospective study, MMS was shown to have a low rate (0.91%; 95% confidence interval, 0.38%-1.45%) of surgical site infection in the absence of prophylactic antibiotics.¹⁶ The highest rates of surgical site infection were closely associated with flap closure. In our study, most patients had an uncomplicated and successful postoperative recovery. Only 1 (3.57%) of the 28 MMS procedures (Patient 22) was complicated by a bacterial wound infection postoperatively. The lesion removed in this case was a severely dysplastic melanocytic nevus on the toe. Infection resolved after a course of oral antibiotics, but the underlying cause of the wound infection in the patient was unclear. Other postoperative complications in our study included delayed wound healing and excess granulation tissue requiring wound debridement.

There are limited data in the dermatologic literature regarding outcomes following MMS for the treatment of cutaneous malignancies localized to the digits. In our study, patients treated with MMS were evaluated for recurrence of the primary lesion during postoperative follow-up appointments at the office or with the patient’s referring dermatologist. Follow-up data evaluating tumor recurrence were obtained for 25 of the patients, demonstrating no recurrence (mean follow-up, 35.4 months). Longer follow-up data would be more informative, but our findings nonetheless demonstrate that MMS is an effective treatment option for cutaneous malignancies of the digits.

Additional limitations of this case review include its single-center and retrospective design, the small sample size, and 1 Mohs surgeon having performed all surgeries.

Conclusion

This study provides further evidence of the benefit of MMS for the treatment of malignant melanoma and NMSCs of the digits. This procedure provides margin-controlled excision of these malignant neoplasms while preserving maximal normal tissue, thereby providing patients with improved postoperative function and cosmesis. Long-term follow-up data demonstrating a lack of tumor recurrence underscores the assertion that MMS is safe and effective for the treatment of skin cancer of the digits.

In critically ill patients, treating blood glucose with a low target of 80-110 mg/dL was associated with a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.

With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST^®.

monkeybusinessimages/Thinkstock

Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.

Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).

These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.

Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.

“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.

Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.

SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.

In critically ill patients, treating blood glucose with a low target of 80-110 mg/dL was associated with a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.

With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST^®.

monkeybusinessimages/Thinkstock

Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.

Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).

These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.

Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.

“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.

Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.

SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.

In critically ill patients, treating blood glucose with a low target of 80-110 mg/dL was associated with a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.

With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST^®.

monkeybusinessimages/Thinkstock

Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.

Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).

These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.

Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.

“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.

Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.

SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.

DALLAS – An investigational device that couples laser spectroscopy with a machine-learning algorithm demonstrated a high sensitivity and specificity for discriminating skin cancers from benign lesions in real time, results from a single-center study showed.

“More than 5.4 million cases of nonmelanoma skin cancer were treated in 2012, but the accuracy of skin cancer screening prior to biopsy is pretty low, about 70%, and is individual dependent,” lead study author Sung Hyun Pyun, PhD, said at the annual conference of the American Society for Laser Medicine and Surgery. “There have been several in vivo skin cancer screening devices based on noninvasive techniques such as multispectral imaging, Raman spectroscopy, and electrical impedance spectroscopy, but their diagnostic accuracies were not sufficient for clinical use and could not be applied in real time.”

dbrunk@mdedge.com

DALLAS – An investigational device that couples laser spectroscopy with a machine-learning algorithm demonstrated a high sensitivity and specificity for discriminating skin cancers from benign lesions in real time, results from a single-center study showed.

“More than 5.4 million cases of nonmelanoma skin cancer were treated in 2012, but the accuracy of skin cancer screening prior to biopsy is pretty low, about 70%, and is individual dependent,” lead study author Sung Hyun Pyun, PhD, said at the annual conference of the American Society for Laser Medicine and Surgery. “There have been several in vivo skin cancer screening devices based on noninvasive techniques such as multispectral imaging, Raman spectroscopy, and electrical impedance spectroscopy, but their diagnostic accuracies were not sufficient for clinical use and could not be applied in real time.”

dbrunk@mdedge.com

DALLAS – An investigational device that couples laser spectroscopy with a machine-learning algorithm demonstrated a high sensitivity and specificity for discriminating skin cancers from benign lesions in real time, results from a single-center study showed.

