Glioblastomaの浸潤・伸展

矢印のごとく神経路に沿った細胞の伸展が認められる

悪性脳腫瘍（グリオーマ）に対する中川らによる新規開発治療抗癌剤による化学療法
1. VP-16 + CDDPによる超選択的動注化学療法
Super selective Intraarterial chemotherapy by using microcathter

2. FdUrdによる腫瘍腔内化学療法
Radiation Therapy
1. I-MRTによる放射線療法

その他
1. Sodium Butyrateによる持続腫瘍腔内あるいは髄腔内投与療法
2. IL-2の動注療法

癌生髄膜炎に対する中川らによる新しい治療の試み
1. Low-dose MTXー1 mg x 2 / day
J Neurooncol 13: 81-89, 1992
2. Ventriculo-Lumbar Perfusion Chemotherapy with MTX & Ara-C
Surg Neurol 45: 256-64, I996
3.Continuous Intrathecal Infusion of MTX
4.Treatment of meningeal carcinomatosis resistant to MTX (MTX + 6TG, Verapamil)
90th AACR、1999, Philadelphia
5. Repeated bolus administration of 5 Fluoro-2’-deoxyuridine (FdUrd)
J Neurooncol 37: 115-121, 1998;

J Neurooncol 45: 175-183, 1999

Cancer Chemother Pharmac 43:247-256, 1998
6. Continuous intrathecal administration of FdUrd
Neurosurgery57:266-280,2005
7. Continuous intrathecal administration of Sodium Butyrate (NaB)
95th AACR, 2004, Orlando; 96th AACR, 2005,Anaheim, ICACT,2006,Paris; ECCO 15/ESMO 34,2009,Berlin;
43rd ASCO,2007,Ghicago

8. NS-101 (DepoCyte:Cytarabine徐放剤)による髄膜癌腫症の治療-Phase I癌と化学療法 34：1799-1805, 2007
9 .Basic research for intrathecal administration of Y-27632 (Rock inhibitor)
Mol Cancer Res 3:425-433, 2005

Leptomeningeal carcinomatosis

Survival in 34 patients with meningeal carcinomatosis(1984~1990)
Ommaya Reservoir

ventricle

Treatment

Number of cases

No treatment

5

MST (days) (mean ± SEM)
18 ± 3 (11-30)

IT only*** 11177 ± 41 (20-436)

IT + SC128 ± 32 (34-485)

IT + RT** 8* 4

IT + SC + RT

* 6

118 ± 33 (20-215)

249 ± 72 (150-461)

IT: intrathecal chemotherapy with MTX and/or Ara-C
SC:systemic chemotherapy, RT: radiation therapy*, P<0.05; **, p<0.001; ***, p<0.005

Ventriculolumbar perfusion chemotherapy (VLP) with MTX & Ara-C

Nakagawa H, et al.:Ventriculolumbar perfusion chemotherapy with methotrexate andcytosine arabinoside for meningeal carcinomatosis: A pilot study in 13 patients.

Surg Neurol 45: 256-64, I996

Ommaya Reservoir

Clinical response to ventriculolumbar perfusion (VLP) chemotherapy***
Response Survival
Responding
Pt. cranial spinal Ambulatory Status CSF
time(months)
post
No. nerves roots preexamination CSF parameters grade
good

12.0

no response

minor

8.0

bedridden bedriddenno response

none

3.0

2/2

walking(a) walking(a)responsemoderate

7.0

2/2

2/3

walking(a) walking(a)response

Ce

minor

7.0

1/2

1/2

bedridden bedridden

normalizationCe, BG, Cy

moderate

4.0

6/6

2/2

bedridden walking

normalizationCe, BG, Cy, MBP

good

6.0

1/1

3/3

walking(a) walking

normalizationCe, BG, Cy, MBP

good

18.0

9.
10.

0/5

0/4

bedridden bedridden

slight response

Ce

none

4.0

6/13

3/3

walking(a) walking

normalizationCe, BG, Cy, MBP

good

9.0

11.

4/6

3/3

bedridden walking

response

Ce, BG

moderate

6.0

12.

8/10

1/2

walkingwalking

normalizationCe, BG, Cy, MBP

good

1.0

13.

2/2

0/0

walkingwalking

response

Ce, BG, MBP

good

8.0

1.
2.

