PEDIATRIC HEMATOLOGY/ONCOLOGY

INTER-HOSPITAL CONFERENCE

King Chulalongkorn Memorial Hospital

16 NOV 2010

2

History

ผู้��ป่�วยเด็กชายไทย อาย� 2 เด็�อน ภู�มิ�ลำ�าเนาเด็�มิแลำะป่�จจ�บั�น สมิ�ทรป่ราการ

ร�บัไว�ในโรงพยาบัาลำคร�&งท'(1 เมิ�(อ15 มิ'นาคมิ 53 ป่ระว�ติ�ได็�จากใบัส*งติ�วแลำะมิารด็า เช�(อถื�อได็�

Chief complaint : ไอ 2 ส�ป่ด็าห์-ก*อนมิาร.พ. Present illness : 2 ส�ป่ด็าห์-ก*อนมิาร.พ. มิ'อาการไอแห์�ง ไมิ*ห์อบัเห์น�(อย ไมิ*มิ'ไข้� ไมิ*ซึ0มิ ป่�สสาวะอ�จจาระป่กติ� ไมิ*มิ'จ�&าเลำ�อด็ติามิติ�วผู้�ด็ป่กติ� ไมิ*มิ'ส�าลำ�ก มิ'อาการนาน 1 ส�ป่ด็าห์-จ0งไป่พบัแพทย-ท'(คลำ�น�กได็�ยาแก�ไอ ยาฆ่*าเช�&อไมิ*ทราบัชน�ด็ มิาร�บัป่ระทาน

2 ว�นก*อนมิาร.พ. อาการไมิ*ด็'ข้0&น ไอมิาก แมิ*ส�งเกติเวลำาทานนมิไอมิากข้0&น จ0งไป่ พบัแพทย-ท'(โรงพยาบัาลำ

3

History แรกร�บัท'(โรงพยาบัาลำ จ�งห์ว�ด็สมิ�ทรป่ราการPhysical exam: pale, tachypnea.

Lungs: crepitation both lungs with subcostal retraction both lungs.

Abdomen: Liver1 cm. BRCM , spleen not enlargeInvestigation

CBC: Hb. 5.9 g/dL Hct. 18.7% MCV 89 fL WBC 15,790/mm3 N50% L37% Mo7% Eo 5%

Ba1% Platelet 27,000 /mm3 PBS: anisocytosis 1+, poikilocytosis 1+, microcyte

1+ , tear drop few, decrease platelet. CXR : RUL LUL patchy infiltration

Impression : pneumonia and anemia with thrombocytopeniaRx : Ampicillin100 mg/kg/day , erythromycin, PRC10 ml/kg จ0งส*งติ�วมิาร�กษาติ*อท'(โรงพยาบัาลำจ�ฬา

14/3/53

5

Past history ไมิ*เคยเจบัป่�วยเข้�าโรงพยาบัาลำก*อนห์น�าน'& ป่ฏิ�เสธป่ระว�ติ�การแติ*งงานในเคร�อญาติ� ป่ฏิ�เสธสมิาช�กในครอบัคร�วป่�วยเป่7นโรคเลำ�อด็/มิะเรง ข้ณะอาย� 4 ว�น แมิ*พาไป่กวาด็ลำ�&น ห์ลำ�งจากน�&นลำ�&นเป่7นแผู้ลำ ไป่คลำ�น�ก ได็�ยาฆ่*าเช�&อมิาทานไมิ*ทราบัชน�ด็ ห์ลำ�งจากไมิ*มิ'อาการอ'ก

อาย�7ว�น มิ'ผู้�(นแด็งท'(ข้าห์น'บั ไป่คลำ�น�กบัอกว*าเป่7นผู้�(นผู้�าอ�อมิได็�ยามิาทา

6

Pediatrics history : Prenatal : มิารด็าผู้ลำเลำ�อด็ป่กติ� , serology neg. all ระห์ว*างติ�&งครรภู- ไมิ*มิ'ไข้� ห์ร�อเจบัป่�วย Perinatal : บั�ติร1/1, birth weight 2,970 gm.,

term NL ,no complication แรกเก�ด็มิ'ป่�ญห์า microcephaly head circumference 30 cm (< P3)