“More than 5.4 million cases of nonmelanoma skin cancer were treated in 2012, but the accuracy of skin cancer screening prior to biopsy is pretty low, about 70%, and is individual dependent,” lead study author Sung Hyun Pyun, PhD, said at the annual conference of the American Society for Laser Medicine and Surgery. “There have been several in vivo skin cancer screening devices based on noninvasive techniques such as multispectral imaging, Raman spectroscopy, and electrical impedance spectroscopy, but their diagnostic accuracies were not sufficient for clinical use and could not be applied in real time.”

dbrunk@mdedge.com

A group of oncologists is urging the Food and Drug Administration to review a new, flat-pricing strategy for all doses of ibrutinib (Imbruvica), calling the shift potentially dangerous for patients.

Pharmacyclics, an AbbVie company based in Sunnyvale, Calif., recently introduced a new, single-tablet formulation of ibrutinib in varying strengths (140 mg, 280 mg, 420 mg, and 560 mg) and set a flat price across all doses. At the same time, they removed the drug’s original 140-mg capsules – which cost about a third of the new, flat-rate price – from the market. The drug company says the new, single-tablet formulations give patients a convenient, once-a-day dosing regimen that could improve therapy adherence.

Ibrutinib is approved to treat a number of hematologic cancers, including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

But in an April letter published in the Cancer Letter, nine physicians from cancer centers across the country expressed concern that the new dosage and pricing scheme could compromise patient safety and limit doctors’ dosage decisions.

“While the prescribing information is complex, prescribers and patients have had the flexibility of taking anywhere from one to four 140-mg capsules, readily permitting dose reduction to all but the lowest labeled dose [70 mg],” the authors wrote. “However, the new formulation and its associated marketing scheme [YOU&i] greatly impact the ability of the prescriber and patient to follow the prescribing information, resulting in the potential for a greatly enhanced risk of toxicities relative to that observed in the clinical trials which utilized multiples of the 140-mg capsules.”

The problems stem from a cancer drug that often requires dosage adjustments, the authors noted. The specific dosage for an ibrutinib patient depends on the indication, prior toxicities, concomitant medications, occurrence of ibrutinib intolerance, and current hepatic function. Because of such diverse criteria, dosage modifications are made frequently.

The new pricing system makes it harder for physicians to adjust the dose without running afoul of insurers and potentially affecting access for patients.

A group of oncologists is urging the Food and Drug Administration to review a new, flat-pricing strategy for all doses of ibrutinib (Imbruvica), calling the shift potentially dangerous for patients.

Pharmacyclics, an AbbVie company based in Sunnyvale, Calif., recently introduced a new, single-tablet formulation of ibrutinib in varying strengths (140 mg, 280 mg, 420 mg, and 560 mg) and set a flat price across all doses. At the same time, they removed the drug’s original 140-mg capsules – which cost about a third of the new, flat-rate price – from the market. The drug company says the new, single-tablet formulations give patients a convenient, once-a-day dosing regimen that could improve therapy adherence.

Ibrutinib is approved to treat a number of hematologic cancers, including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

But in an April letter published in the Cancer Letter, nine physicians from cancer centers across the country expressed concern that the new dosage and pricing scheme could compromise patient safety and limit doctors’ dosage decisions.

“While the prescribing information is complex, prescribers and patients have had the flexibility of taking anywhere from one to four 140-mg capsules, readily permitting dose reduction to all but the lowest labeled dose [70 mg],” the authors wrote. “However, the new formulation and its associated marketing scheme [YOU&i] greatly impact the ability of the prescriber and patient to follow the prescribing information, resulting in the potential for a greatly enhanced risk of toxicities relative to that observed in the clinical trials which utilized multiples of the 140-mg capsules.”

