J AM ACAD DERMATOL
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finding may justify the skin atrophy and the vein depression, as seen in the biopsies of our patients. Interestingly, the depression palpated on the veins of our patients started approximately at the point of the initial hairline location, supporting our hypothesis. Long-term application of topical steroids can probably worsen this condition and could also explain its presence in some patients. However, skin atrophy and depression of the frontal veins may appear spontaneously in patients with FFA simply due to the scarring potential of the disease. In conclusion, we describe a series of FFA patients presenting with depression of the frontal veins. This finding may be considered a new clinical sign indicative of FFA. Sergio Va~ n o-Galv an, MD, PhD,a,b Ana Rita Rodrigues-Barata, MD,b Marta Urech, MD,a Natalia Jimenez-G omez, MD,a David Sacedaa Corralo, MD, John Paoli, MD, PhD,d Jes us Cuevas, MD, PhD,c and Pedro Jaen, MD, PhDa,b Ram on y Cajal Hospital, Dermatology Servicea and Trichology Unit,b Grupo Pedro Jae n Clinic,c Madrid, Spain; Department of Dermatology, Sahlgrenska University Hospital, Institute of Clinical Sciences at the Sahlgrenska Academy,d University of Gothenburg, Sweden Funding sources: None. Conflicts of interest: None declared. Correspondence to: Sergio Va~ n o-Galv an, MD, PhD, Dermatology Department, Ram on y Cajal Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain E-mail: [email protected] REFERENCES 1. Kossard S. Postmenopausal frontal fibrosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol. 1994;130: 770-774. 2. Vano-Galvan S, Molina-Ruiz AM, Serrano-Falcon C, et al. Frontal fibrosing alopecia: a multicenter review of 355 patients. J Am Acad Dermatol. 2014;70:670-678. 3. Donati A, Molina L, Doche I, Valente NS, Romiti R. Facial papules in frontal fibrosing alopecia: evidence of vellus follicle involvement. Arch Dermatol. 2011;147:1424-1427. 4. Pirmez R, Donati A, Valente NS, Sodre CT, Tosti A. Glabellar red dots in frontal fibrosing alopecia: a further clinical sign of vellus follicle involvement. Br J Dermatol. 2014;170:745-746. 5. Bernardez C, Molina-Ruiz AM, Requena L. Histologic features of alopecias: Part II: Scarring alopecias. Actas Dermosifiliogr. 2014. http://dx.doi.org/10.1016/j.ad.2014.06.016 [Epub ahead of print]. http://dx.doi.org/10.1016/j.jaad.2015.02.1129
The efficacy of methotrexate for lymphomatoid papulosis To the Editor: Lymphomatoid papulosis (LyP) is a CD301 lymphoproliferative disorder, a group that includes primary cutaneous anaplastic large cell lymphoma and ‘‘borderline cases.’’1 Low-dose methotrexate (5 to 25 mg weekly) is the most commonly reported single agent chemotherapy used to treat LyP,2 with retrospective studies finding that it effectively suppresses the development of new lesions.2-5 European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphomas (ISCL), and the United States Cutaneous Lymphoma Consortium (USCLC) guidelines describe a rapid relapse rate of 63% following methotrexate cessation, indicating that long-term maintenance therapy is often required.2-5 No data are available regarding factors that may predispose patients to methotrexate dependence. Our study evaluated the safety and efficacy of methotrexate in our patient cohort. We also sought to identify factors that may predict which patients are more likely to require long-term maintenance therapy. Retrospective analysis of the cutaneous lymphoma database at Peter MacCallum Cancer Centre and St Vincent’s Hospital, Melbourne, Australia, representing a 39-year period, was undertaken. Data collection and analysis was approved in accordance with the Human Research Ethics Committee at our institution. Fifty-three patients fulfilled the WHO-EORTC classification of LyP based on clinical and histopathologic criteria.1 Patients were treated per physician’s choice. Patient demographic and disease characteristics are outlined in Table I. Those deemed to require methotrexate were dosed as per our policy of 20 to 30 mg/wk orally for a minimum of 6 months (if responding), followed by a 2- to 6-month weaning period. We defined methotrexate dependence as (1) an inability to wean methotrexate below 5 mg weekly without progressive disease (PD) or relapse and/or (2) relapse or PD less than or equal to 6 months after drug cessation. The term methotrexate successfully weaned was defined as (1) cessation of methotrexate therapy with a partial or complete response (PR or CR) to treatment and (2) maintenance of this response for greater than or equal to 6 months. A group labeled observation cohort received no treatment for LyP apart from intermittent topical corticosteroid application. Not surprisingly, given that therapeutic intervention was based on physician judgment, our observation cohort had milder disease (Table I).
