1438 Correspondence
early stages of an acral lentiginous melanoma in situ. In all cases of similar lesions, where histopathological findings are unspecific, the diagnosis and the complete excision of the lesion must be guided by clinical features and dermoscopy. 1
Department of Dermatology and 2 Department of Anatomic Pathology, Hospital Doce de Octubre, Madrid, Spain E-mail: [email protected]
D. MENIS1 L . M A R O N~ A S - J I M EN E Z 1 J . R O D R IG U E Z - P E R A L T O 2 R. MARTIN-LLAMAS1 F . V A N A C L O C H A - S E B A S T I A N 1
References 1 Nogita T, Wong TY, Ohara K et al. Atypical melanosis of the foot. A report of three cases in Japanese populations. Arch Dermatol 1994; 130:1042–5. 2 Nogita T. Atypical melanosis of the foot. J Dermatol 1996; 23:825–7. 3 Ichimiya M, Yamamoto K, Hamamoto Y, Muto M. A case of atypical melanosis of the foot. J Dermatol 2002; 29:117–18. 4 Cho KH, Kim YG, Seo KI, Suh DH. Black heel with atypical melanocytic hyperplasia. Clin Exp Dermatol 1993; 18:437–40. 5 Saida T. Malignant melanoma in situ on the sole of the foot. Its clinical and histopathologic characteristics. Am J Dermatopathol 1989; 11:124–30. 6 Yamamura M, Takata M, Miyazaki A, Saida T. Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ. Arch Dermatol 2005; 141:1413–18. 7 Saida T, Miyazaki A, Oguchi S et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in Japan. Arch Dermatol 2004; 140:1233–8. 8 Oh TS, Bae EJ, Ro KW et al. Acral lentiginous melanoma developing during long-standing atypical melanosis: usefulness of dermoscopy for detection of early acral melanoma. Ann Dermatol 2011; 23:400–4. Funding sources: none. Conflicts of interest: none declared.
Distinctive clinical and dermoscopic features of BRAF V600K mutated melanomas DOI: 10.1111/bjd.13484 DEAR EDITOR, The dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma have recently been analysed by Pozzobon et al.1 in an interesting study published in BJD. The authors found out that a peppering pattern was significantly increased among BRAF mutant melanoma, being present in 68% of their cases series, with an odds ratio of 168 (95% confidence interval 109–258, P = 0015).1 The intent of this letter is to underline the distinctive dermoscopic and clinical features of BRAF p.V600K melanoma (the second most common BRAF V600 mutation, detected in 5–30% of cases), which might be slightly different from the features of BRAF V600E melanoma. Although BRAF inhibitors are efficacious in melanomas with V600E and V600K mutations, the two tumour types should be considered distinct entities with slightly different age of onset and clinical behaviour.2–5 Recently published scientific studies reported that BRAF V600K melanomas are characterized by an older age of onset and an increased risk for brain and lung metastases, as well as a shorter time from diagnosis to metastasis and death.3 Other reports of patients with melanoma with BRAF V600K mutations recognized significant differences in sex, age, primary melanoma location, interval from the time of initial melanoma diagnosis to diagnosis of stage IV disease, and overall survival after the diagnosis of stage IV disease. V600K mutation was significantly associated with older age, male sex, head and neck primary melanoma site, higher degree of chronic sun damage and short overall survival from the time of diagnosis of stage IV disease.3–5
Table 1 Clinicopathological and dermoscopic features in patients with BRAF V600K mutated melanoma treated with BRAF inhibitors Patient Sex/age (years) Location TNM ECOG (baseline) Time to metastasis (years) Treatment duration (months) Objective response Adverse effects Time to progression (months) Follow-up (months) Status ECOG (follow-up) Blue-grey blotches Reticular grey-blue areas White regression Peppering Blue-white veil
1 M/75 Scalp T1NxM0 1 8 6 Partial – 6 8 Dead 2 No Yes No Yes No
2 M/48 Scalp T4bN3M1 0 05 13 Partial – 13 14 Alive 0 Yes No Yes No Yes
3 M/62 Scalp T3bN2bM0 0 0 – – – 0 35 Alive 0 Yes Yes Yes No Yes
4 M/82 Scalp T3N0M0 1 – 3 Partial – 3 3 Dead 1 Yes No No No Yes
5 M/74 Trunk T2N1M0 1 4 – – – 6 6 Dead 2 – – – – –
6 M/69 Chest T2aN0M0 2 25 03 – – – 3 Alive 4 – – – – –
7 F/51 Leg T1N0M0 0 0 – – – – 4 Alive 0 – – – – –
M, male; F, female; TNM, tumour, nodes, metastasis; ECOG, Eastern Cooperative Oncology Group.
