Controversies in Melanoma

1
Controversies in Melanoma

• Prof Ravi Kant, Dr Ajay Yadav, Dr Vivek Gupta, Dr
  Vishal Gupta, Ms Tanmya Stuti Ravi

2
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

3
Biology of melanoma

• development and progression

4
Biology of melanoma

1. Melanocytes ?
2. Nevus ?
3. Dysplastic nevus ?
4. Radial growth phase ?
5. Vertical growth phase ?
6. Metastases.

5
Melanoma Nevi

• Class I Precursor
• Class II Intermediate
• Class III VGP tumorigenic
• VGP vertical growth phase

6
Cell cycle regulation in melanoma
7
Expression of defined molecules in melanoma cell
8

• Express adhesions receptors,
• Integrins, Adherine, and cellular
• adhesions molecules

9

• melanoma cells express N-adherine instead of
  E-adherine.
• E-adherine allows melanocytes to adhere to
  keratinocytes, while melanoma cells can not
  adhere to keratinocytes

10
(No Transcript)
11
B- catenin pathway
12
Biology- what is new?

• PTEN pathway phosphatase and tensin deleted on
  chromosome 10 ?
• IGF-1 ? Akt / PKB (Oncogene)PtdIns(3,4)P2? P13
  kinase ?growth factor adhesion receptor
  (integrin)

13
Biology what is new?

• Ras pathway ?Grb2/Sos ?ras ?Raf ?MEK 1,2 ?MAPK
  1.2 ?TCF/SRF/Elk-1 ?Proliferation
• As apoptosis is blocked by depriving
• Bad Caspase-9 from p13 kinase
• Apoptosis turned into growth

14
Naevi
15
Nevus

• Proliferative lesion of melanocytes
• Scattered along basal layer
• Acquired - mostly
• congenital

16
Naevi types

1. Lentigo Flat
2. Junctional
3. Compound slightly elevated
4. Intradermal papillomatous

17
Naevi Lentigo simplex-1

• Pigmented macule, lt5mm, jet black color
• In infants children
• Melanocytic proliferation along basal layer

18
Naevi Lentigo simplex-2

• Abundant melanocytes along basal layer
• Associated with Peutz-Jegher syndrome
• P-J syndrome hamartomatous polypes in GIT
  naevi in oral buccal mucosa

19
Naevi Junctional

• Next stage after lentigo
• Macular lesions, lt 7mm
• Less deeply pigmented than lentigo
• Homogenous brown black areas
• Melanocytic proliferation along basal layer
• Highest malignant potential

20
Naevi Compound

• Next stage of maturation of junctional naevi
• In children adolescent
• Pale brown papular
• Junctional dermal component

21
Naevi Intradermal

• Last stage in maturation
• Mostly after 30 years of age
• Flesh colored papule with little pigment
• Melanocytes confined to dermis only

22
Blue naevi

• Benign melanocytic naevi
• Slate blue color
• Two types common cellular

23
Common Blue naevi

• Mostly in scalp dorsum of hand, feet
• Dermal collection of spindle melanocytes
• F gt M , max. in 4th decade

24
Blue naevi Cellular type

1. Uncommon
2. F gt M
3. gt 50 in sacrococcygeal area buttock
4. lt 1 under go malignancy
5. Rx simple excision

25
Nevus

• Common
• Atypical
• Congenital
• Spitz
• Familial

26
Malignant Melanoma

• Arises from transformed melanocytes of epidermis
• Accounts for almost all deaths from skin cancer
• 4 fold increase in incidence in Australia

27
Melanoma Risk Factors-1

• Congenital naevi gt5 BSA, 1000X
• Previous melanoma
• Family history
• 5 naevi gt 5mm (Common nevi)
• 50 naevi gt 2mm (Common nevi)

28
Melanoma Risk Factors-2

• Dysplastic nevi, Atypical 2X for single 12X for
  gt10
• Family history Atypical 37-148X
• Dysplatic naevi syndrome

29
Melanoma Risk factors-3

• White race,
• Red hair,
• Blond hair,
• Blue eyes
• Poor tanning ability,
• Sunburns during childhood
• Albinism