The problems stem from a cancer drug that often requires dosage adjustments, the authors noted. The specific dosage for an ibrutinib patient depends on the indication, prior toxicities, concomitant medications, occurrence of ibrutinib intolerance, and current hepatic function. Because of such diverse criteria, dosage modifications are made frequently.

The new pricing system makes it harder for physicians to adjust the dose without running afoul of insurers and potentially affecting access for patients.

A group of oncologists is urging the Food and Drug Administration to review a new, flat-pricing strategy for all doses of ibrutinib (Imbruvica), calling the shift potentially dangerous for patients.

Pharmacyclics, an AbbVie company based in Sunnyvale, Calif., recently introduced a new, single-tablet formulation of ibrutinib in varying strengths (140 mg, 280 mg, 420 mg, and 560 mg) and set a flat price across all doses. At the same time, they removed the drug’s original 140-mg capsules – which cost about a third of the new, flat-rate price – from the market. The drug company says the new, single-tablet formulations give patients a convenient, once-a-day dosing regimen that could improve therapy adherence.

Ibrutinib is approved to treat a number of hematologic cancers, including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma.

But in an April letter published in the Cancer Letter, nine physicians from cancer centers across the country expressed concern that the new dosage and pricing scheme could compromise patient safety and limit doctors’ dosage decisions.

“While the prescribing information is complex, prescribers and patients have had the flexibility of taking anywhere from one to four 140-mg capsules, readily permitting dose reduction to all but the lowest labeled dose [70 mg],” the authors wrote. “However, the new formulation and its associated marketing scheme [YOU&i] greatly impact the ability of the prescriber and patient to follow the prescribing information, resulting in the potential for a greatly enhanced risk of toxicities relative to that observed in the clinical trials which utilized multiples of the 140-mg capsules.”

The problems stem from a cancer drug that often requires dosage adjustments, the authors noted. The specific dosage for an ibrutinib patient depends on the indication, prior toxicities, concomitant medications, occurrence of ibrutinib intolerance, and current hepatic function. Because of such diverse criteria, dosage modifications are made frequently.

The new pricing system makes it harder for physicians to adjust the dose without running afoul of insurers and potentially affecting access for patients.

WASHINGTON – A U.S. grant program that was started in 2004 to fund youth suicide prevention efforts throughout the country was linked with nearly 900 youth suicide deaths prevented by 2015, according to a matched, case-control analysis.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

mzoler@mdedge.com .

WASHINGTON – A U.S. grant program that was started in 2004 to fund youth suicide prevention efforts throughout the country was linked with nearly 900 youth suicide deaths prevented by 2015, according to a matched, case-control analysis.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

mzoler@mdedge.com .

WASHINGTON – A U.S. grant program that was started in 2004 to fund youth suicide prevention efforts throughout the country was linked with nearly 900 youth suicide deaths prevented by 2015, according to a matched, case-control analysis.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

mzoler@mdedge.com .

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

aotto@mdedge.com

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

aotto@mdedge.com

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

aotto@mdedge.com

Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.

The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.

—Jake Remaly

Suggested Reading

Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.

Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.

The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.

—Jake Remaly

Suggested Reading

Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.

Deep gray matter volume loss drives disability accumulation in multiple sclerosis (MS), according to a multicenter, longitudinal study published in the February issue of Annals of Neurology.

The results “suggest that the development of deep gray matter atrophy may drive disability accumulation irrespective of clinical phenotypes, thereby becoming a useful outcome measure in neuroprotective clinical trials,” said Arman Eshaghi, MD, of the Queen Square MS Centre at the University College London Institute of Neurology, and colleagues.

—Jake Remaly

Suggested Reading

Eshaghi A, Prados F, Brownlee WJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210-222.

LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.

While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.

Sara Freeman/MDedge News

“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.

Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.

Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.

A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.