British Journal of Dermatology (2015) 172, pp1436–1461
© 2014 British Association of Dermatologists
Correspondence 1439 Table 2 Dermoscopic features of BRAF V600K mutated melanoma in four patients Dermoscopic feature
Frequency, n (%)
Globules irregularly distributed Blue-grey blotches Blue-white veil Reticular grey-blue areas Atypical network Irregular vessels White regression Ulceration Dots irregularly distributed Peppering Irregular streaks
3 3 3 2 2 2 2 2 1 1 1
(75) (75) (75) (50) (50) (50) (50) (50) (25) (25) (25)
Regarding the response to treatment, clinical trials with vemurafenib/dabrafenib including patients with V600K mutations reported worse outcomes and a strong trend for shorter overall survival among patients with BRAF V600K melanoma compared with V600E.2–7 We studied seven patients with BRAF V600K mutated melanomas, diagnosed at the University of Modena and Reggio Emilia from January 2010 (Table 1). Among these, four patients had dermoscopic images stored in our database and available for evaluation. The dermoscopic characteristics were recorded when observed. Vascular patterns were also assessed (Table 2). Our case series confirms that V600K mutated melanomas arise at an older age (53 vs. 65 years) and are predominant in
men. Furthermore, they more often arise in the head and neck area. Their biological behaviour is more aggressive, with a tendency to systemic disease, compared with their V600E counterparts (Table 1). Peppering was present in only one case (25%) in our series, which is different from previously reported V600E melanomas (68%) (Table 2). On the other hand, different patterns associated with regression were found: blue-grey blotches and bluewhite veil were each present in 75% of cases, while reticular grey-blue areas and white regression were each present in 50% of cases (Fig. 1). This is in accordance with the role of the BRAF gene in cellular immune regulation, as previously suggested by other studies.8,9 In our opinion the aggressive growth of BRAF V600K mutated melanomas might give rise to regression patterns different from peppering, according to a more advanced and invasive phenotype that is correlated with Breslow thickness and aggressive clinical behaviour. Regarding histopathological features, our cases showed mainly negative histological prognostic findings: vertical growth phase (75%), high number of mitoses (50%) and ulceration (50%). Regression phenomena were observed by the pathologist in two cases (50%), especially in association with epithelioid cellularity as previously described.10 In conclusion, even though this study was performed on a small sample, it improves our understanding of the subtle correlations between the clinical, dermoscopic and genetic findings of BRAF mutation phenotypes, leading the way to other studies on larger populations. BRAF V600K mutated melanomas seem to constitute a specific clinical and pathological entity, showing distinctive dermoscopic features from their V600E counterparts.
