Accepted Manuscript
Multiple brain metastases from pancreatic adenocarcinoma presenting with
simultaneous intratumoral hemorrhages: A case report
Satoshi Matsuo, MD, PhD, Toshiyuki Amano, MD, PhD, Shigeto Kawauchi, MD, PhD,
Akira Nakamizo, MD, PhD
PII:

S1878-8750(18)32859-6

DOI:

https://doi.org/10.1016/j.wneu.2018.12.036

Reference:

WNEU 10982

To appear in:

World Neurosurgery

Received Date: 10 October 2018
Accepted Date: 5 December 2018

Please cite this article as: Matsuo S, Amano T, Kawauchi S, Nakamizo A, Multiple brain metastases
from pancreatic adenocarcinoma presenting with simultaneous intratumoral hemorrhages: A case report,
World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2018.12.036.
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Multiple brain metastases from pancreatic adenocarcinoma presenting with simultaneous

intratumoral hemorrhages: A case report

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Satoshi Matsuo, MD, PhDa, Toshiyuki Amano, MD, PhDa, Shigeto Kawauchi, MD, PhDb, Akira Nakamizo,

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MD, PhDa

Kyushu Medical Center, Fukuoka, Japan

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Declarations of interest: None.

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Departments of aNeurosurgery and bPathology, Clinical Research Institute, National Hospital Organization

Address all correspondence to: Satoshi Matsuo, MD, PhD

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Department of Neurosurgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical

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Center, 1-8-1 Jigyo-hama, Fukuoka 810-8563, Japan

TEL: +81-92-852-0700; FAX: +81-92-846-8485; E-mail: smatsuo1979@gmail.com

Keywords: Intratumoral hemorrhage, Metastatic brain tumor, Pancreatic adenocarcinoma

Abbreviation List: CT, computed tomography; MRI, magnetic resonance imaging

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Abstract
Background

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Pancreatic adenocarcinoma rarely metastasizes to the brain, and the clinical features of brain metastasis in

such cases remain elusive. To the best of our knowledge, only 21 cases of brain metastasis from pancreatic

adenocarcinoma have been previously reported in the English-language literature.

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Case Description

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One year 4 months before the current admission, a 61-year-old woman was diagnosed with pancreatic

adenocarcinoma and began chemotherapy. Three days before the current admission, she developed acute

dysarthria. She was referred to a cancer center, where neuroradiological examination revealed multiple

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metastatic brain tumors, including a 30-mm-diameter tumor in the right cerebellar region. She was

transferred to our institute. Three days after admission, she developed sudden-onset disturbance of

consciousness and left hemiparesis. Head computed tomography and magnetic resonance imaging showed

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that the multiple metastatic lesions had increased in size with the development of intratumoral hemorrhage

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and obstructive hydrocephalus. She underwent urgent removal of the tumor in the cerebellum. The

obstructive hydrocephalus was relieved and her consciousness improved immediately after the surgery.

She was transferred to the palliative care unit of the cancer center and died under hospice care 3 weeks

after the surgery.

Conclusions

This case demonstrates that brain metastases from pancreatic adenocarcinoma can enlarge suddenly and

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simultaneously by intratumoral hemorrhage even without coagulation disorders, resulting in neurological

deterioration in a short time. Surgical resection of metastatic brain lesions from pancreatic adenocarcinoma

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improve the patient’s quality of life in selected cases.

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has an extremely limited role, but such treatment can remove the neurological symptoms and temporarily

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Introduction
Pancreatic adenocarcinoma is a relentlessly progressive and fatal disease with an overall 5-year survival

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rate of <5%.1 Because of the absence of early signs or characteristic symptoms, most patients with

pancreatic adenocarcinoma present with metastatic disease involving the lymph nodes, liver, peritoneum,
lungs, or bone at the time of diagnosis.1,2 Pancreatic adenocarcinoma can metastasize to the central

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nervous system, but this is quite rare.2,3 Due to recent advancements in the treatment of pancreatic cancer,

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the incidence of brain metastasis in such patients may be increasing.4

We herein describe a case of multiple brain metastases from pancreatic adenocarcinoma that

progressively enlarged by intratumoral hemorrhage and were treated surgically. To our knowledge, this is

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the first report of a patient with multiple hemorrhagic brain metastases that progressively and

Case report

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simultaneously enlarged within a short time.