“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.

The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.

Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.

Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.

The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).

GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.

“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”

From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.

SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.

LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.

While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.

Sara Freeman/MDedge News

“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.

Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.

Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.

A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.

“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.

The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.

Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.

Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.

The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).

GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.

“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”

From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.

SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.

LIVERPOOL, ENGLAND – Cardiovascular disease was the predominant cause of death of patients with granulomatosis with polyangiitis 1-5 years after a diagnosis in a study by U.K. researchers, suggesting that this could be a target for future intervention.

While active disease was the No. 1 cause of death within the first year of diagnosis in 40% of patients with granulomatosis with polyangiitis (GPA), it was overtaken by cardiovascular disease (CVD) as the main cause of death in 37.5% of patients in the next 4 years from diagnosis.

Sara Freeman/MDedge News

“Of course, the important clinical question was, “Can we then improve things?’ ” Dr. Pearce said.

Two U.K. databases – Clinical Practice Research Datalink and Hospital Episode Statistics – were used to identify patients with GPA diagnosed between 1998 and 2014 and match each case to 10 controls based on age, gender, and family practice. Data on the cause and date of any deaths were then obtained from the Office of National Statistics.

Overall, 465 cases of GPA were matched to 4,610 controls. The median age of participants was 61 years and 57% were male. There were 50 cases with more than 10 years of follow-up data available and data on 139 deaths could be analyzed.

A survival analysis showed that there was a significant reduction in cases versus controls, “but it’s not a constant,” Dr. Pearce noted.

“In the time immediately after diagnosis, the risk of death in people with GPA is very high, and over the first 6 months it tails off.” Then the mortalities are very similar, albeit much lower, to those of controls, but with another dip around 8 years.

The number at risk of death in the second year was 310 for GPA vs. 3,543 for controls and 230 vs. 2,622 at 4 years, 138 vs. 1,704 at 6 years, 93 vs. 1,136 at 8 years, and 49 vs. 658 at 10 years.

Looking at the data another way, the hazard ratios for death comparing GPA cases to controls was 24.5 in the first month, 14.6 in months 1-2, 7.5 by 2-3 months, 4.3 at 3-6 months, 1.6 at 6 months to 8 years, and 3.2 at 8-10 years.

Mortality seems to have improved with time. Splitting the cohort into two time periods based on their diagnosis, those diagnosed between 2008 and 2014 had a lower risk of death than did those diagnosed between 1998 and 2007, although it was still more than four times higher than the background population.

The leading cause of death in patients with GPA 5-10 years after diagnosis was cancer (30.3% of cases), but when this was compared against the general population, the risk was no greater (hazard ratio, 1.0).

GPA cases were also 2.9 times more likely than controls to die as a result of an infection, suggesting that this together with CVD could be a target for mortality reduction strategies.

“We can’t get away from the fact that although this is a large study, there are still small numbers of patients because this is rare disease,” Dr. Pearce observed. “We also don’t have detailed clinical information on each patient, so we can’t look for associations or clinical phenotypes at diagnosis, and there are no biomarkers.”

From a clinical perspective, she noted, it is important to remember that deaths in the first year are mainly from active disease and to continue to try to diagnose and treat the condition as early as possible.

SOURCE: Pearce F et al. Rheumatology. 2018;57(Suppl. 3):key075.204.

Dr. Lenchus serves as the Society of Hospital Medicine’s Public Policy Committee chair. He is noted for his work as a clinician, hospital administrator, educator, and researcher.
 

J. Kevin Shushtari, MD, FHM, recently was named chief medical officer at the New Britain (Conn.) Hospital for Special Care, where he will focus on managing the medical staff, admissions, credentials, infection prevention, and clinical affiliations.

Tianzhong Yang, MD, has been selected as the new long-term care medical director for Van Dyk Healthcare in Montclair, N.J. Dr. Yang began his career 3 decades ago in China and has been a hospitalist at Hackensack University Medical Center Mountainside, also in Montclair, since 2013.