30
Melanoma Risk factors-4

• Freckles
• Equatorial latitude
• Xeroderma pigmentosa
• Psoralen sunscreen
• Tanning salons
• Junctional naevi

31
Melanoma Risk factors-5

• Spitz Nevi benign except when
• gt10 y age
• ulceration
• gt1cm
• Involve subcut fat
• Mitotic activity gt6/mm2

32
Melanoma Risk factors-6

• Familial syndromes
• B-K nevus syndromes
• Atypical nevus
• CDKN2A mutation
• CDK4 mutation

33
DD

• Pigmented Basal cell CA
• Seborrheic keratitis
• Solar lentigines
• Atypical nevi

34
MM Clinical features

• Lentigo maligna Hutchinson's freckle
  (7-15)
• Superficial spreading most common (60-70)
• Nodular 12-25
• Acral lentiginous
• Amelanotic

35
1. Superficial spreading Melanoma

• Most common type 70
• Occur any where on skin except hands feet
• Usually gt 5 mm , flat
• Variegated color pattern
• Irregular edge with areas of regression
• Long radial growth phase

36
2. Nodular Melanoma

• Most malignant
• Younger age group
• Any part of the body
• raised and always palpable with sharp irregular
  border
• Blue, black or gray color
• Lack of radial growth phase

37
2. Nodular Melanoma

• Second most common 15-30
• Rapid onset
• ?gt?

38
3. Lentigo maligna Melanoma

• Hutchinsons melanotic freckle
• Least common type 5
• Most commonly on face of elderly
• Begins as irregularly pigmented ,flat, brown
  macule
• quite large at the time of diagnosis late
  invasive growth phase
• Good prognosis

39
4. Acral lentiginous

• Uncommon 1-3
• Palm, sole, heel subungual
• More common in dark skin persons
• Subungual common in big toe or thumb
• Poor prognosis , 29_at_20Y
• 70 ulcerate, 74 gt1.5 mm

40
4. Acral lentiginous-risk factor

• gt50 y age
• gt3mm width, variegated border
• Extension of pigment in to nail bed/ nail fold
• Dark complexioned patient

41
5. Amelanotic Melanoma

• Desmoplastic, 1.7
• HN
• Pink, reveal some pigment on close inspection
  Stain with S-100
• Worse prognosis
• Often present with regional lymph nodes metastases

42
5. Amelanotic Melanoma

• Locally aggressive
• Known for local recurrences
• Stain ? S-100

43
MM spread

• Local extension
• Blood stream lung, liver, brain, skin
• Lymphatic
• embolisation, permeation
• satellite nodule
• in-transit nodule

44
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

45
MM Diagnosis

• Signs of transformation of mole in to MM
• Major
• Change in size, shape, color
• Minor
• Inflammation, itching
• Crusting or bleeding
• gt 5mm diameter

46
MM Diagnosis

• A Asymmetry
• B irregular border
• C color variegation
• D diameter gt 5 mm
• E enlargement or evolution

47
Detection- Vision

• A asymmetry
• B border irregularity
• C color variegation
• D diameter gt 6mm
• E elevation, enlargement, evolutionary changes
• F any funny change

48
Detection- Vision

1. Change in size
2. Change in shape
3. Change in Color
4. Inflammation
5. Crusting / bleeding
6. Sensory change
7. gt 7mm in size enlargement

49
Detection- Digital Vision

• Epiluminescence microscopy
• Dermatoscopy
• Surface microscopy
• Incident light microscopy
• Can see the dermis, epidermo-dermal junction

50
Epiluminescence microscopy-ominous signs

• Melanin pigment network
• Black dots
• Globules
• Streaks
• Radial streaming
• Blue-white milky veils

• Pseudopods
• Pseudo network
• Structure less area
• Melanin reticulum
• Epidermo-dermal junction
• Multiple brown dots

51
Epiluminescence microscopy-good signs

• Axial symmetry of pigmentation
• Presence of one color only
• Sensitivity 92
• Specificity 71

52
Detection-digital vision

• Computer based Dermatoscopy
• Spectrophotometric image analysis
• Reflectance spectroscopy
• Computer aided image analysis Topodermatographic
• USG, MR and OCT in vivo histology
• Virtual histology

53
USG for Regional LN

• 7.5-20 mhZ for LN 20-100 for Virtual
• USG B scan-LN
• Vassallo indexlt2 (LongTrans)
• Hypoechoic central area
• Color Doppler-peripheral perfusion
• USG Guided FNAC RT-PCR Tyro
• USG guided anchor wire for mets

54
Screening

• Dermatologist
• or
• non-Dermatologists?