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One year 4 months before the present admission, a 61-year-old woman was found to have a tumor in the

tail of the pancreas with ascites. Cytological analysis of the ascites led to a diagnosis of pancreatic

adenocarcinoma. She underwent multi-agent systemic chemotherapy regimens involving gemcitabine,

nab-paclitaxel, and S-1 (tegafur, gimeracil, and oteracil potassium). Three months before the present

admission, she developed difficulty breathing, and chest computed tomography (CT) showed that the

pleural effusion was due to carcinomatous pleurisy. After the patient underwent a modified FOLFIRINOX

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regimen, her pleural effusion resolved and her dyspnea was relieved. Three days before the current

admission, she presented to an emergency department with acute onset of dysarthria. Head CT and

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magnetic resonance imaging (MRI) showed multiple lesions, including a 3-cm cerebellar lesion (Fig. 1). A
prognosis of at least a few months was predicted despite the presence of carcinomatous peritonitis and

pleurisy and liver and brain metastases. Palliative whole-brain radiation was planned; however, the patient

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and her family expressed their desire to pursue treatment as long as she could tolerate it. On admission, her

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mental status was alert and she exhibited mild dysarthria. Laboratory data revealed no thrombocytopenia

or blood coagulation disorders (platelet count, 299 × 103/L; activated partial thromboplastin time, 22.8 s;

prothrombin time–international normalized ratio, 1.11). Suboccipital craniotomy with resection of the

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tumors in the cerebellum was planned to avoid obstructive hydrocephalus and brain stem compression

induced by the enlargement of the lesions. Three days after admission, she developed a sudden disturbance

of consciousness (Glasgow coma scale score of E3V3M6) and left hemiparesis. CT and MRI showed that

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the multiple metastatic lesions in the initial imaging studies had increased in size with intratumor

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hemorrhage and obstructive hydrocephalus (Fig. 2). After a lengthy discussion regarding the extent of her
disease and the prognosis, the patient’s family expressed their desire to pursue treatment as long as she

could tolerate it. She underwent removal of the tumors in the cerebellum through a suboccipital craniotomy,

and the obstructive hydrocephalus was improved (Fig. 3). Histopathological analysis revealed moderately
to highly differentiated tubular adenocarcinoma, which was consistent with metastasis from the pancreatic

adenocarcinoma (Fig. 4). Her disturbance of consciousness recovered immediately after the surgery, and

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she could communicate with her family. Although removal of the supratentorial lesions was planned, the

patient declined the additional surgery and was transferred to hospice care. Her clinical condition

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deteriorated, and she died under hospice care 3 weeks after the surgery.

Discussion

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Brain metastasis, which occurs in 10% to 35% of adult patients with cancer,5,6 is frequently diagnosed in

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patients with lung cancer (48%), breast cancer (15%), testicular cancer (10%), and malignant melanoma
(6%–10%); however, brain metastasis rarely arises from gastrointestinal tract cancers (<4%).2 Brain
metastasis from pancreatic adenocarcinoma is extremely rare (0.33%),3 and its clinical features remain

elusive. To the best of our knowledge, only 22 cases of brain metastasis from pancreatic adenocarcinoma,

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including the present case, have been reported (Table 1).3,7-17 Most of the patients (86.4%, 19/22) showed
other remote metastases in the liver, lungs, lymph nodes, or bone.16 The median time from diagnosis of

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pancreatic adenocarcinoma to brain metastasis was 17.8 months (range, 0–65 months). The brain

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metastasis occurred late in the clinical course, but it was the first clinical manifestation in 22.7% (5/22) of

the patients. More than half of the patients showed a single lesion rather than multiple lesions (59.1%,

13/22). Seven of the 22 patients showed cystic brain metastases, and 10 patients showed solid metastases.

Only one patient in addition to the herein-described patient developed intratumoral hemorrhage
of brain metastasis from pancreatic adenocarcinoma.8 However, intratumoral hemorrhage is common in
brain metastasis from melanoma, breast, thyroid, and renal cell carcinoma.6 Kamar et al.8 reported a case

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of multiple brain metastases from pancreatic adenocarcinoma accompanied by small frontoparietal

hemorrhage, and repeated MRI showed tumor enlargement with intratumoral hemorrhage in a short time.

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The authors did not conclude that the cause of the intratumoral hemorrhage was thrombocytopenia. In our

case, the patient’s blood pressure was stable during the hospital stay, and no coagulation disorders were

evident. The exact cause remains elusive; however, some systemic factors may result in simultaneous

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intratumoral hemorrhage. Aside from the etiology of the multiple tumor enlargement observed in the

can enlarge suddenly and simultaneously.