Dr. Yang has been an instructor at Brigham and Women’s Hospital in Boston, specializing in anesthesiology. At Van Dyk, he will work with the nursing staff to help patients recover their independence outside of the hospital setting.

Brent W. Burkey, MD, SFHM, a longtime hospitalist at the Cleveland Clinic, has been named the president of Fisher-Titus Medical Center in Norwalk, Ohio. Dr. Burkey has been the chief medical officer at the Cleveland Clinic’s Avon, Ohio, location the past 2 years. He helped the clinic open the Avon hospital in 2016 when he served as vice president of medical affairs.

Dr. Burkey has been a clinical hospitalist since 2004, and he has a master’s degree in business administration from Cleveland State University. He will run all hospital and medical center operations at Fisher-Titus, including quality and safety.
 

Dr. Maiona has extensive experience as a practicing hospital physician and as an executive. Most recently, he served as national medical director for TeamHealth of Knoxville, Tenn. He also has been an instructor at Tufts University and Harvard Medical School, both in Boston.

Tom Cummins, MD, has been appointed chief medical officer at Bon Secours St. Francis Health System in Greenville, S.C. Dr. Cummins comes to Bon Secours from Catholic Health Initiatives St. Vincent, Arkansas, where he was senior vice president and CMO; he also first served as a hospitalist within that system.

At Bon Secours, Dr. Cummins will oversee the regional health system’s 11 facilities, including St. Francis Downtown in Judson, S.C., and St. Francis Eastside in Greenville.
 

BUSINESS MOVES

The South Korean government recently announced that it has given permission for all general hospitals that use integrated nursing care to take part in a hospitalist system.

The Korean hospitalist program is a pilot in which those physicians provide all medical care for inpatients. It was adopted in September 2016, and 15 hospitals take part in the program. Prior to the recent ruling, those facilities with integrated nursing services were not eligible for the hospitalist program.

Surgical Affiliates (Sacramento, Calif.), a provider of surgical hospitalist services, has announced a partnership with Regional Medical Center in San Jose, Calif. The surgical hospitalists will assist and support local providers, providing 24/7 access to RMC of San Jose, a Level II trauma center.

Dr. Lenchus serves as the Society of Hospital Medicine’s Public Policy Committee chair. He is noted for his work as a clinician, hospital administrator, educator, and researcher.
 

J. Kevin Shushtari, MD, FHM, recently was named chief medical officer at the New Britain (Conn.) Hospital for Special Care, where he will focus on managing the medical staff, admissions, credentials, infection prevention, and clinical affiliations.

Tianzhong Yang, MD, has been selected as the new long-term care medical director for Van Dyk Healthcare in Montclair, N.J. Dr. Yang began his career 3 decades ago in China and has been a hospitalist at Hackensack University Medical Center Mountainside, also in Montclair, since 2013.

Dr. Yang has been an instructor at Brigham and Women’s Hospital in Boston, specializing in anesthesiology. At Van Dyk, he will work with the nursing staff to help patients recover their independence outside of the hospital setting.

Brent W. Burkey, MD, SFHM, a longtime hospitalist at the Cleveland Clinic, has been named the president of Fisher-Titus Medical Center in Norwalk, Ohio. Dr. Burkey has been the chief medical officer at the Cleveland Clinic’s Avon, Ohio, location the past 2 years. He helped the clinic open the Avon hospital in 2016 when he served as vice president of medical affairs.

Dr. Burkey has been a clinical hospitalist since 2004, and he has a master’s degree in business administration from Cleveland State University. He will run all hospital and medical center operations at Fisher-Titus, including quality and safety.
 

Dr. Maiona has extensive experience as a practicing hospital physician and as an executive. Most recently, he served as national medical director for TeamHealth of Knoxville, Tenn. He also has been an instructor at Tufts University and Harvard Medical School, both in Boston.