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VOLUME 72, NUMBER 6
Table I. Patient and disease characteristics of study population
All, no. (%)
All Gender Female Male Age at diagnosis (median 1 range) Female Male LyP Subtype A B C D T stage at diagnosis T1 T2 T3 Associated lymphoma MF PC-ALCL Hematologic/solid organ malignancy
Observation cohort No (% of cohort)
Methotrexate dependent No (% of cohort)
53 (100)
20 (38)
16 (30)
24 29 39 34 39
(45) (55) (3-77) (8-77) (3-77)
10 10 40 43 27
(50) (50) (3-77) (27-77) (3-63)
9 7 50 54 52
(56) (44) (8-77) (8-76) (19-77)
40 4 8 1
(75) (8) (15) (2)
14 1 4 1
(70) (5) (20) (5)
13 1 2 0
(81) (6) (13) (0)
Methotrexate successfully weaned No (% of cohort)
P value
6 (11) 1.0 3 3 30.5 30 47
(50) (50) (21-66) (21-31) (26-66)
.4375
.8054 5 0 1 0
(83) (0) (17) (0) .1602
14 (26) 7 (13) 32 (60)
12 (60) 1 (5) 7 (35)
1 (6) 1 (6) 14 (88)
1 (17) 2 (33) 3 (50)
10 (19) 10 (19) 4 (8)
3 (15) 2 (10) 0 (0)
4 (25) 3 (19) 2 (13)
0 (0) 2 (33) 2 (33)
N/A
N/A
Data analysis of methotrexate dependent and methotrexate successfully weaned groups. Analysis was performed in GraphPad Prism 6.0 (GraphPad Software, San Diego, CA). Categorical variables were analyzed using Fisher’s exact test or chi-square test. Continuous variable were compared using the nonparametric Mann-Whitney test. A P-value of less than .05 was considered significant. LyP, Lymphomatoid papulosis; T, tumor; MF, mycosis fungoides; PC-ALCL, primary cutaneous anaplastic large cell lymphoma. LyP subtypes (EORTC-WHO definition): Type A lesions, scattered or small clusters of large, sometimes multinucleated or Reed-Sternberg-like, CD301 cells, intermingled with numerous inflammatory cells. Type B lesions, epidermotropic infiltrate of small atypical cells with cerebriform nuclei. Type C lesions, monotonous population or large clusters of large CD301 T cells with relatively few admixed inflammatory cells. Type D lesions, epidermotropism of CD81 cytotoxic T lymphocytes demonstrating CD30 positivity. T stages (ISCL/EORTC TNM Classification of Cutaneous Lymphomas other than MF/SS): T1, solitary skin involvement. T2, regional skin involvement (multiple lesions limited to one body region or two contiguous body regions). T3, generalized skin involvement.
Methotrexate was the most common treatment for LyP, with 47% (n ¼ 25) of patients receiving the drug at some point. We measured best response to treatment with methotrexate; 44% (n ¼ 11) patients had CR, 44% (n ¼ 11) had PR, and 12% (n ¼ 3) had PD. Of patients treated with methotrexate, 64% (n ¼ 16) remained methotrexate-dependent, 24% (n ¼ 6) were successfully weaned off drug, and 12% (n ¼ 3) ceased treatment due to PD (Fig 1). The patient and disease characteristics of the methotrexate-dependent and the methotrexate successfully weaned groups were compared to determine any factors predicting which patients were more likely to be successfully weaned off drug (Table I). None were identified, although a numerical trend suggested that younger patients may
be easier to wean off methotrexate (median age 30.5 vs 50 years). Methotrexate was extremely well tolerated by our cohort. The only reported significant adverse drug reactions were single episodes of chronic thrombocytopenia and severe nausea. Our study demonstrates that once systemic therapy is deemed necessary, methotrexate is effective with limited toxicity, but two-thirds of patients remain methotrexate-dependent and it is not possible to predict which patients will successfully wean off drug. Kate M. Newland, FACD,a,b Christopher J. McCormack, FACD,b,c Robert Twigger,a Odette Buelens, MANP,a Charlotte F. M. Hughes, MBBS,a,c Stephen Lade, FRCPA,d Michael
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Fig 1. Methotrexate for lymphomatoid papulosis. Pie chart depicting the number of patients in each treatment group. Total number of patients, N ¼ 53: methotrexate dependent, n ¼ 16; methotrexate successfully weaned, n ¼ 6; progressive disease (PD) on methotrexate, n ¼ 3; observation cohort, n ¼ 20; other treatment, that is, patients not treated with methotrexate but given ultraviolet B/psoralen plus ultraviolet A phototherapy or more than 3 months of oral antibiotics (doxycycline, tetracycline, erythromycin), n ¼ 8.