5/7

3/3

bedridden walking

5/5

1/1

walking

3.

1/9

0/2

4.

1/2

5.
6.
7.
8.

walking

normalizationCe, BG, Cy

BG, Cy* No. of improved cranial nerves** No. of improved spinal root signs (motor, sensory ,tendon reflex, urinary incontinence : total, 4 / no. of involved spinal roots.
Ce, cell count; BG, beta-glucuronidase; Cy, cytology; MBP, myelin basic protein

Clinical response to ventriculolumbar perfusion (VLP) chemotherapy

1. Ambulatory status
walking with assist ~bedridden
2. Improved cranial nerves

walking : 5 / 7: 12 / 13

3. Improved spinal roots signs : 10 / 13
4. CSF examination
normalization : 6
response : 5
no response : 2

5. Survival time : 1 ~ 18 months , 7.2 ± 1.2 months (M± SEM) (n=13)
Remission period : 0 ~ 13 months , 4.0 ± 1.0 (M ± SEM) (n=13)

Bolus or Continuous Intrathecal Administration of 5fluoro- 2-deoxyuridine (FdUrd)
Basic

Yamada M, Nakagawa H, et al.: In vitro study on intrathecal use of 5-fluoro-2’- deoxyuridine(FdUrd) for meningeal dissemination of malignant brain tumors. J Neurooncol 37: 115-121, 1998

clinicalNakagawa H, et al. : Clinical trial of intrathecal administration of 5-fluoro- 2’-deoxyuridine
for treatment of meningeal dissemination of malignant tumors.
J Neurooncol 45: 175-183, 1999
Nakagawa H, et al. : Continuous intrathecal administration of 5-fluoro-2’-deoxyuridine
for the treatment of neoplstic meningitis. Neurosurgery 57:266-280, 2005.

Survival of Patients with Leptomeningeal Carcinomatosis treated byContinuous Intrathecal Chemotherapy with FdUrd-Comparison with theHistorical Control (the survival of patients treated with MTX and Ara-C)
1

0.9
0.8
0.7
0.6
0.5

%Svuoarfli

0.4
0.3
0.2
0.1
0
0

100

200

300

400
days

500

600

700

Historical control:the patients were treated by bolus intrathecal administrationof MTX (5 mg) and Ara-C (20 mg) twice a weekResults
1. No apparent toxicity has been observed to date.
2. Evidence of CSF response was observed in 13 pts.
3. Headache and nausea was improved in all pts and cranial nerve
impairment was improved in 12 pts.
4. MR image response was observed in 5 pts.
5. Overall response was observed in 14 pts when cases of stable disease were excluded
from the responding cases.
6. Survival time (mean ±sem days, n) was 251±30, 25. The survival times in
pts with and without WBI were 182±37, 8 and 285±39, 17, respectively(p=0.057).

Conclusion
Continuous intrathecal administration of FdUrd, when a subcutaneously
implantable infusion pump is available, may be useful for the treatment of
leptomeningeal carcinomatosis, especially for maintenance therapy in outpatients,
although WBI seems to cause adverse effects.
Further studies in larger populations are necessary to properly evaluate thebenefits of continuous intrathecal FdUrd chemotherapy.

Clinical Trial of Continuous Intrathecal Administration of
Sodium Butyrate in Leptomeningeal Carcinomatosis
Sodium butyrate has been expected to be clinically useful because of its effects on cellular differentiation
and apoptosis and its inhibition of invasion with minimal effects on metabolism since sodium butyrate ispresent at high concentrations in the membrane of the intestine as a metabolite of food.

Basic Research

Nakagawa H, et al. : Intrathecal or intracavitary administration of sodium butyrate
totreat
neoplastic
meningitis
andmalignantglioma.
95th AACR, Orlando, USA, March, 2004

Clinical Trial

Nakagawa H, et al. : Clinical trial of continuous intrathecal or intracavitary infusion of
sodium butyrate for leptomeningeal carcinomatosis or recurrent malignant glioma.
96th AACR, Anaheim,CA, USA, April 16-20, 2005
Nakagawa H, et al. : Clinical trial of continuous intrathecal or intracavitary infusion of
sodium butyrate for recurrent or progressive malignant glioma.
98th ASCO, Chicago ,IL, USA, June 1-5, 2007