55
Screening

• Dermatologist
• sensitivity 89 - 97
• positive predictive value - 17-75
• specificity - 97

56
PET vs CT
Sensitive Specificity
FDG PET 94-100 83 -94
CT 55-84 68-84
Holder Ann Surg 1998 Rinne Cancer 1998
57
FDG PET gtCT

• regional and mediastinum lymph nodes
• abdominal visceral and soft tissue metastasis

58
CTgtPET

• Lung mets
• 87 vs 70

59
MRI for brain
60
PET

• A single whole body PET scan could replace all
  other imaging modalities in melanoma.

61
Limitations of PET

1. Cost
2. Limited availability
3. Lack of sufficient data

62
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

63
Prognostic factors

• Tumor thickness Breslow
• Vs
• Level of invasion Clark level

64
Thickness vs. Level

• 54 multivariate analysis of
• prognostic factors using data from 48 papers
• Vollmer

65
Thickness vs. Level

• Tumor thickness significant
• in 42 of 54 studies
• Vollmer

66
Thickness vs. Level

• Level of invasion important
• prognostic factor in only 8 of 48
• Studies
• Vollmer

67
Thickness vs. Level

• Tumor thickness
• 1 , 2, 4 mm
• Best for survival data
• Adopted in 2002 AJCC
• Buttner
• Buzaid

68
Thickness vs. Level- conclusion

• Clark level of invasion is a minor prognostic
  factor
• cutoffs of tumor thickness such as 1mm, 2mm and
  4mm provide better prognostic information
• 2002 AJCC staging of melanoma

69
Ulceration prognostic significance

• Significant prognostic factor
• Vollmer - multivariate analysis in
• 7 of 11 studies

70
Ulceration prognostic significance

• strongest predictors of outcome
• Balch - meta-analysis that
• included 15,798 patients with
• localized melanoma

71
Ulceration prognostic significance

• Ulceration has the most significant impact on
  survival.
• Buzaid influence of ulceration according to the
  tumor thickness

72
Ulceration

• Acantholysis
• Shows autocrine and paracrine pathways are active
• Adverse prognosis

73
Ulceration prognostic significance

• Independent prognostic factor
• Included in AJCC 2002 staging
• Upstage patients compared with those having tumor
  of same thickness

74
Satellites vs. In-transit metastases

• In transit and satellite metastases common
  manifestations of intralymphatic metastasis
• associated with poor prognosis

75
Satellites vs. In-transit metastases

• prognosis of patient with satellites is usually
  worse than that of patient with in-transit or
  nodal metastasis (stage III)
• Buzaid J Clin Oncol 1997
• Haffner Br J Cancer 1992
• Cascinelli J Surg Oncol 1986

76
Satellites vs. In-transit metastases

• Satellites
• pT4b (1997) ? N2c / N3 (2002)
• Stage II ? stage III

77
Lymph node size vs. number-Prognostic value

• Size not a significant prognostic
• factor even after stratification
• according to cutoff size
• Drepper Cancer 1993
• Buzaid J Clin Oncol 1995

78
Lymph node size vs. number-Prognostic value

• Number of LN most consistent prognostic factor by
  multivariate analysis
• Buzaid J Clin Oncol 1997

79
Author Pt No OS Survival by LN no 1 2-4 5 or ? Survival by LN no 1 2-4 5 or ? Survival by LN no 1 2-4 5 or ?
Buzaid 95 442 42 55 34 25
Drepper 93 112 39 47 31 20
Singletary 92 264 NS 45 31
Balch 92 234 NS 40 28 18
Coit 91 449 32 40 40 19
80
Lymph node number-Prognostic value

• number of positive nodes has replaced size of
  lymph node mass
• Current 2002 AJCC staging system.