Dickinson, FRACP, FRCPA,a Lee Mei Yap, FACD,b Gail Ryan, FRANZCR,e and H. Miles Prince, MDa,c Division of Haematology and Cancer Medicine,a Department of Pathology,d and Division of Radiation Oncology,e Peter MacCallum Cancer Centre, Melbourne; Department of Dermatology, St Vincent’s Hospital Department of Medicine,b Melbourne; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville,c Australia Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kate M. Newland, FACD, Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, Victoria, Australia 8006 E-mail: [email protected] REFERENCES 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785. 2. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011;118:4024-4035. 3. Bekkenk MW, Geelan FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD301 lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. 2000;95: 3653-3661. 4. Kadin ME. Current management of primary cutaneous CD301 lymphoproliferative disorders. Oncology (Williston Park). 2009; 23:1158-1164.
5. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. 1996;34:470-481. http://dx.doi.org/10.1016/j.jaad.2015.03.001
Association between psoriasis and neovascular age-related macular degeneration: A population-based study To the Editor: Prior studies found that ocular complications are common in patients with psoriasis.1 Neovascular age-related macular degeneration (AMD) is a degenerative disease of the retina and its incidence might be affected by inflammation and oxidative stress, among other causes.2 Even though both psoriasis and AMD may share similar pathophysiologic inflammatory characteristics, few studies have investigated the association between these 2 disorders. This case control study was aimed at investigating the association between AMD and prior psoriasis. The data for this study were retrieved from the Taiwan Longitudinal Health Insurance Database 2000 (LHID2000). The LHID2000 contains longitudinal data on medical claims for 1 million enrollees under the Taiwan National Health Insurance program. We identified 2666 patients who received a firsttime diagnosis of AMD (ICD-9-CM codes 362.42, 362.43, 362.52, or 362.53) from ophthalmologists during an ambulatory care visit between 2002 and 2011. The date of the first diagnosis of AMD was set as the index date. We excluded patients younger than 50 years old (n ¼ 479). The remaining 2187 patients with AMD were selected as cases.
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JUNE 2015
finding may justify the skin atrophy and the vein depression, as seen in the biopsies of our patients. Interestingly, the depression palpated on the veins of our patients started approximately at the point of the initial hairline location, supporting our hypothesis. Long-term application of topical steroids can probably worsen this condition and could also explain its presence in some patients. However, skin atrophy and depression of the frontal veins may appear spontaneously in patients with FFA simply due to the scarring potential of the disease. In conclusion, we describe a series of FFA patients presenting with depression of the frontal veins. This finding may be considered a new clinical sign indicative of FFA. Sergio Va~ n o-Galv an, MD, PhD,a,b Ana Rita Rodrigues-Barata, MD,b Marta Urech, MD,a Natalia Jimenez-G omez, MD,a David Sacedaa Corralo, MD, John Paoli, MD, PhD,d Jes us Cuevas, MD, PhD,c and Pedro Jaen, MD, PhDa,b Ram on y Cajal Hospital, Dermatology Servicea and Trichology Unit,b Grupo Pedro Jae n Clinic,c Madrid, Spain; Department of Dermatology, Sahlgrenska University Hospital, Institute of Clinical Sciences at the Sahlgrenska Academy,d University of Gothenburg, Sweden Funding sources: None. Conflicts of interest: None declared. Correspondence to: Sergio Va~ n o-Galv an, MD, PhD, Dermatology Department, Ram on y Cajal Hospital, Carretera Colmenar Viejo km 9.100, 28034 Madrid, Spain E-mail: [email protected] REFERENCES 1. Kossard S. Postmenopausal frontal fibrosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol. 1994;130: 770-774. 2. Vano-Galvan S, Molina-Ruiz AM, Serrano-Falcon C, et al. Frontal fibrosing alopecia: a multicenter review of 355 patients. J Am Acad Dermatol. 2014;70:670-678. 3. Donati A, Molina L, Doche I, Valente NS, Romiti R. Facial papules in frontal fibrosing alopecia: evidence of vellus follicle involvement. Arch Dermatol. 2011;147:1424-1427. 4. Pirmez R, Donati A, Valente NS, Sodre CT, Tosti A. Glabellar red dots in frontal fibrosing alopecia: a further clinical sign of vellus follicle involvement. Br J Dermatol. 2014;170:745-746. 5. Bernardez C, Molina-Ruiz AM, Requena L. Histologic features of alopecias: Part II: Scarring alopecias. Actas Dermosifiliogr. 2014. http://dx.doi.org/10.1016/j.ad.2014.06.016 [Epub ahead of print]. http://dx.doi.org/10.1016/j.jaad.2015.02.1129