Patient 1 : spinal dissemination derived from esophageal cancer

Spinal MRI at the commencement ofContinuous IT of NaB

One month later

Improved points: pain -free from morphine hydrochloride and pentazocine

Neurological Improvements

No. of
cells

50

10
CSF CEAHeadache, nausea
Back pain
Rt.oculomotor palsy
Rt. abducens palsy
Bulbar palsy
Hearing disturbanceDisturbed consciousness

convulsion
5
CSF CEA<0.1 ng/ml

2W
Commencement of
intrathecal administration

Patient 2 :breast cancer

4w

6W
Negative cytologicalconversion

Results of continuous intrathecal infusion of sodium butyrate in patientswith leptomeningeal carcinomatosis
Pt.
No.

CSF
Response

Improved Symptoms& Signs

Responseon MRI

Adverse effects &complications

PFS(months)

Survival(months)1

reponseresponse2

response

pain relief
cranial nerves
meningeal signs
increased appetite
increased activity

none

2.5

2.5 deadstablenone

2.0

2.0 deadheadacheno response

cauda equina syndrome

stableconvulsion0

11.0 dead4

response

cranial nerve (rt.NV)
diplopia, taste

stableloss of appetite

4.0

4.0 dead5

responseheadachestablebacterial meningitis

3.0 <4.0 dead6g

responselevel of consciousness

stableconvulsion

5.0 <38.0 dead7g

response

18.0

28.0 alive

8g

responsenone

no response bacterial meningitis

0

5.0 deadg

response

none

response

7.0

15.0 dead3

9level of consciousness

ataxic respiration

responseg, malignant glioma, PFS, progression free survival

bradycardia

convulsionnoneNS-101(DepoCyt)による髄膜癌腫症(癌性髄膜炎)の治療-Phase I studycytarabine liposome injection
化学名：
4-Amino-1-β-D-arabinofuranosylpyrimidin-2(1H)-one

分子式：C9H13N3O5
分子量：243.22
2週間に1回投与で有効濃度を維持することが可能
中川b秀光、その他：NS-101 (DepoCyte:Cytarabine徐放剤)による髄膜癌腫症の治療-Phase I癌と化学療法 34：1799-1805, 2007

外国における承認状況
国

承認、適応

米国
（FDA）

1999.4.1 承認 （Accelerated Approval）
リンパ腫由来の髄膜癌腫症
intrathecal treatment of lymphomatous meningitis

カナダ
（TPP）

1999.11.17 承認
固形腫瘍及びリンパ腫由来の髄膜癌腫症
intrathecal management of neoplastic meningitis due tosolid tumours or lymphoma

EU
2001.7.11 承認 （中央審査方式）（EMEA） リンパ腫由来の髄膜癌腫症
intrathecal treatment of lymphomatous meningitis.
In the majority of patients such treatment will be part ofsymptomatic palliation of the disease

Time course of Ara-C
Concentration in CSF
遊離シタラビン濃度 ○：脳室より採取

Free Ara-C Conentration (ng/mL)△：腰椎より採取

100000

Cycle 2

Cycle 1

10000

1000

100

Therapeutic level
10

投与

1

投与

5

10

15

20

投与後の経過日数25Results of Phase I Study of NS-101
1. CSF Concentrations of Free Ara-C andEncapsulated Ara-C at 2 wks : > 20 ng/ml

2. CSF: CR, 2; PR, 6; NC, 0; PD, 0; NE, 1

3. Clinical Effects: Response, 5(4) ; No response, 2 ; NE, 2
4. MRI: Improved, 1 ; No Change, 6 ; Progressive, 1

5. Adeverse Effects: Grade-1, 4Grade-2, 6
Grade-3, 3
Grade-4, 0

Intrathecal administration of Y-27632 (Rock inhibitor)
LPA

Rho-Family Protein and Y-27632
Rho

Y-27632
N

NHCO・・・

C3 exoenzyme

CHNH2
CH3

Rho kinase (ROCK)Y-27632

MLC20-phosphorylator

KT-5926

Tumor invasion
Nakagawa H, et al. : Intrathecal administration of Y-2732, a specific Rho-associated kinase inhibitor, for rat
neoplastic meningitis. Mol Cancer Res 3: 425-433, 2005.