Tom Cummins, MD, has been appointed chief medical officer at Bon Secours St. Francis Health System in Greenville, S.C. Dr. Cummins comes to Bon Secours from Catholic Health Initiatives St. Vincent, Arkansas, where he was senior vice president and CMO; he also first served as a hospitalist within that system.

At Bon Secours, Dr. Cummins will oversee the regional health system’s 11 facilities, including St. Francis Downtown in Judson, S.C., and St. Francis Eastside in Greenville.
 

BUSINESS MOVES

The South Korean government recently announced that it has given permission for all general hospitals that use integrated nursing care to take part in a hospitalist system.

The Korean hospitalist program is a pilot in which those physicians provide all medical care for inpatients. It was adopted in September 2016, and 15 hospitals take part in the program. Prior to the recent ruling, those facilities with integrated nursing services were not eligible for the hospitalist program.

Surgical Affiliates (Sacramento, Calif.), a provider of surgical hospitalist services, has announced a partnership with Regional Medical Center in San Jose, Calif. The surgical hospitalists will assist and support local providers, providing 24/7 access to RMC of San Jose, a Level II trauma center.

Dr. Lenchus serves as the Society of Hospital Medicine’s Public Policy Committee chair. He is noted for his work as a clinician, hospital administrator, educator, and researcher.
 

J. Kevin Shushtari, MD, FHM, recently was named chief medical officer at the New Britain (Conn.) Hospital for Special Care, where he will focus on managing the medical staff, admissions, credentials, infection prevention, and clinical affiliations.

Tianzhong Yang, MD, has been selected as the new long-term care medical director for Van Dyk Healthcare in Montclair, N.J. Dr. Yang began his career 3 decades ago in China and has been a hospitalist at Hackensack University Medical Center Mountainside, also in Montclair, since 2013.

Dr. Yang has been an instructor at Brigham and Women’s Hospital in Boston, specializing in anesthesiology. At Van Dyk, he will work with the nursing staff to help patients recover their independence outside of the hospital setting.

Brent W. Burkey, MD, SFHM, a longtime hospitalist at the Cleveland Clinic, has been named the president of Fisher-Titus Medical Center in Norwalk, Ohio. Dr. Burkey has been the chief medical officer at the Cleveland Clinic’s Avon, Ohio, location the past 2 years. He helped the clinic open the Avon hospital in 2016 when he served as vice president of medical affairs.

Dr. Burkey has been a clinical hospitalist since 2004, and he has a master’s degree in business administration from Cleveland State University. He will run all hospital and medical center operations at Fisher-Titus, including quality and safety.
 

Dr. Maiona has extensive experience as a practicing hospital physician and as an executive. Most recently, he served as national medical director for TeamHealth of Knoxville, Tenn. He also has been an instructor at Tufts University and Harvard Medical School, both in Boston.

Tom Cummins, MD, has been appointed chief medical officer at Bon Secours St. Francis Health System in Greenville, S.C. Dr. Cummins comes to Bon Secours from Catholic Health Initiatives St. Vincent, Arkansas, where he was senior vice president and CMO; he also first served as a hospitalist within that system.

At Bon Secours, Dr. Cummins will oversee the regional health system’s 11 facilities, including St. Francis Downtown in Judson, S.C., and St. Francis Eastside in Greenville.
 

BUSINESS MOVES

The South Korean government recently announced that it has given permission for all general hospitals that use integrated nursing care to take part in a hospitalist system.

The Korean hospitalist program is a pilot in which those physicians provide all medical care for inpatients. It was adopted in September 2016, and 15 hospitals take part in the program. Prior to the recent ruling, those facilities with integrated nursing services were not eligible for the hospitalist program.

Surgical Affiliates (Sacramento, Calif.), a provider of surgical hospitalist services, has announced a partnership with Regional Medical Center in San Jose, Calif. The surgical hospitalists will assist and support local providers, providing 24/7 access to RMC of San Jose, a Level II trauma center.