The efficacy of methotrexate for lymphomatoid papulosis To the Editor: Lymphomatoid papulosis (LyP) is a CD301 lymphoproliferative disorder, a group that includes primary cutaneous anaplastic large cell lymphoma and ‘‘borderline cases.’’1 Low-dose methotrexate (5 to 25 mg weekly) is the most commonly reported single agent chemotherapy used to treat LyP,2 with retrospective studies finding that it effectively suppresses the development of new lesions.2-5 European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphomas (ISCL), and the United States Cutaneous Lymphoma Consortium (USCLC) guidelines describe a rapid relapse rate of 63% following methotrexate cessation, indicating that long-term maintenance therapy is often required.2-5 No data are available regarding factors that may predispose patients to methotrexate dependence. Our study evaluated the safety and efficacy of methotrexate in our patient cohort. We also sought to identify factors that may predict which patients are more likely to require long-term maintenance therapy. Retrospective analysis of the cutaneous lymphoma database at Peter MacCallum Cancer Centre and St Vincent’s Hospital, Melbourne, Australia, representing a 39-year period, was undertaken. Data collection and analysis was approved in accordance with the Human Research Ethics Committee at our institution. Fifty-three patients fulfilled the WHO-EORTC classification of LyP based on clinical and histopathologic criteria.1 Patients were treated per physician’s choice. Patient demographic and disease characteristics are outlined in Table I. Those deemed to require methotrexate were dosed as per our policy of 20 to 30 mg/wk orally for a minimum of 6 months (if responding), followed by a 2- to 6-month weaning period. We defined methotrexate dependence as (1) an inability to wean methotrexate below 5 mg weekly without progressive disease (PD) or relapse and/or (2) relapse or PD less than or equal to 6 months after drug cessation. The term methotrexate successfully weaned was defined as (1) cessation of methotrexate therapy with a partial or complete response (PR or CR) to treatment and (2) maintenance of this response for greater than or equal to 6 months. A group labeled observation cohort received no treatment for LyP apart from intermittent topical corticosteroid application. Not surprisingly, given that therapeutic intervention was based on physician judgment, our observation cohort had milder disease (Table I).
J AM ACAD DERMATOL
Letters 1089
VOLUME 72, NUMBER 6
Table I. Patient and disease characteristics of study population
All, no. (%)
All Gender Female Male Age at diagnosis (median 1 range) Female Male LyP Subtype A B C D T stage at diagnosis T1 T2 T3 Associated lymphoma MF PC-ALCL Hematologic/solid organ malignancy
Observation cohort No (% of cohort)
Methotrexate dependent No (% of cohort)
53 (100)
20 (38)
16 (30)
24 29 39 34 39
(45) (55) (3-77) (8-77) (3-77)
10 10 40 43 27
(50) (50) (3-77) (27-77) (3-63)
9 7 50 54 52
(56) (44) (8-77) (8-76) (19-77)
40 4 8 1
(75) (8) (15) (2)
14 1 4 1
(70) (5) (20) (5)
13 1 2 0
(81) (6) (13) (0)
Methotrexate successfully weaned No (% of cohort)
P value
6 (11) 1.0 3 3 30.5 30 47
(50) (50) (21-66) (21-31) (26-66)
.4375
.8054 5 0 1 0
(83) (0) (17) (0) .1602
14 (26) 7 (13) 32 (60)
12 (60) 1 (5) 7 (35)
1 (6) 1 (6) 14 (88)
1 (17) 2 (33) 3 (50)
10 (19) 10 (19) 4 (8)
3 (15) 2 (10) 0 (0)
4 (25) 3 (19) 2 (13)
0 (0) 2 (33) 2 (33)
N/A
N/A
Data analysis of methotrexate dependent and methotrexate successfully weaned groups. Analysis was performed in GraphPad Prism 6.0 (GraphPad Software, San Diego, CA). Categorical variables were analyzed using Fisher’s exact test or chi-square test. Continuous variable were compared using the nonparametric Mann-Whitney test. A P-value of less than .05 was considered significant. LyP, Lymphomatoid papulosis; T, tumor; MF, mycosis fungoides; PC-ALCL, primary cutaneous anaplastic large cell lymphoma. LyP subtypes (EORTC-WHO definition): Type A lesions, scattered or small clusters of large, sometimes multinucleated or Reed-Sternberg-like, CD301 cells, intermingled with numerous inflammatory cells. Type B lesions, epidermotropic infiltrate of small atypical cells with cerebriform nuclei. Type C lesions, monotonous population or large clusters of large CD301 T cells with relatively few admixed inflammatory cells. Type D lesions, epidermotropism of CD81 cytotoxic T lymphocytes demonstrating CD30 positivity. T stages (ISCL/EORTC TNM Classification of Cutaneous Lymphomas other than MF/SS): T1, solitary skin involvement. T2, regional skin involvement (multiple lesions limited to one body region or two contiguous body regions). T3, generalized skin involvement.