Infiltrated cells

A

0

5

10

20

40

Y-27632 (M)

Control

10 M Y-27632

投稿論文の表紙になったAnti-tumor effects of continuous intrathecal injections of Y-27632 on rat
leptomeningeal carcinomatosis using Walker 256 carcinoma cells

Histological appearances at 14 days after tumor inoculation

Nakagawa H, ET AL: Selective intra-arterial chemotherapy with a combination of
etoposide and cisplatin for malignant gliomas. Surg Neurol 41 : 19-27, 1994

m3-Micro-Multileaf Collimator (Brain LAB社製)% of survival
△ ○
△

○
△ ○
△ ○
○
△
○
△
○
△
△
△
△
△
△

SRT群:487±84日
convent.ional RT群:326±40日

Logrank, p=0.0648)

○
○
○
○
○
△

○

days
中川秀光：先端医療シリーズ18・脳神経外科,脳腫瘍の最新医療、高倉公朋監修、第6章
放射線治療、4.マイクロマルチリーフ照射、pp.203-209, 2003、先端医療技術研究所発行。
中川秀光、西山謹司：マイクロマルチリーフ療法、Clinical Neuroscience 21:566-567, 2003.

5-fluoro-2’-deoxy uridine (FdUrd)の基礎から臨床Intrathecal administration of FdUrdで米国特許収得
Concentrations of FdUrd in tumor and surrounding brain after intracavitary injection of FdUrd

Time after injection

FdUrd

A

31.8 ng/g

B

7.7

C

73.6

D

9.9

E

3.4

F

0.8

Ten microgram of FdUrd was injected and the breadth of tissues sampled were 5.0 mm.
FdUrd was not detected in the plasma during the course of therapy
Nakagawa H, et al.: Clinical trial of intrathecal administration of 5-fluoro- 2’-deoxyuridine for treatmentof meningeal dissemination of malignant tumors. J Neurooncol 45: 175-183, 1999
Nakagawa H, et al: Intracavitary chemotherapy with 5-fluoro-2'-deoxyuridine (FdUrd) in malignant
brain tumors. Jpn J Clin Oncol 31: 251-258, 2001

Remodeling of postoperative cavity to closed cavity for intracavitarychemotherapy with FdUrd
galea aponeurotica

post-removal cavity

coated with fibrin grueStudy Population
Other
therapy

Result

none

PR

none

stable1 x 10chemo + Ra

recurrent anaplastic astrocytoma

1 x 25

none

N.E.
CR

57/F

metastatic brain tumor (breast)

5 x 21none

CR

6 S.H.

42/F

metastatic brain tumor (ovary)

none

PD

7 M.U.

53/F

glioblastomanone

8 K.K.

24/F

glioblastoma

5 x 1310 x 305 x 50none

PDstable9 K.K.
10 K.F.

recurrent glioblastoma

5 x 25none

PDglioblastoma

5 x 29RaCR

11 T.H.

58/F
60/F
63/M

metastatic brain tumor (lung)5 x 25none

CR

12 H.T.

59/M

malignant change (glioblastoma)

5 x 38Ra

CR

Pt.No.

Age/Sex

Diagnosis

Dose(μg) X Times

1 S.U.

68/F

glioblastoma

2 S.H.

59/F

metastatic brain tumor (lung)1 x 252 x 25

3 T.O.

61/M

metastatic brain tumor (lung)

4 O.T.

50/M

5 K.E.

pre-chemotherapy

1. S.U.

4.O.T.

5.K.E.

post-chemotherapy

pre-chemotherapy

8.K.K.

10. H.F.

12.HT

post-chemotherapy

Nakagawa H,et al.: Experimental study on the effect of intracarotid recombinant IL-2 on brain capillary permeability of Gd-DTPA in ENUinduced rat glioma model-dynamic study using animal MRI system- 97th Anual Meeting of Ameican Society of Cancer Research,
Washington DC, USA, April 1-5, 2006

Measurements of Signal Intensity in Brain Tumor and Surrounding Brain

T: solid region
N: necrotic region
B: surrounding brain
T: tumor
B
T
N

B
B

Signal intensity of tumor was measured in solid region of the tumor and signal intensityof surrounding brain was expressed as a mean value of the three regions.