(a)
(b)
(c)
(d)
Fig 1. Dermoscopic view of BRAF V600K mutated melanomas: reticular grey-blue areas (b and c) and white regression (a and b) were each present in 50% of cases. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1436–1461
1440 Correspondence 1
Department of Clinical and Diagnostic Medicine and Public Health and 2 Department of Dermatology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy E-mail: [email protected]
G. PONTI1 M. MANFREDINI2 A. TOMASI1 G. PELLACANI2 (a)
References 1 Pozzobon FC, Puig-Butille JA, Gonzalez-Alvarez T et al. Dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma. Br J Dermatol 2014; 171:754–9. 2 Long GV, Menzies AM, Nagrial AM et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239–46. 3 Menzies AM, Haydu LE, Visintin L et al. Distinguishing clinicopathologic features of patients with p. V600E and p.V600K BRAFmutant metastatic melanoma. Clin Cancer Res 2012; 18:3242–9. 4 Zalaudek I, Ciarrocchi A, Piana S et al. A novel BRAF mutation in association with primary amelanotic melanoma with oral metastases. J Eur Acad Dermatol Venereol 2015; 29:387–90. 5 Maurichi A, Miceli R, Camerini T et al. Prediction of survival in patients with thin melanoma: results from a multi-institution study. J Clin Oncol 2014; 32:2479–85. 6 Ponti G, Pellacani G, Tomani A et al. Molecular targeted approaches for advanced BRAF V600, N-RAS, c-KIT, and GNAQ melanomas. Dis Markers 2014; 2014:671283. 7 Ponti G, Pellacani G, Tomasi A et al. The somatic affairs of BRAF: tailored therapies for advanced malignant melanoma and orphan non-V600E (V600R-M) mutations. J Clin Pathol 2013; 66:441–5. 8 Wilmott JS, Long GV, Howle JR et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 2012; 18:1386–94. 9 Liu C, Peng W, Xu C et al. BRAF inhibition increases tumour infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 2013; 19:393–403. 10 Viros A, Fridlyand J, Bauer J et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008; 5:e120. Funding sources: none. Conflicts of interest: none declared.
Comparison of reflectance confocal microscopy and standardized skin surface biopsy for three different lesions in a pityriasis folliculorum patient DOI: 10.1111/bjd.13506 DEAR EDITOR, Pityriasis folliculorum1 (PF) is a human demodicosis caused by the proliferation of Demodex folliculorum (D); Chen and Plewig2 have proposed that it is one of the primary British Journal of Dermatology (2015) 172, pp1436–1461
(b)
(c) Fig 1. Three types of lesion on the patient’s face. Lesion a: rosacealike lesions of left cheek. Lesion b: brown flat macula. Lesion c: numerous small grey spike changes, looking like normal skin.
forms of the condition. PF consists of very small, discrete and regularly dispersed follicular scales, involving sebaceous hair follicles, often without visible inflammation. Patients may complain about pruritus and dry, sensitive, irregular or rough skin.1 Forton et al.3 report that PF is the most frequent demodicosis, is commoner than papulopustular rosacea and has a higher demodex density (D = 61 cm 2, n = 45) tested by standardized skin surface biopsy (SSSB). An alternative method of diagnosis, reflectance confocal microscopy (RCM) now shows promising results.4 A 33-year-old woman from Algeria with recalcitrant rosacea-like lesions presented with a 2-year history of persistent facial stinging, mild pruritus, dryness and a sandpaper-like texture of her left cheek. Eight months before our assessments, a brown flat macula with follicular scales had appeared on her right cheek, and had grown and spread. Previous treatment with oral metronidazole had been stopped because of the adverse side-effect of a severe headache. Her left cheek had multiple papulopustular lesions and mild telangiectasia, covering an area of 25 9 23 mm (Lesion A). The brown flat macula without inflammation was located lateral to her right nasolabial fold and covered an area of 4 9 5 mm (Lesion B). Fine desquamation and follicle orifices were present on this lesion which was not sun-induced or sun-aggravated over the 8 months. Although the skin of her right cheek looked normal, there were also many small grey spike changes (Lesion C) (Fig. 1). Noninvasive examination of the three lesions was performed with RCM (VivaScopeâ 1500, Lucid Inc., Rochester, NY, U.S.A.). Then SSSB was carried out on the same areas. This method consists of collecting 1 cm2 of the superficial part of the horny layer and the follicle content.5 © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