Postnatal : ก�นนมิแมิ* 3 มิ�&อ/ว�น ร*วมิก�บันมิผู้สมิ 2 oz. x 8 feeds

Immunization : แรกเก�ด็ได็�ร�บั BCG, HBV G&D : ช�นคอได็� จ�องมิองติา

7

Pedigree

40ป่9 36ป่9 34ป่9

ไมิ*ได็�ท�างานไมิ*มิ'โรคป่ระจ�าติ�วอย�*จ.ก�าแพงเพชร

ไมิ*ได็�ท�างานไมิ*มิ'โรคป่ระจ�าติ�วอย�*จ.ก�าแพงเพชร

พนง.บับัร�ษ�ทเคร�(องด็�(มิไมิ*มิ'โรคป่ระจ�าติ�วอย�*กทมิ.

พนง.บัร�ษ�ทเคร�(องด็�(มิไมิ*มิ'โรคป่ระจ�าติ�วอย�*กทมิ.

ทห์ารไมิ*มิ'โรคป่ระจ�าติ�ว

ไมิ*ได็�ท�างานไมิ*มิ'โรคป่ระจ�าติ�วอย�*กทมิ.

ผู้��ป่�วย 2 mo.

42 ป่9 38ป่9

35ป่9 32ป่921ป่9

72 ป่9

63 ป่9 42 ป่9 47 ป่9

22ป่9 19ป่9

I

II

III

8

Physical examination

GA: A Thai male infant active , tachypnea Measurement : Weight 3.22kg (<P3) ,Length

52 cm (<P3), HC 33cm (<P3) V/S: BT 37.2 ◦c PR110/min BP 86/50 mmHg RR 38/min SpO2 97% Skin: no rash, no petechiae, no ecchymosis

BCG scar positive HEENT: AF: 2x2cm., not bulging, not

depress ,PF: FT Eye: not pale conjunctiva ,anicteric

sclera Ears: intact both TM.

9

Physical examination

RS : subcostal retraction, medium crepitation both lungs, occasional rhonchi, inspiratory stridor

CVS : normal S1S2 ,no murmur Abd : not distension, soft, liver 1 cm BRCM span 6cm,

no splenomegaly Musculoskeletal : no edema, capillary refill time<2 sec NS : active, pupil 3 mmRTLBE, equal movement ,

Brudzinski sign negative, DTR 1+ all extremities.

11

Head circumference

12

Problem lists

Thrombocytopenia with anemia Failure to thrive with microcephaly Pneumonia

13

Differential diagnosis

Infection Pneumonia Septicemia Congenital infection: ToRCH infection HIV infection

Bone marrow disease Congenital bone marrow failure Infiltrative disease

14

Initial investigation (15 มิ'นาคมิ 53) CBC post PRC transfusion

Hb 9.6 g/dL, Hct 30.2%, MCV 89 fL., RDW 16%

WBC 10,610 /mm3 (N 61% L 23.3% Mo 6.1% Eo 3.9% Ba 0.6%) Platelet 39,000/mm3

Reticulocyte count 3.1% Absolute neutrophil count = 6,472/mm3

Absolute lymphocyte count = 2,493/mm3

15

16

17

Initial investigation (15 มิ'นาคมิ 53) BUN 5 g/dl Cr 0.2 d/dl Electrolyte Na 134 mmol/L K 3.1 mmol/L

Cl 105 mmol/L HCO3 26 mmol/L LFT : TB 0.56 mg/dL DB 0.24 mg/dL

SGOT 69 U/L, SGPT 49 U/L Alp 117 U/L

Alb 2.7 g/L globulin 2.6 g/L TP 5.3 g/L Calcium 9.3 mmol/L

18

15/3/53

CXR

19

Investigation

KOH preparation at groin : pseudo hyphae and budding yeast cells

H/C: no growth Stool occult blood: negative

20

Investigation

TORCH titer (15/3/53) Rubella IgG negative Rubella IgM negative Anti CMV IgG positive (147.12 unit)

(cut off 40 unit ) Anti CMV IgM negative Anti HSV IgG negative Anti HSV IgM negative CMV viral load: pending

21

Investigation

Anti-HIV : negative

22

Bone marrow aspiration

BMA (16/3/2553) The specimen shows hypercellular marrow with mild

erythroid and myeloid hyperplasia and normal maturation. Megakaryocytes were increased. Mildly increased mature histiocytes were observed.