Pre-treatment

Post-treatment

Histological findings of surgical specimensfrom patient with preoperative IL-2 injection

Routine treatment
Latest Standard Therapy for Malignant Glioma: Surgery + Chemotherapy + Radiation

Chemotherapy (temozolomide)(1999)(Malcolm Stevens: Aston Univ. Birmingham)
A dervative of imidazotetrazine(dacarbazine)
Therapeutic benefit depends on the ability to alkylate / methylate DNA
Epigenetic silencing of MGMT, AGT or AGAT gene prevent the synthesis of the enzyme
DNA repaie enzyme: O6-methylguanine-DNA methyltransferase(MGMT)*MGMT陰性例で腫瘍縮小効果が著明であるのに比して陽性例は効果が見られない（MGMT methylation did predict improved overall survival (23.2 versus 14.3 months,
P<0.001) and PFS (14.1 versus 8.2 months, P<0.001).

How to overcome over-expression of MGMT*STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT
Expression (北海道大学）、proteosome inhibitor MG132も関与？
*Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells (U138, LN18
and T98G) to temozolomide. Neuro-Oncol 12:917-927, 2010
*Glycogen synthase kinase 3β inhibition sensitizes human glioblastoma cells to temozolomide by affecting
O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling*A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect oftemozolomide*anti-MGMT sh(short hairpin)RNA therapy*HDAC inhibitor*DNA-PK inhibitor NU7026: knock down Rad51 or BRCA2->MGMT減少

Sodium Butyrate (酪酸ナトリウム）について
1.Sodium butyrate (NaB：酪酸ナトリウム)は自然に存在する単鎖飽和脂肪酸であり培養系で種々の腫瘍細胞の成長抑制、遺伝子変換や分化の促進に使用されてきた。食物の代謝物質として人腸管膜の細胞や門脈血中に高濃度に存在するが故に、この薬剤の悪性腫瘍細胞の分化の促進からアポトーシス,および少ない代謝への影響と腫瘍細胞の浸潤抑制効果を期待した臨床応用が期待されてきた。しかしながら血中におけるその半
減期は6分と短く、その効果は可逆性であるが故に標的腫瘍で効果を発揮するには有効濃度での持続投与が必要になる。一方髄液腔での半減期は血清におけるよりも長いことが推測される。
2.細胞周期抑制蛋白であるp21 と p27がsodium butyrateによって増加する。

3.Sodium butyrate はmM濃度で形態学的にもそしてbiochemicalな変化を可逆性にもたらす。主な直接的な効果はhistone deacetylase 酵素を抑制し、その結果histonecore
蛋白のhyperacetylation をもたらすとされている。そしてhistone deacetylase 抑制の機序はprotein phosphatase の導入がありうると考えられている.
3.ヒトretinoblastomaの培養系での vincristine, cisplatin あるいはcamptothecinのsodium butyrate による抗腫瘍効果増強が報告され、種々の機序の可能性が推測されている。
4.Sodium butyrate は放射線との相乗効果を示す。