early stages of an acral lentiginous melanoma in situ. In all cases of similar lesions, where histopathological findings are unspecific, the diagnosis and the complete excision of the lesion must be guided by clinical features and dermoscopy. 1
Department of Dermatology and 2 Department of Anatomic Pathology, Hospital Doce de Octubre, Madrid, Spain E-mail: [email protected]
D. MENIS1 L . M A R O N~ A S - J I M EN E Z 1 J . R O D R IG U E Z - P E R A L T O 2 R. MARTIN-LLAMAS1 F . V A N A C L O C H A - S E B A S T I A N 1
References 1 Nogita T, Wong TY, Ohara K et al. Atypical melanosis of the foot. A report of three cases in Japanese populations. Arch Dermatol 1994; 130:1042–5. 2 Nogita T. Atypical melanosis of the foot. J Dermatol 1996; 23:825–7. 3 Ichimiya M, Yamamoto K, Hamamoto Y, Muto M. A case of atypical melanosis of the foot. J Dermatol 2002; 29:117–18. 4 Cho KH, Kim YG, Seo KI, Suh DH. Black heel with atypical melanocytic hyperplasia. Clin Exp Dermatol 1993; 18:437–40. 5 Saida T. Malignant melanoma in situ on the sole of the foot. Its clinical and histopathologic characteristics. Am J Dermatopathol 1989; 11:124–30. 6 Yamamura M, Takata M, Miyazaki A, Saida T. Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ. Arch Dermatol 2005; 141:1413–18. 7 Saida T, Miyazaki A, Oguchi S et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in Japan. Arch Dermatol 2004; 140:1233–8. 8 Oh TS, Bae EJ, Ro KW et al. Acral lentiginous melanoma developing during long-standing atypical melanosis: usefulness of dermoscopy for detection of early acral melanoma. Ann Dermatol 2011; 23:400–4. Funding sources: none. Conflicts of interest: none declared.
Distinctive clinical and dermoscopic features of BRAF V600K mutated melanomas DOI: 10.1111/bjd.13484 DEAR EDITOR, The dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma have recently been analysed by Pozzobon et al.1 in an interesting study published in BJD. The authors found out that a peppering pattern was significantly increased among BRAF mutant melanoma, being present in 68% of their cases series, with an odds ratio of 168 (95% confidence interval 109–258, P = 0015).1 The intent of this letter is to underline the distinctive dermoscopic and clinical features of BRAF p.V600K melanoma (the second most common BRAF V600 mutation, detected in 5–30% of cases), which might be slightly different from the features of BRAF V600E melanoma. Although BRAF inhibitors are efficacious in melanomas with V600E and V600K mutations, the two tumour types should be considered distinct entities with slightly different age of onset and clinical behaviour.2–5 Recently published scientific studies reported that BRAF V600K melanomas are characterized by an older age of onset and an increased risk for brain and lung metastases, as well as a shorter time from diagnosis to metastasis and death.3 Other reports of patients with melanoma with BRAF V600K mutations recognized significant differences in sex, age, primary melanoma location, interval from the time of initial melanoma diagnosis to diagnosis of stage IV disease, and overall survival after the diagnosis of stage IV disease. V600K mutation was significantly associated with older age, male sex, head and neck primary melanoma site, higher degree of chronic sun damage and short overall survival from the time of diagnosis of stage IV disease.3–5
Table 1 Clinicopathological and dermoscopic features in patients with BRAF V600K mutated melanoma treated with BRAF inhibitors Patient Sex/age (years) Location TNM ECOG (baseline) Time to metastasis (years) Treatment duration (months) Objective response Adverse effects Time to progression (months) Follow-up (months) Status ECOG (follow-up) Blue-grey blotches Reticular grey-blue areas White regression Peppering Blue-white veil
1 M/75 Scalp T1NxM0 1 8 6 Partial – 6 8 Dead 2 No Yes No Yes No
2 M/48 Scalp T4bN3M1 0 05 13 Partial – 13 14 Alive 0 Yes No Yes No Yes
3 M/62 Scalp T3bN2bM0 0 0 – – – 0 35 Alive 0 Yes Yes Yes No Yes
4 M/82 Scalp T3N0M0 1 – 3 Partial – 3 3 Dead 1 Yes No No No Yes
5 M/74 Trunk T2N1M0 1 4 – – – 6 6 Dead 2 – – – – –
6 M/69 Chest T2aN0M0 2 25 03 – – – 3 Alive 4 – – – – –
7 F/51 Leg T1N0M0 0 0 – – – – 4 Alive 0 – – – – –
M, male; F, female; TNM, tumour, nodes, metastasis; ECOG, Eastern Cooperative Oncology Group.
