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 Sun-Whe Kim
Hiroki Yamaue
Editors

Pancreatic Cancer

With Special Focus

on Topical Issues and
Surgical Techniques

123
Pancreatic Cancer
Sun-Whe Kim • Hiroki Yamaue
Editors

Pancreatic Cancer
With Special Focus on Topical
Issues and Surgical Techniques
Editors
Sun-Whe Kim Hiroki Yamaue
Department of Surgery Department of Surgery
Seoul National University Wakayama Medical University
College of Medicine Wakayama
Seoul Japan
Republic of Korea

ISBN 978-3-662-47180-7    ISBN 978-3-662-47181-4 (eBook)

DOI 10.1007/978-3-662-47181-4

Library of Congress Control Number: 2017937897

© Springer-Verlag Berlin Heidelberg 2017

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Preface

Why is publishing a textbook so important? While people in younger ages

want to keep what they know to themselves, seniors tend to think otherwise.
Seniors want to give out and share their knowledge and experiences accumu-
lated over the decades with others. For experts and senior professionals, just
wanting to do so is not enough. These people with invaluable ideas, knowl-
edge, and experiences have the obligation to pass and share them with others.
Publication of a textbook is one of the means to fulfill this obligation. And
what better ways than a textbook? A textbook can hold knowledge and expe-
riences of many experts and can be passed to anyone who can get a hold of it.
Pancreatic cancer is one of the most dreaded cancers worldwide. Pancreatic
cancer continues to demonstrate dismal outcomes, despite all the efforts
poured in by many competent clinicians and scientists throughout the world.
But we dare say that these efforts were not all in vain, and that we have been
making progresses: slow and not so dramatic but gradual. Therefore, we feel
that it is the right time to put current insights of the pancreatic cancer formed
over decades by many dedicated experts into a textbook. In addition, the case
volume of pancreatic cancer is restricted and this limits the number of pancre-
atic cancer experts globally. This is another very important reason to bring the
experts’ insights together into a single textbook. This will allow the experts’
knowledge and experiences to diffuse to many growing minds. These grow-
ing minds will build upon them and advance our knowledge of pancreatic
cancer, and ultimately stand on high ground in the battle against pancreatic
cancer.
To make a firm foothold for the future pancreatologists, we are very happy
and honored to have world-renowned pancreatic cancer experts of various
fields from all over the world to participate in making this textbook. We are
certain that this textbook contains current guidelines to help understand dif-
ferent aspects of pancreatic cancer, and it will greatly influence many young
and emerging pancreatologists and pancreatic surgeons.
The editors would like to express gratitude to Drs. Ho-Seong Han,
­Jin-Young Jang, Manabu Kawai, Mee Joo Kang, and Wooil Kwon for their
tremendous efforts and dedication to make the publication of this textbook
possible.

Seoul, Republic of Korea Sun-Whe Kim

Wakayama, Japan Hiroki Yamaue

v
Contents

Part I Pathology and Tumor Biology

1 Epidemiology������������������������������������������������������������������������������������   3
Young-Joo Won
2 Molecular Alterations in Pancreatic Cancer ������������������������������� 11
Toru Furukawa
3 Pathological Classification�������������������������������������������������������������� 25
Yue Xue, Michelle D. Reid, and Nazmi Volkan Adsay
4 Controversial Issues in Pathological Diagnosis ���������������������������� 53
Akio Yanagisawa
5 Operative Specimen Handling and Evaluation
of Resection Margins ���������������������������������������������������������������������� 67
Caroline Sophie Verbeke
6 Tumor Markers�������������������������������������������������������������������������������� 89
Ji Kon Ryu

Part II Diagnostic Modalities

7 Imaging Diagnosis of Pancreatic Cancer: CT and MRI�������������� 95

Jeong Min Lee and Jeong Hee Yoon
8 Endoscopic Diagnosis�������������������������������������������������������������������� 115
Takao Itoi and Atsushi Sofuni
9 PET and Other Functional Imaging�������������������������������������������� 123
Keon Wook Kang

Part III Treatment Guideline

10 Staging and Determination of Resectability

of Pancreatic Cancer���������������������������������������������������������������������� 133
Motoki Miyazawa, Seiko Hirono, and Hiroki Yamaue

vii
viii Contents

11 Current Issues of Borderline Resectable

Pancreatic Ductal Adenocarcinoma �������������������������������������������� 139
Jason W. Denbo and Jason B. Fleming
12 Guidelines for the Management of Pancreatic
Cystic Neoplasms �������������������������������������������������������������������������� 151
Masao Tanaka
13 Guideline for the Management of Pancreatic
Neuroendocrine Tumor ���������������������������������������������������������������� 161
Gabriele Spoletini, Domenico Tamburrino,
Francesca Muffatti, Stefano Crippa, Valentina Andreasi,
Stefano Partelli, and Massimo Falconi