Conclusions : Increase peripheral destruction

of platelet and erythroid series.

23

24

25

26

U/S abdomen (18/3/53)

Mild splenomegaly size ~ 6.2 cm , normal size of liver , unremarkable otherwise.

27

Film lateral + AP skull

29

Diagnosis

Infection Pneumonia √ Candidiasis √ CMV infection ? Septicemia x HIV infection x

Bone marrow disease x Congenital bone marrow failure Infiltrative disease

Anemia with thrombocytopenia due to peripheral destruction

30

Treatment

Antibiotics: ampicillin 100 mg/kg/day Platelet transfusion: 1 unit Topical cotrimazole Oxygen support: canula 0.5 LPM

31

Progress note

32

Admission day 4 (19/3/53)

ผู้��ป่�วยไข้�ส�ง ห์ายใจเรวเห์น�(อย ก�นนมิลำด็ลำง ซึ0มิDiagnosis: pneumonia, respiratory failure with septic shockCBC: Hb 7.9 g/dl Hct25.1% WBC15,790/mm3 (N91% ,L 1%, Mo 3%) Plt 50,000/mm3 ALC 1,579

H/C: E. coli TSC, stool C/S, urine C/S :candida albicans

Treatment ETT 5 days Antibiotics: meropenam + fluconazole PLT and LPRC transfusion

33

CBC มิ'นาคมิ 2553Date 15 /3 17 /3 19 / 3 20/ 3

WBC(/mm3)

10,610

9,82015,79

022,59

0

N (%) 61 84 91 54

L(%)23.3 8 1 36.9

M(%)6.1 5 3 6.1

E(%)3.9 3 5 3

Hb (g/dl) 9.6 6

7.9▲

9.2▲

Hct (%) 30.7 28.2 25 28

Plt (/mm3)

39,000 6,000▲

50,000 38,000▲

34

Admission day 10 (25/3/53)

Extubation ย�งมิ'ไข้�ติ�(า ๆ ห์ายใจห์อบัเท*าเด็�มิ CBC : Hb 10.7 g/dl Hct 32.8% WBC

6,240/mm3 (N 62% ,L 14% , Mo 5%) Plt 74,000/mm3

CMV viral load 52,800 copies/ml Treatment: O2 Box 10 LPM

Gangcyclovir 5 mg/kg/dose q12hr(25/3-12/5) LPRC 10 ml/kg. Plt. Conc. 1unit

35

CBC มิ'นาคมิ 2553Date 15 /3 17 /3 19 / 3 20/ 3 21/ 3 22/ 3 24/ 3 25/ 3

WBC(/mm3)

10,610

9,82015,79

022,59

07,700 5,460 5,800 6,290

N (%) 61 84 91 54 74 56.7 60 62

L(%)23.3 8 1 36.9 17 27.8 27 14

M(%)6.1 5 3 6.1 4 10 8 5

E(%)3.9 3 5 3 5 5.5 5 10

Hb (g/dl) 9.6 6

7.9▲

9.2▲

10 10 11.5 10.7

Hct (%) 30.7 28.2 25 28 30.4 30.6 34.8 32.8

Plt (/mm3)

39,000 6,000▲

50,000 38,000▲

98,000(CCI

21,000)

28,000▲

53,000 11,000▲

74,000

36

Problem lists

Thrombocytopenia and anemia Failure to thrive Microcephaly Pneumonia Systemic candida infection

Infection : CMV

37

progressDate PE investigation Management

31/3/53(day 16)

มิ'ไข้�ติ�(า ๆ เห์น�(อยมิากข้0&น ติ*อมิาถื*ายเห์ลำวเป่7น Melena ป่ร�มิาณมิาก

V/S: BT 37.5 C RR 60 /min BP 64/37 mmHg PR 150/min Lung: subcostal retraction, coarse crepitation

•CBC : Hb 7.1 g/dl Hct 21.3% WBC 8,250 /mm3

(N 58 , L 34.3 , Mo 3) Plt 117,000/mm3

•Central line pus c/s : A. baumanii •Stool Rota virus antigen : Positive•TSC :S. maltophilia•H/C : NG