British Journal of Dermatology (2015) 172, pp1436–1461
© 2014 British Association of Dermatologists
Correspondence 1439 Table 2 Dermoscopic features of BRAF V600K mutated melanoma in four patients Dermoscopic feature
Frequency, n (%)
Globules irregularly distributed Blue-grey blotches Blue-white veil Reticular grey-blue areas Atypical network Irregular vessels White regression Ulceration Dots irregularly distributed Peppering Irregular streaks
3 3 3 2 2 2 2 2 1 1 1
(75) (75) (75) (50) (50) (50) (50) (50) (25) (25) (25)
Regarding the response to treatment, clinical trials with vemurafenib/dabrafenib including patients with V600K mutations reported worse outcomes and a strong trend for shorter overall survival among patients with BRAF V600K melanoma compared with V600E.2–7 We studied seven patients with BRAF V600K mutated melanomas, diagnosed at the University of Modena and Reggio Emilia from January 2010 (Table 1). Among these, four patients had dermoscopic images stored in our database and available for evaluation. The dermoscopic characteristics were recorded when observed. Vascular patterns were also assessed (Table 2). Our case series confirms that V600K mutated melanomas arise at an older age (53 vs. 65 years) and are predominant in
men. Furthermore, they more often arise in the head and neck area. Their biological behaviour is more aggressive, with a tendency to systemic disease, compared with their V600E counterparts (Table 1). Peppering was present in only one case (25%) in our series, which is different from previously reported V600E melanomas (68%) (Table 2). On the other hand, different patterns associated with regression were found: blue-grey blotches and bluewhite veil were each present in 75% of cases, while reticular grey-blue areas and white regression were each present in 50% of cases (Fig. 1). This is in accordance with the role of the BRAF gene in cellular immune regulation, as previously suggested by other studies.8,9 In our opinion the aggressive growth of BRAF V600K mutated melanomas might give rise to regression patterns different from peppering, according to a more advanced and invasive phenotype that is correlated with Breslow thickness and aggressive clinical behaviour. Regarding histopathological features, our cases showed mainly negative histological prognostic findings: vertical growth phase (75%), high number of mitoses (50%) and ulceration (50%). Regression phenomena were observed by the pathologist in two cases (50%), especially in association with epithelioid cellularity as previously described.10 In conclusion, even though this study was performed on a small sample, it improves our understanding of the subtle correlations between the clinical, dermoscopic and genetic findings of BRAF mutation phenotypes, leading the way to other studies on larger populations. BRAF V600K mutated melanomas seem to constitute a specific clinical and pathological entity, showing distinctive dermoscopic features from their V600E counterparts.