81
Lymph node number-Prognostic value

• N1 1 LN
• N2 2 or 3 LNs
• N3 ? 4 LNs
• AJCC 2002 staging

82
Prognostic Value of Biochemical serologic
markers

• Significant prognostic factor in melanoma
• LDH
• S-100-B
• melanoma inhibitory activity serum markers

83
Prognostic Value of Biochemical serologic
markers

• After logistic regression analysis,
• LDH is found to be the only
• statistically significant marker for
  progressive disease and the most relevant overall
  parameter

84
Prognostic Value of Biochemical serologic
markers

• AJCC staging 2002 includes LDH
• Distant metastases elevated serum LDH M1c
  category
• Two or more reports gt 24 hrs apart.

85
Prognostic Markers-1

• Micro stage
• Breslow 1,2,4
• Clark levels
• Ulceration
• Mitotic figures
• Inflammatory regression
• Micro satellites

• Vertical growth fraction
• Tumor infiltrating lymphocytes
• Molecular markers
• Micro staging approaches

86
Prognostic Markers-2

• S phase fraction
• Mitotic index
• Ulceration
• RT-PCR
• Tyrosinase or
• MelanA or
• MART1 m rna

• Integrins ß3 subunit of vitronectin-receptor for
  Vertical growth phase
• ?1integrin for LN mets

87
Prognostic Markers-3

• MMP-2 ?
• VEGF ?
• Mitf Microphtalmia transcription factor ??

• CD 40
• CD 40 L CD 40 worse prognosis

88
Prognostic Markers-4

• Mutation in Codon 12 or 61 of N-ras ? OS
• Mutation in Codon 18 of N-ras exon 1 ?
• (No mets)

• Transcription factor Activator Protein-2AP-2
• Regulates gene in cell cycle and growth control
• ? AP-2 ? p21
• ? RFS ?OS

89
MM prognostic factors

• Depth of invasion (BRESLOW)
• Ulceration
• High mitotic rate
• Anatomic location
• Histologic type
• Lymphoid dendritic cell infiltration
• regression

90
Depth of invasion in mm Breslow

• I ? 1
• II 1-2
• III 2-4
• IV gt4

91
Depth of invasion Clark

• I superficial to basement membrane
• II papillary dermis
• III papillary/reticular dermis junction
• IV reticular dermis
• V subcutaneous fat

92
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

93
Elective LN dissection

• Persistent area of controversy
• Micro metastases in Clinically N- 14 -20

94
Arguments for Elective LN dissection

• retrospective prospective studies
• Goldsmith
• Memorial hospital
• 1552 patients
• 5 yr survival
• 78 vs. 68

95

• Melanoma Inter-group Trial 1996
• 700 patients
• Prospective study
• Significantly improved survival rates with ELND
  in a subgroup lt60 years, non-ulcerated 1-4 mm
• Balch Ann Surg 1996

96
Balch Cancer 1979
At 5 Year Distant Metastases Survival
ELND 15 83
TLND 78 37
97

• Survival advantage ?
• Positive nodes after ELND 16
• Slingluff Ann Surg 1994

98
Elective LN dissection no benefit
WHO 1998 Prospective
Intergroup Melanoma 1996 Prospective
Mayo Clinic, 1986 Prospective
WHO, 1977 Prospective
Sydney melanoma, 1995 Retrospective
Duke university, 1994 Retrospective
University of Pennsylvania,1985 Retrospective
99
Elective LN dissection benefit
Romple, 1995 Retrospective
Drepper, 1993 Retrospective
Sydney melanoma unit, 1985 Retrospective
Duke university, 1983 Retrospective
University of Alabama, 1982 Retrospective
Memorial, 1975 Retrospective
100

• ELND
• or
• Sentinel LN biopsy ?