Anti CMV IgG positiveAnti CMV IgM positiveCMV viral load 79,800

-Transfer to PICU

-on ETT* 3 days - Vancomycin- Ciprofloxin- Gangcyclovir

- LPRC 10 ml/kg- Platelet 1U

Rota diarrhea with central line infection with hypovolemic and septic shock

38

CBC มิ'นาคมิ 2553Date 15 /3 17 /3 19 / 3 20/ 3 21/ 3 22/ 3 24/ 3 25/ 3 29/ 3 30/ 3 31/ 3

WBC(/mm3)

10,610

9,82015,79

022,59

07,700 5,460 5,800 6,290 9,520 7,890 8,250

N (%) 61 84 91 54 74 56.7 60 62 71 48 58.7

L(%)23.3 8 1 36.9 17 27.8 27 14 22 42 34.3

M(%)6.1 5 3 6.1 4 10 8 5 5 5 3

E(%)3.9 3 5 3 5 5.5 5 10 2 5 5

Hb (g/dl) 9.6 6

7.9▲

9.2▲

10 10 11.5 10.7 97.6▲

7▲

Hct (%) 30.7 28.2 25 28 30.4 30.6 34.8 32.8 26.8 24.4 21

Plt (/mm3)

39,000 6,000▲

50,000 38,000▲

28,000▲

53,000 11,000▲

74,000 24,000▲

21,000▲

77,000▲

31 /3/53

40

progressDate PE investigation Management

2-27/4/53 Extubationได็� ถื*ายลำด็ลำงเห์น�(อยน�อยลำง

V/S: stableLungs : crepitation both lungs Abd : soft , mild distension , active bowel soundSkin : petechial

CBC -Continue ganciclovir-Oxygen canular 0.5 LPM-PLT and PRC transfusion

41

Date 15/3/53 23/3/53 29/3/53 31/3/53 19/4/53 20/4/53

CMV viral load

52,800 79,800 13,300 4,680

CMV IgM neg pos pos

CMV IgG pos pos pos

Platelet 44,000 24,000 77,000 57,000

Ganciclovir start 25/3/53

Date  1 /4  2 /4  3 /4  4 /4  5 /4 6 /4 7 /4 10 /4 11 /4 16 /4 18 /4 22 /4 26 /4

WBC(/mm3)

5,430 6,04010,84

08,140 7,420 5,230 5,280 5,550 7,910 11,870 7,710 4,310 5,860

N (%)46 47 62 57.3 52 43 40 51 64 53 40 85 48.9

L(%)40 45 30 32 37 43 52 37 26 40 50 10 36.9

M(%)8 6 4 4.5 6 8 6 5 3 4 5 2 10.5

E(%)6 2 4 6 5 6 1 6 6 2 4 1 3

Hb (g/dl) 8.8 9 9 7.7

7.4▲

8.8 8.6 7.87▲

9.8 9.7 7.3 8.7

Hct (%) 25.7 27.5 28 24.2 23.3 28 25.4 24.6 22 29.8 30 21.3 24.7

Plt /mm3

 177,000

 93,000

 54,000

 27,000  19,000▲

109,000

80,000 12,000▲

59,000 11,000▲

57,000 26,000 22,000

43

2nd Bone marrow aspiration 19/4/53

Hypercellular marrow ,increase of megakaryocyte peripheral destruction

44

progressDate

PE investigation Management

1-27 พ.ค. 53

ท'(รพ.แห์*งห์น0(ง : อาการท�(วไป่ด็'ข้0&น ก�นได็� ไมิ*มิ'ไข้� ไมิ*เห์น�(อยSkin : erythematous papule at both cheeks , generalized petechiae at face , extremities , buccal mucosaAbd : soft , liver 3 cm BRCM , spleen 2cmBLCM

3/5/53: CMV viral load 1650 copies/ml 12/5/53 = 3120 copies/ml•eye and hearing exam: normal

3/5/53BMA: Normal cellular for age, increased megakaryocyte, normal myeloid and erythroid series, no blast, no histiocyte

เคยได็�เกรด็เลำ�อด็ -> CCI at 1 hr. =1,840

Continue Ganciclovir รวมิ 7 wks. off

-IVIG 5 gm (4,6/5/53) no response

-Platelet and PRC transfusion

-Prednisolone 1MKday(start 17/5/53)

Thrombocytopenia from immune process

45

progressDate PE investigation Management

CBC ก*อน refer กลำ�บัโรงพยาบัาลำจ�ฬา (23/5/53) Hb 11.2 g/dl Hct 30.7% MCV 81 fL WBC 10,500 /mm3 (N 42% L43% Mo 13% E 2%) Platelet 33,000/mm3 MPV 8 fL

27/5/53 ร�บั refer กลำ�บัมิาโรงพยาบัาลำจ�ฬา

CMV viral load: 57,600 copies/ml.