(a)
(b)
(c)
(d)
Fig 1. Dermoscopic view of BRAF V600K mutated melanomas: reticular grey-blue areas (b and c) and white regression (a and b) were each present in 50% of cases. © 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1436–1461
1440 Correspondence 1
Department of Clinical and Diagnostic Medicine and Public Health and 2 Department of Dermatology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy E-mail: [email protected]
G. PONTI1 M. MANFREDINI2 A. TOMASI1 G. PELLACANI2 (a)
References 1 Pozzobon FC, Puig-Butille JA, Gonzalez-Alvarez T et al. Dermoscopic criteria associated with BRAF and NRAS mutation status in primary cutaneous melanoma. Br J Dermatol 2014; 171:754–9. 2 Long GV, Menzies AM, Nagrial AM et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239–46. 3 Menzies AM, Haydu LE, Visintin L et al. Distinguishing clinicopathologic features of patients with p. V600E and p.V600K BRAFmutant metastatic melanoma. Clin Cancer Res 2012; 18:3242–9. 4 Zalaudek I, Ciarrocchi A, Piana S et al. A novel BRAF mutation in association with primary amelanotic melanoma with oral metastases. J Eur Acad Dermatol Venereol 2015; 29:387–90. 5 Maurichi A, Miceli R, Camerini T et al. Prediction of survival in patients with thin melanoma: results from a multi-institution study. J Clin Oncol 2014; 32:2479–85. 6 Ponti G, Pellacani G, Tomani A et al. Molecular targeted approaches for advanced BRAF V600, N-RAS, c-KIT, and GNAQ melanomas. Dis Markers 2014; 2014:671283. 7 Ponti G, Pellacani G, Tomasi A et al. The somatic affairs of BRAF: tailored therapies for advanced malignant melanoma and orphan non-V600E (V600R-M) mutations. J Clin Pathol 2013; 66:441–5. 8 Wilmott JS, Long GV, Howle JR et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 2012; 18:1386–94. 9 Liu C, Peng W, Xu C et al. BRAF inhibition increases tumour infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 2013; 19:393–403. 10 Viros A, Fridlyand J, Bauer J et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 2008; 5:e120. Funding sources: none. Conflicts of interest: none declared.
Comparison of reflectance confocal microscopy and standardized skin surface biopsy for three different lesions in a pityriasis folliculorum patient DOI: 10.1111/bjd.13506 DEAR EDITOR, Pityriasis folliculorum1 (PF) is a human demodicosis caused by the proliferation of Demodex folliculorum (D); Chen and Plewig2 have proposed that it is one of the primary British Journal of Dermatology (2015) 172, pp1436–1461
(b)
(c) Fig 1. Three types of lesion on the patient’s face. Lesion a: rosacealike lesions of left cheek. Lesion b: brown flat macula. Lesion c: numerous small grey spike changes, looking like normal skin.
forms of the condition. PF consists of very small, discrete and regularly dispersed follicular scales, involving sebaceous hair follicles, often without visible inflammation. Patients may complain about pruritus and dry, sensitive, irregular or rough skin.1 Forton et al.3 report that PF is the most frequent demodicosis, is commoner than papulopustular rosacea and has a higher demodex density (D = 61 cm 2, n = 45) tested by standardized skin surface biopsy (SSSB). An alternative method of diagnosis, reflectance confocal microscopy (RCM) now shows promising results.4 A 33-year-old woman from Algeria with recalcitrant rosacea-like lesions presented with a 2-year history of persistent facial stinging, mild pruritus, dryness and a sandpaper-like texture of her left cheek. Eight months before our assessments, a brown flat macula with follicular scales had appeared on her right cheek, and had grown and spread. Previous treatment with oral metronidazole had been stopped because of the adverse side-effect of a severe headache. Her left cheek had multiple papulopustular lesions and mild telangiectasia, covering an area of 25 9 23 mm (Lesion A). The brown flat macula without inflammation was located lateral to her right nasolabial fold and covered an area of 4 9 5 mm (Lesion B). Fine desquamation and follicle orifices were present on this lesion which was not sun-induced or sun-aggravated over the 8 months. Although the skin of her right cheek looked normal, there were also many small grey spike changes (Lesion C) (Fig. 1). Noninvasive examination of the three lesions was performed with RCM (VivaScopeâ 1500, Lucid Inc., Rochester, NY, U.S.A.). Then SSSB was carried out on the same areas. This method consists of collecting 1 cm2 of the superficial part of the horny layer and the follicle content.5 © 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