101
Sentinel Lymph Node Biopsy

• Sensible approach
• In view of low occult metastasis - 12-15 It
  allows upto 85 of patients with melanoma to be
  spared a formal lymph node dissection, thus
  avoiding complication associated with that
  procedure

102

• SLN biopsy
• 100 sensitive
• 97 specific
• Pu Plast Reconstruct Surg 1999
  

103

• No decrease in survival compared with patients
  undergoing ELND
• Therapeutically equivalent but prognostically
  more accurate than ELND
• Essner Ann Surg Oncol 1999

104
SLN Indications

• 5-10 risk of mets to Node
• Candidate for High dose interferon alfa-2b
• Melanoma lt 1mm thickness but Clarke level III or
  ? (10 risk of recurrence)

105

• Primary tumors between 1mm and 4mm thickness
• up to 45 incidence of occult nodal metastases

106
SLN Contraindication-1

• lt 1 mm thickness melanoma (lt 2 N or M)
• gt 4mm thickness melanoma, Clinically N-
• (as 60-70 N occult M 70)

107
SLN Contraindication-2

• FNAC LN
• Prior wide excision of primary

108
SLN Micromets Significance

• Gershenwald 1999 J Clin Oncol
• SLN 23 rec rate 16 death rate
• - SLN9 recurrence rate, 35 death
• Clary 2001, Ann Surg 233250-258
• SLN40 recurrence, 58DFS_at_3y
• -SLN14 recurrence, 75DFS_at_3y

109
SLN Micromets Significance

• Short term DFS ? HE-, IH-, RT PCR
• Short term DFS ? HE-, IH-, RT PCR

110
SLN
Method Success in
Blue dye 70-82
Isotope 84-94
Both 96-98
False in False- in
0,5, 27


111
Blue dye for SLN

• Patent blue V Isosulfan blue
• Anaphylaxis in 3 / 406 cases
• Incidence with Isosulfan blue 1
• Prepared for anaphylaxis treatment

112
Blue dye for SLN

• 2-5 ml of 1 Isosulfan blue into the dermis (not
  sub cut) around the intact tumor Exercise 5-15
  minutes wait
• Clears from SLN within 45 minutes

113
Isotope

• Tc 99m labeled sulfur colloid
• 100 µm filtered Tc 99m labeled sulfur colloid-
  even better
• 99m Tc DTPA mannosyl-dextran ? affinity for lymph
  node avoid distal lymph node imaging
• 3 hours prior injection, intradermally around the
  tumor

114
Isotope

• Allows dissection down to the LN without need to
  create flaps
• Keep hand held array at an angle avoid Shine
  Through
• If ? 31 resection bed background ratio
  search more SLN

115
SLN

• H/E stain
• Immunohistochemistry to S-100 protein, HMB-45
  antigen,
• RT-PCR Tyrosinase, Mel A
• 14 are HE and by IH
• 20-30 are HE-, IH- but RT-PCR
• Cell culture technique

116
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

117
Current recommendations for surgical margins
primary cutaneous melanoma thickness based
decision

• In situ 5 mm
• lt2mm 1cm
• gt2mm 2cm
• Sober AJ J Am Acad Dermatol 2001

118
Diameter, Location Surgical Margins Zitelli
1997
Location ? Head Neck, Hand Trunk Extremity
Size in cm ? Margin in cm ? Margin in cm ?
lt 2 1.5 1
gt2 2.5 1.5
119
Surgical margins

• No significant difference in survival for
  excision margin 2 cm or 4 cm for tumor between
  1mm and 4mm
• Balch Ann Surg 1993

120
Margin WHO Melanoma group

• Tumor thickness 1-2 mm
• Margin 1cm or 3cm
• OS same

121
Margin 2 or 5 cm

• No significant difference in survival for
  margins 2 or 5 cm for tumors between 0.6 mm to
  2mm
• Swedish melanoma group.
• Cancer 1998

122
Mohs Micrographically controlled Surgery

• In situ fixation- earlier by ZnO
• Now micrography-sectioned and inked and
  orientedmapped

123
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Surgical margins
• Adjuvant treatment Vaccines
• Summary

124
Isolated Limb Perfusion

• No Role of prophylactic (adjuvant)

125
Isolated Limb Perfusion

• EORTC
• WHO
• North American Perfusion Group
• No improvement in survival

126
Therapeutic isolated limb perfusion

• Better DFS
• No significant change in OS
• Hafstrom J Clin Oncol 1991

127

• Who are candidates for ILP?