Methotrexate was the most common treatment for LyP, with 47% (n ¼ 25) of patients receiving the drug at some point. We measured best response to treatment with methotrexate; 44% (n ¼ 11) patients had CR, 44% (n ¼ 11) had PR, and 12% (n ¼ 3) had PD. Of patients treated with methotrexate, 64% (n ¼ 16) remained methotrexate-dependent, 24% (n ¼ 6) were successfully weaned off drug, and 12% (n ¼ 3) ceased treatment due to PD (Fig 1). The patient and disease characteristics of the methotrexate-dependent and the methotrexate successfully weaned groups were compared to determine any factors predicting which patients were more likely to be successfully weaned off drug (Table I). None were identified, although a numerical trend suggested that younger patients may
be easier to wean off methotrexate (median age 30.5 vs 50 years). Methotrexate was extremely well tolerated by our cohort. The only reported significant adverse drug reactions were single episodes of chronic thrombocytopenia and severe nausea. Our study demonstrates that once systemic therapy is deemed necessary, methotrexate is effective with limited toxicity, but two-thirds of patients remain methotrexate-dependent and it is not possible to predict which patients will successfully wean off drug. Kate M. Newland, FACD,a,b Christopher J. McCormack, FACD,b,c Robert Twigger,a Odette Buelens, MANP,a Charlotte F. M. Hughes, MBBS,a,c Stephen Lade, FRCPA,d Michael
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Fig 1. Methotrexate for lymphomatoid papulosis. Pie chart depicting the number of patients in each treatment group. Total number of patients, N ¼ 53: methotrexate dependent, n ¼ 16; methotrexate successfully weaned, n ¼ 6; progressive disease (PD) on methotrexate, n ¼ 3; observation cohort, n ¼ 20; other treatment, that is, patients not treated with methotrexate but given ultraviolet B/psoralen plus ultraviolet A phototherapy or more than 3 months of oral antibiotics (doxycycline, tetracycline, erythromycin), n ¼ 8.
Dickinson, FRACP, FRCPA,a Lee Mei Yap, FACD,b Gail Ryan, FRANZCR,e and H. Miles Prince, MDa,c Division of Haematology and Cancer Medicine,a Department of Pathology,d and Division of Radiation Oncology,e Peter MacCallum Cancer Centre, Melbourne; Department of Dermatology, St Vincent’s Hospital Department of Medicine,b Melbourne; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville,c Australia Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kate M. Newland, FACD, Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, Victoria, Australia 8006 E-mail: [email protected] REFERENCES 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785. 2. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011;118:4024-4035. 3. Bekkenk MW, Geelan FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD301 lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. 2000;95: 3653-3661. 4. Kadin ME. Current management of primary cutaneous CD301 lymphoproliferative disorders. Oncology (Williston Park). 2009; 23:1158-1164.
5. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. 1996;34:470-481. http://dx.doi.org/10.1016/j.jaad.2015.03.001
Association between psoriasis and neovascular age-related macular degeneration: A population-based study To the Editor: Prior studies found that ocular complications are common in patients with psoriasis.1 Neovascular age-related macular degeneration (AMD) is a degenerative disease of the retina and its incidence might be affected by inflammation and oxidative stress, among other causes.2 Even though both psoriasis and AMD may share similar pathophysiologic inflammatory characteristics, few studies have investigated the association between these 2 disorders. This case control study was aimed at investigating the association between AMD and prior psoriasis. The data for this study were retrieved from the Taiwan Longitudinal Health Insurance Database 2000 (LHID2000). The LHID2000 contains longitudinal data on medical claims for 1 million enrollees under the Taiwan National Health Insurance program. We identified 2666 patients who received a firsttime diagnosis of AMD (ICD-9-CM codes 362.42, 362.43, 362.52, or 362.53) from ophthalmologists during an ambulatory care visit between 2002 and 2011. The date of the first diagnosis of AMD was set as the index date. We excluded patients younger than 50 years old (n ¼ 479). The remaining 2187 patients with AMD were selected as cases.