14/6/53 CMV viral load 5, 850 copies/ml

-Re-start Gangcyclovir

-Prednisolone 1.5 mg/kg/day

46

47

progressDate PE investigation Management

3/6/53

28/6/53

ฝ้<าข้าวท'(ลำ�&น แลำะผู้�(นท'(ก�น

มิ'ไข้� ห์อบัเห์น�(อย Lungs :tachypnea, mild subcostal retraction

KOH: positive

CBC : Hb 8 g/dl Hct 24% WBC8,770/ mm3

(N29% L 60% Mo3.5%Eo7.5%) Plt 48,000/mm3

H/C : NGCXR

-Nystatin oral qid-Cotrimazole cream -Start Fluconazole 6 MKday x 7day

-IVIG 2.5 gm. (3/6/53)

-On O2 box 5 LPM-Meropenam- LPRC

Oral candidiasis and skin candidiasis

Pneumonia

48

CXR

49

CBC เด็�อน พ.ค.-มิ�.ย.

Date 27/5 31/5 7/6 12/6 20/6 26/6 28/6 1/7 8/7 9/7

WBC(/mm3) 14,500 7,760 8,730 6,610 7,120 6,900 8,870 4,730 7,780 6,370

N (%)78 71 65 53 48 48.4 29 57 60 47

L(%)15 5 29 38 43 42 60 27 30 47

M(%)3 13 3 5 4 6 3.5 6 5 3

E(%)4 11 3 3 4 4 7.5 10 5 3

Hb (g/dl) 10.2 10.4 9

8▲

106.6▲

8▲

10.5 9.4 9

Hct (%)29 30 26.8 25 30 19 24 31 28.2 27.3

Plt /mm3

13,000 21,000 22,000 9,00011,000

▲91,000 48,000

8,000▲

122,000 70,000

IVIG 2.5 gm. 3/6/53

50

CMV viral load and platelet count

23/3 29/3 31/3 19/4 20/4 3/5 12/5 31/5 14/6 28/6

CMV viral load 52,800 79,800 13,300 4,680 1,650 3,120 57,600 5,850 688

Anti-CMV IgG pos pos pos

Anti-CMV IgM neg

Pos(0.4)

Pos(0.6)

Platelet 11,000 24,000 77,000 57,000 26,000 - - 13,000 11,000 48,000

Ganciclovir (23/3-12/5)

Re-start 31/5

51

CMV viral load and platelet count

12/7 22/7 2/8 16/8 8/10 19/10 27/10

CMV viral load 2,160 1,380 833 1,120 900 5,320 5,190

Anti-CMV IgG

Anti-CMV IgM

Platelet 25,000 22,000 13,000 5,000 33,000 13,000 6,000

Ganciclovir (31/5-25/8)

25/3/53 31/3/53 22/4/53

CMV infection Rota diarrhea +Pneumonia Phlebitis lt.foot

27/5/53 3/6/53 30/6/53

CMV infection Oral candidiasis Pneumonia

Skin candidiasis

15/3/53 19/3/53 23/3/53

Pneumonia Respiratory failure Systemic fungal with septic shock infection

53

Problem lists

Multiple infection CMV infection Recurrent pneumonia with respiratory failure with sepsis

Systemic candida infection Persistent Thrombocytopenia Eczema

IMMUNODEFICIENCY ∞

WISKOTT-ALDRICH SYNDROME

55

Investigation

Complete blood count Absolute lymphocyte count = 2,493 /mm3

Absolute neutrophil count = 6,472 /mm3

Platelet count =39,000 MPV = 7 fL

56

Screening test for B-cell defects IgG 1140 (normal 340 +/- 119) IgM 59.1 (normal 30 +/- 11) IgA 113 (normal 21 +/- 13) Total IgE 3,750 (<15)