128
Therapeutic

• Patients with in transit disease
• confined to a limb, with no signs of distant
  metastases at presentation.

129
Drugs for ILP

• DTIC Others
• Melphalan others
• TNF ?
• Interferon

130
Palliative

• Bulky regional disease with limited systemic
  metastases

131
Adjuvant Indications?risk for metastatic disease

• identified by prognostic factors or
• identified by sentinel lymph node biopsy.
• Clark J Natl Cancer Inst 1989

132
High risk melanoma Interferon

• Thickness gt4mm
• Mitotic index
• Location
• Gender
• Ulceration
• SLN
• AP-2 index

133
Interferon 2b

• v US FDA for high risk melanoma
• ?Recurrence
• Interferon alpha2b ?DFS , ? OS by EOCG HDI 1684,
  EOCG1690 and French LDI Grob 2000- in selected
  cases

134
Adjuvant ?

• high dose interferon alpha 2b
• tamoxifen,
• cisplatin, and
• Vindesine
• GM CSF
• Levamisole.

135
Adjuvant ?

• TNF
• Interleukin-2
• Biochemotherapy
• Cytokines
• Ab3
• Peptide based vaccines
• MAGE tumor specific shared ag

136
What are New Options

• Biochemotherapy
• DTIC or temozolomideNitrosureas
• Interferon antiproliferative and
  immunomodulatory
• Interleukin-2 Immunostimulatory cytokine ?NK
  cells

137
Vaccines

• Vaccines-ganglioside GM2
• MAGE Tumor specific antigens
• Ab3 a cytokine
• Antibody based vaccines
• HLA based
• Cell based vaccines
• Peptide vaccines
• Recombinant viruses

138
Controversies in Melanoma

• Biology
• Detection-Computer, USG, RT-PCR
• Staging- AJCC 2000 Prognosis
• SLN Biopsy ELND
• Treatment margins
• Adjuvant treatment Vaccines
• Summary

139
Major changes in AJCC classification in 2002 -1

• v Thickness
• X not levels
• v Ulceration
• v Number of LN
• X size of LN
• v LDH

140
Major changes in AJCC classification in 2002-2

• v Upstaging with ulceration
• v Merge micro satellite in-transit mets into
  stage III
• v Include SLN into staging

141
Major changes

• Ultrasound of LN
• RT-PCR Tyrosinase of SLN
• 1? 106109
• Detect 1 cancer cell out of 106 109 normal
  cells
• Thin margins
• Adjuvant interferon /-

142
Current recommendations for surgical margins
primary cutaneous melanoma

• In situ 5 mm
• lt2mm 1cm
• gt2mm 2cm
• Sober AJ J Am Acad Dermatol 2001

143
Summary

• No role of wide margins
• No role of ELND
• No role of Prophylactic ILP
• Role of SLN
• Interferon alpha2b ?DFS , ? OS
• ? EOCG HDI 1684, EOCG1690
• French LDI Grob 2000- in selected cases

144
Summary Rx

• Primary surgical
• Surgical principles
• Complete surgical excision
• Minimum margin 1.0 cm
• Maximum margin 2.0 cm
• Do not excise beyond deep fascia

145
MM management of lymph nodes

• Biopsy FNAC preferred
• Elective dissection for
• Clinically involved nodes,
• Satellitosis,
• Lymphatic invasion

146
Sentinel lymph node biopsy

• Detects micrometastasis in lymph nodes
• Inrtadermal injection of radioactive colloid
  around lesion
• Lymph node identified by gamma probe

147
Sentinel lymph node biopsy

• Intraoperative identification by using patent
  blue dye
• Identify patients appropriate for elective
  dissection
• Identify patients among high risk for adjuvant
  interferon.

148
Thank You