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present case, we should be aware that multiple brain metastatic lesions from pancreatic adenocarcinoma

Until recently, pancreatic adenocarcinoma has been an aggressive malignancy with an extremely

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poor prognosis, and surgical resection of brain metastasis has had a very limited role. However,

advancements in imaging techniques for early diagnosis and therapeutic agents have improved the
prognosis of pancreatic adenocarcinoma over the past few decades.4 Among 13 patients with a single

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metastatic lesion, 9 (69.2%) patients underwent surgical resection and 6 (46.2%) survived for >12 months

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after surgery (Table 1). Unless a single metastasis is located in a high-risk area or the patient has a poor
performance status, surgical resection appears to have a significant benefit for single metastatic lesions. In

patients with multiple metastases (n = 9), the prognosis is extremely poor, and only two patients underwent
surgical resection (Table 1). Kumar et al.15 described a patient who underwent three craniotomies followed
by whole-brain irradiation during the disease course. However, the postoperative course was not described.

In the present case, the patient died 3 weeks after the craniotomy because of worsening of the primary

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lesion, and resection of the tumors might not have improved the prognosis. However, her disturbance of

consciousness improved immediately after the surgery, and she was able to spend the remainder of her life

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meaningfully. In this regard, surgical resection might be of benefit to selected patients, even those with

multiple brain metastases.

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Conclusion

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Brain metastases from pancreatic adenocarcinoma can enlarge suddenly and simultaneously by

intratumoral hemorrhage even without coagulation disorders and cause neurological deterioration within a

short time. Surgical resection of brain metastases from pancreatic adenocarcinoma has an extremely

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limited role, but it can improve the neurological symptoms even in patients with multiple brain metastases.

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Acknowledgement
We would like to thank Angela Morben, DVM, ELS, from Edanz Group (www.edanzediting.com/ac), for

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editing a draft of this manuscript.

Funding

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This research did not receive any specific grant from funding agencies in the public, commercial, or

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not-for-profit sectors.

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Figure legends
Figure 1. Head CT and MRI on admission. (a, b) Axial CT and (c, d) fluid-attenuated inversion recovery

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MRI showed multiple mass lesions scattered throughout the parenchyma, including a 3-cm cerebellar

lesion.

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Figure 2. Head CT and MRI on Day 3. (a–c) Axial CT images showed an increase in the size of the lesions

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with intratumoral hemorrhage. (b) Mild enlargement of the ventricle was apparent.

Figure 3. Postoperative head CT images. (a) Axial CT showed complete removal of the tumors in the

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cerebellum. (b) Enlargement of the ventricle improved after the operation.

Figure 4. Histological examination of the resected brain tumor. At ×200, the tumor displayed cribriform,

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acinar, and papillary architectural patterns infiltrating the brain parenchyma.

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References
Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605-1617.

2.

Go PH, Klaassen Z, Meadows MC, Chamberlain RS. Gastrointestinal cancer and brain

RI
PT

1.

metastasis: a rare and ominous sign. Cancer. 2011;117:3630-3640.

3.

Park KS, Kim M, Park SH, Lee KW. Nervous system involvement by pancreatic cancer. J

Sun H, Ma H, Hong G, Sun H, Wang J. Survival improvement in patients with pancreatic cancer

M
AN
U

4.

SC

Neurooncol. 2003;63:313-316.

by decade: a period analysis of the SEER database, 1981-2010. Sci Rep. 2014;4:6747. doi:

10.1038/srep06747.

Lin X, DeAngelis LM. Treatment of Brain Metastases. J Clin Oncol. 2015;33(30):3475-3484.

6.

Barajas RF Jr, Cha S. Metastasis in Adult Brain Tumors. Neuroimaging Clin N Am.

2016;26:601-620.

Kuratsu J, Murakami M, Uemura S, Ushio Y. Brain and skull metastases of hepatic or pancreatic

EP

7.

TE
D

5.

8.

AC
C

cancer--report of six cases. Neurol Med Chir (Tokyo). 1990;30:476-482.

El Kamar FG, Jindal K, Grossbard ML, Mizrachi HH, Kozuch PS. Pancreatic carcinoma with

brain metastases: case report and literature review. Dig Liver Dis. 2004;36:355-360.

9.

Caricato M, Borzomati D, Ausania F, Garberini A, Rabitti C, Tonini G, Coppola R. Cerebellar

metastasis from pancreatic adenocarcinoma. A case report. Pancreatology. 2006;6:306-308.

10.

Marepaily R, Micheals D, Sloan A, Hatfield J, Adsay V, Joyrich R, Ullah N, Tobi M. Octreotide

Matsuo

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uptake in intracranial metastasis of pancreatic ductal adenocarcinoma origin in a patient with a

prolonged clinical course. Dig Dis Sci. 2009;54:188-190.