57

Screening test for T-Cell defect Absolute lymphocyte count = 2,493 /mm3

Candida albican intradermal skin test positive

PHA : impair T-cell function Screening test for phagocytic cell defects

Absolute neutrophil count = 6,472 Respiratory burst assay : DHR assay normal

Screening test for complement deficiency CH50 =14.6 (19-40 U/ml)

58

Flow cytometry %CD3 (Total T lymphocyte) 79% (55-

78%) %CD4 (Helper/inducer T lymphocyte)11% (21-64 %) %CD8 (Suppressor/cytotoxic T lymphocyte)

57%(16-35%) %CD 19 (B cell) 2% (7.7-25.4) %CD 56 (NK cell) 18% (10.6 +/- 5.4)

Combine T-cell and B-cell defect

60

Combine T-cell and B-cell defect Primary immune defect

Severe combined immunodeficiency (SCID) Ataxia-Telangiectasia syndrome (AT) Wiskott-Aldrich syndrome (WAS) Reticular dysgenesis

Secondary immune defect CMV infection

61

Suspected combine T-Cell and B-Cell defect

Persistent thrombocytopenia Eczema

Wiskott-Aldrich syndrome (WAS)

63

64

Wiskott-Aldrich syndrome

1st described by Wiskott in 1937 and was further characterized by Aldrich in 1954.

1 in 250,000 live male births X-linked recessive immunodeficiency

disorder characterized by the triad of recurrent bacterial sinopulmonary

infections eczema (atopic like dermatitis) bleeding diathesis caused by

thrombocytopenia and platelet dysfunction. Pediatr. Dec 1994;125(6 Pt 1):876-85

65

Wiskott-Aldrich syndrome

only 30% of patients with the syndrome have the classic triad 90% of patients have manifestations of

thrombocytopenia at presentation 20% have only hematologic abnormalities 5% have only infectious manifestations,

Mol There. May 2008;16(5):836-44.

66

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome gene localized to Xp11.22-23 consists of 12 exons encode a 502 amino acid (53 kD) protein

Wiskott–Aldrich syndrome protein (WASP) WASP

signal transduction and regulates actin filament assembly

explains the abnormalities in platelet and lymphocyte cytoskeleton and signaling.

J Leukoc Biol. Jun 2005;77(6):993-8.

67

Clinical manifestations

The first clinical signs are petechiae and ecchymosis of the skin and oral mucosa and bloody diarrhea.

One series of 154 patients found petechiae or purpura in 78% serious GI bleeding (hematemesis or

melena) in 28% epistaxis in 16% intracranial bleeding in 2% of patients.

J Pediatr. Dec 1994;125(6 Pt 1):876-85.

68

Hematologic Findings in WAS

Thrombocytopenia (platelet count 10,000–100,000/mm3);

Microthrombocytes; low mean platelet volume (MPV).(This is not obvious in the newborn and the MPV is unreliable when the platelet count is low.)

Platelets have abnormal aggregation in response to agonists such as ADP, epinephrine and collagen.

Platelets have reduced platelet survival to half normal.

Ineffective megakaryocytopoiesis reflected by a platelet turnover 25% that of normal megakaryocyte mass.

69

Hematologic Findings in WAS

Anemia (due to blood loss).

Leukocytosis (due to infection). Normal or increased megakaryocytes.

70

Normal platelets

Small platelets

71

Other ManifestationsOther Manifestations

Autoimmune manifestations Hemolytic anemia Vasculitis Inflammatory bowel disease Glomerulonephritis Arthritis

Malignancies: adolescents, young adults The most common malignancy

is non-Hodgkin lymphoma.

72

Diagnostic tests; immunologicDiagnostic tests; immunologic

Decrease CD3, CD4, CD8 T-cell Normal B-cell and NK cell Markedly decreased/ Absent

isohemagglutinins (PHA) Decreased IgM Normal/ slightly low IgG Normal/ Elevated IgA, IgE Defective production of pneumococcal Ab Depressed lymphocyte response to

mitogens

73

Treatment

Allogeneic SCT is treatment of choice when matched donor available.

If no matched donor is available the patient should be managed as follows:

Aggressive treatment of infections

Platelet transfusions for hemorrhagic episodes

Steroid cream for eczema

Splenectomy, reserved only for severe case with usual pre- and post-splenectomy precautions pertain

Thrombopoietic agents are being explored.

74

Thank you for your attention