Sodium Butyrate(NaB)の持続的腫瘍腔内投与療法
NaBはin vitroで濃度依存性に殺細胞効果を示し、ラット癌性髄膜炎モデルで同様の効果を示
し、in vitroでは初代神経培養および星細胞培養にて極めて少ない毒性を示し、 またWalker 256細胞やヒトA-172神経膠芽腫細胞での浸潤抑制効果を報告した。これらの結果
より、NaBの髄腔内あるいは腫瘍腔内の持続投与は悪性神経膠腫ならびに癌制髄膜炎のよい治療法になることが示された。これらの結果をもって当院倫理委員会に臨床応用を申請し、その許諾をもって試験を開始した。
1.Nakagawa H, : Intrathecal or intracavitary administration of sodium butyrate to treat neoplastic meningitis and malignant glioma. 95th
Anual Meeting of AACR, Orlando, USA, March, 2004
2. Nakagawa H: Clinical trial of continuous intrathecal or intracavitary infusion of sodium butyrate for leptomeningeal carcinomatosis orrecurrent malignant glioma. 96th Anual Meeting of Ameican Society of Cancer Research, Anaheim,CA, USA, April 16-20, 2005
3. Nakagawa H,: Intrathecal or intracavitary administration of sodium butyrate in patients with malignant glioma-Basic research andClinical trial. 17th International Congress on Anti-Cancer Treatment (ICACT), Paris, France, January 30~Feb.2, 2006.
4. H Nakagawa, : Clinical results of continuous intrathecal or intracavitary administration of sodium butyrate for patients with recurrent
and progressive malignant glioma. Experience with 23 cases 43rd Annual Meeting of American Society of Clinical Oncology (ASCO), June
1-5, 2007, MacCormic Place, Chicago, IL, USA
5. Nakagawa H:Evaluation of immunoreactivity of monocarboxylate transporter (MCT) 1 in recurrent and progressive malignant
glioma(MG): Speculation of the favorable factor in immunoreactivity in the response to the continuous intrathecal infusion of sodium
butyrate (NaB). April 12-16, 2008,SanDiego, Ca
6. Nakagawa H:Correlation between immunoreactivity of monocarboxylate transporter 1 in malignant glioma and tumor response tocontinuous intrathecal infusion of sodium butyrate , ECCO15-ESMO34, September 20-24, Berlin, Germany,2009
Association for Cell Biology. Philadelphia, PA, December 11~15, 2010
7. Nakagawa H :Intrathecal Sodium Butyrate for Neoplastic Meningitis- Experimental Study and Clinical Trial Stockholm, Sweden,
September 23~27, 2011.
8.Kazuyuki Itoh and Hidemitsu Nakagawa: Sodium butyrate induced cellular senescence and inhibited invasion of cancer cells with
distinct mechanism. AACR 2013, 6-10, Washington DC, USAMorphological changes induced bysodium butyrate (SB) in Walker 256 cells

Red: F-actin Green: vinculin Blue: DAPIBar : 20 m

Clinical procedure for continuous intracavitary administrations of
sodium butyrate for recurrent or progressive malignant glioma
Infusion Tube

Ommaya Reservoir

Tumor

NaB infusion
Sodiumbutyrate

OmmayaReservoir

Baxter 7 day Infusor)
MRI port
60mM NaB

Case 6 : anaplastic
astrocytoma
BeforeControlled respiration by
respirator

3.0 mos.

Possible oral intake

9.0 mos.

13.0 mos.
response, PFS:>13.0 mos

Case 9: anaplastic astrocytoma
before

2.5 mos.

5.0 mos.

8.0 mos.

10.0 mos.

13.0 mos.

Case 14: glioblastoma

Before2.0 mos.

3.0 mos.

4.0 mos.

5.0 mos.

6.0 mos.

Fig.8
Case 3: AA with CSF disseminationof tumor cells
◯

◯

□

□

No. of cells

lumbar CSF
ventricular CSF

◯

50□
□

◯

10

start
cytology +

◯
□

□

◯
□

◯

◯
□

◯

□
◯

□

□

2W

4W

6 W 2.0 mos.

3.0 mos.

4.0 mos.

5.0 mos.

+

+

+

+

(-)

+ (-)

(-)

◯
□

□

◯

◯
□

□

(-)

20.0 mos.

Response to continuous intrathecal NaB infusion in 5 patientswith cerebrospinal fluid dissemination of tumor cells.
No. of cells (/mm3)
100

○
○

50

○

○

○

before○○○○Ventricular CSF○○

Lumbar CSF

○
○
○
○

dead

○
○ dead ○

○

○

○

○
○○

○
○
○

○

○
○
○
○
○

2

○
○
○
○
○
○

○
○
○
○
○

○
○

○
○
○
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4
(months)

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6

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8

結論
４０年程前に新しいニトロソウレア系抗癌剤としてBCNU,CCNU,MeCCNUの出現が見られ、本邦でもACNUの出現にて若年齢の症例で神経膠芽腫の長期生存例が見られるようになった。われわれも３８、３５、３４、２５年の長期生存例を経験しているが、いずれもACNUと放射線療法を行った例で、２０歳前後の若い年齢である以外特別な長期生存のfactorは発見できない。長期生存例の出現にかかわらず、平均生存期間については４０年前の１年から１年6ヶ月程に延長したにすぎない。今後、手術摘出度の向上、新しい角度からの治療法や遺伝子解析からの分子標的治療の出現の芽がでてきており、今後４０年後には平均生存期間は数年になっていることを期待する。