Lemke J, Barth TF, Juchems M, Kapapa T, Henne-Bruns D, Kornmann M. Long-term survival

following

resection

of

brain

metastases

2011;31:4599-4603.

pancreatic

cancer.

Anticancer

Res.

Chiang KC, Yu CC, Chen JR, Huang YT, Huang CC, Yeh CN, Tsai CS, Chen LW, Chen HC, Hsu

SC

12.

from

RI
PT

11.

M
AN
U

JT, Wang CH, Chen HY. Oncocytic-type intraductal papillary mucinous neoplasm

(IPMN)-derived invasive oncocytic pancreatic carcinoma with brain metastasis - a case report.

World J Surg Oncol. 2012;10:138. doi: 10.1186/1477-7819-10-138.

Rao R, Sadashiv SK, Goday S, Monga D. An extremely rare case of pancreatic cancer presenting

TE
D

13.

with leptomeningeal carcinomatosis and synchronous intraparenchymal brain metastasis.

Gastrointest Cancer Res. 2013;6:90-92.

Rajappa P, Margetis K, Wernicke G, Ginter P, Cope W, Sherr DL, Lavi E, Fine RL, Schwartz TH,

EP

14.

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C

Bruckner H, Pannullo SC. Stereotactic radiosurgery plays a critical role in enhancing long-term

survival in a patient with pancreatic cancer metastatic to the brain. Anticancer Res.

2013;33:3899-3903.

15.

Kumar A, Dagar M, Herman J, Iacobuzio-Donahue C, Laheru D. CNS involvement in pancreatic

adenocarcinoma: a report of eight cases from the Johns Hopkins Hospital and review of

literature.

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J Gastrointest Cancer. 2015;46:5-8.

Matsumoto H, Yoshida Y. Brain metastasis from pancreatic cancer: A case report and literature

EP

TE
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M
AN
U

SC

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review. Asian J Neurosurg. 2015;10:35-39.

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Table 1. Summary of reported cases of brain metastasis from pancreatic adenocarcinoma
Authors

Age (y)/sex

Cyst or solid

Intratumoral

Therapy for brain metastasis

Single metastatic lesion
Kuratsu et al.7

56/M

Cyst

-

Interval*

Survival after

(mo)

BM diagnosis

LN

15

9 mo

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hemorrhage

Other metastatic lesions

Biopsy, Ommaya reservoir
placement, radiation

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11

Lemke et al.

Liver

5

2w

51/M

Cyst

-

BSC

Lung, liver, bone

0

2.9 ± 1.0 mo

52/M

Solid

-

Radiation

Liver

5

2.9 ± 1.0 mo

67/M

Solid

-

Resection

LN

24

12 mo

36/F

NA

-

Resection

Liver

11

BSC, NA

48/F

NA

-

Resection, radiation

Liver

65

139 mo

-

Resection, radiation

LN

12

72 mo

-

Resection, radiation

-

0

20 mo

-

Resection, radiation

Liver

48

36 mo

-

Resection

-

13

108 mo

-

Radiation

Lung

43

NA

-

Resection

LN

0

3 mo

Solid

-

Radiation

Lung

4

2.9 ± 1.0 mo

Cyst

-

BSC

Lung

0

2.9 ± 1.0 mo

Solid

+

Biopsy

Liver, LN

6

4d

Solid

54/M

Cyst

14

Rajappa et al.

67/M

Cyst

Kumar et al.15

61.5 (49–70)/NA

Solid

61.5 (49–70)/NA

Solid

68/M

Cyst

Chiang et al.

Matsumoto and Yoshida16
Multiple metastatic lesions
Park et al.3

48/M
62/M
8

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66/M
12

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Resection

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-

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Caricato et al.9

Solid

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Park et al.3

58/M

Kamar et al.

56/M

13

Rao et al.

57/M

Solid

-

Radiation

Lung, liver, bone,

0

BSC, NA

Kumar et al.15

61.5 (49–70)/NA

NA

-

Resection, radiation

-

22

NA

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NA

-

Radiation

Liver, bone

2

NA

61.5 (49–70)/NA

NA

-

NA

Liver, bone

2

NA

61.5 (49–70)/NA

Cyst

-

NA

LN, lung

57

NA

61/F

Solid

+

Resection, BSC

Lung, liver, peritoneal

16

3w

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Present case

61.5 (49–70)/NA

dissemination

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*Interval between diagnosis of pancreatic adenocarcinoma and diagnosis of the metastatic brain tumor. BM, brain metastasis; BSC, best supportive care; d, days; F, female;

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LN, lymph node; M, male; mo, months; NA, not available; w, weeks

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