Part IV Surgical Treatment

14 The History and Evolution of Pancreaticoduodenectomy������������� 175

James F. Griffin and Christopher L. Wolfgang
15 Major Vascular Resection in Pancreatic Carcinoma��������������������� 185
Karl-Frederick Karstens, Yogesh K. Vashist,
and Jakob R. Izbicki
16 Retroperitoneal Nerve Plexus Dissection
During Pancreatoduodenectomy�������������������������������������������������� 193
Tsutomu Fujii, Akimasa Nakao, and Yasuhiro Kodera
17 Mesenteric Approach for Pancreaticoduodenectomy���������������� 201
Seiko Hirono and Hiroki Yamaue
18 Artery-First Approach for Pancreatic Cancer���������������������������� 207
Sanjay Pandanaboyana and John A. Windsor
19 Mesopancreas Excision for Pancreatic Cancer �������������������������� 215
Yosuke Inoue and Akio Saiura
20 Concepts in Isolated Pancreatectomy
for Pancreatic Cancer Using the Nakao Mesenteric
Approach and Catheter Bypass of the Portal Vein �������������������� 225
Akimasa Nakao
21 Role of Extended Resection in Pancreatic Cancer���������������������� 231
Jin-Young Jang
22 Type of Reconstruction After Pancreatoduodenectomy������������ 239
Yi-Ming Shyr and Shin-E Wang
23 The Concept of Customized Pancreatoduodenectomy �������������� 247
Sun-Whe Kim
24 Distal Pancreatectomy with En Bloc Celiac
Axis Resection (DP-CAR) for Advanced
Pancreatic Body Cancer���������������������������������������������������������������� 261
Satoshi Hirano
Contents ix

25 Radical Antegrade Modular

Pancreato-splenectomy (RAMPS)������������������������������������������������ 269
Julie G. Grossman and Steven M. Strasberg
26 Laparoscopic Distal Pancreatectomy
in Pancreatic Cancer���������������������������������������������������������������������� 281
Ho-Seong Han
27 Robotic Application for Pancreatectomy������������������������������������ 285
Jason C. Maggi, Melissa E. Hogg,
Herbert J. Zeh, and Amer H. Zureikat
28 Organ-Preserving Pancreatectomy���������������������������������������������� 295
Wooil Kwon and Sun-Whe Kim
29 Minimally Invasive Surgery for Pancreatic Cancer������������������� 305
Song Cheol Kim and Ki Byung Song

Part V Morbidity and Perioperative Care of Pancreatectomy

30 Pancreatic Fistula�������������������������������������������������������������������������� 317

Alessandra Pulvirenti, Giorvanni Marchegiani,
Antonio Pea, Roberto Salvia, and Claudio Bassi
31 Delayed Gastric Emptying������������������������������������������������������������ 329
Masaji Tani
32 Postoperative Bleeding������������������������������������������������������������������ 335
Dong Wook Choi and Huisong Lee
33 Rare Complications After Pancreatectomy �������������������������������� 349
Dong-Sup Yoon
34 Late Metabolic Complications After Pancreatectomy �������������� 357
Yoo-Seok Yoon
35 Enhanced Recovery Program After Pancreatectomy���������������� 365
Sang-Jae Park
36 Drain Management After Pancreatectomy���������������������������������� 377
Manabu Kawai and Hiroki Yamaue

Part VI Nonoperative Therapy

37 Chemotherapy in the Management

of Pancreatic Cancer���������������������������������������������������������������������� 387
Nai-Jung Chiang and Li-Tzong Chen
38 Radiation Therapy ������������������������������������������������������������������������ 421
Jinhyun Choi and Jinsil Seong
39 Endoscopic Intervention���������������������������������������������������������������� 437
Sung-Hoon Moon and Myung-Hwan Kim
x Contents

40 Personalized Peptide Vaccine for Advanced

Pancreatic Cancer�������������������������������������������������������������������������� 445
Shigeru Yutani and Kyogo Itoh
41 Emerging New Treatment Modalities:
Irreversible Electroporation �������������������������������������������������������� 453
Robert C.G. Martin II

Index�������������������������������������������������������������������������������������������������������� 469
List of Editors

Editors

Sun-Whe Kim Department of Surgery, Seoul National University College

of Medicine, Seoul, Republic of Korea
Hiroki Yamaue Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan

Associate Editors

Ho-Seong Han Department of Surgery, Seoul National University Bundang

Hospital, Seoul, Republic of Korea
Jin-Young Jang Department of Surgery, Seoul National University College
of Medicine, Seoul, Republic of Korea
Manabu Kawai Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan

Assistant Editor

Wooil Kwon Department of Surgery, Seoul National University College of

Medicine, Seoul, Republic of Korea

xi
Contributors

Nazmi Volkan Adsay Department of Pathology and Laboratory Medicine,

Emory University Hospital, Atlanta, GA, USA
Valentina Andreasi Pancreatic Surgery Unit, Pancreas Center, San Raffaele
Hospital, “Vita-Salute” University, Milan, Italy
Claudio Bassi Department of Surgery, Pancreas Institute, University and
Hospital Trust of Verona, Verona, Italy
Li-Tzong Chen National Institute of Cancer Research, National Health
Research Institutes, Tainan, Taiwan
Nai-Jung Chiang National Institute of Cancer Research, National Health
Research Institutes, Tainan, Taiwan
Dong Wook Choi Department of Surgery, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Jinhyun Choi Department of Radiation Oncology, Yonsei University, Seoul,
Republic of Korea
Stefano Crippa Pancreatic Surgery Unit, Pancreas Center, San Raffaele
Hospital, “Vita-Salute” University, Milan, Italy
Jason W. Denbo Department of Surgical Oncology, MD Anderson Cancer
Center, Houston, TX, USA
Massimo Falconi Pancreatic Surgery Unit, Pancreas Center, San Raffaele
Hospital, “Vita-Salute” University, Milan, Italy
Jason B. Fleming Department of Surgical Oncology, MD Anderson Cancer
Center, Houston, TX, USA
Tsutomu Fujii Department of Gastroenterological Surgery (Surgery II),
Nagoya University Graduate School of Medicine, Nagoya, Japan
Toru Furukawa Institute for Integrated Medical Sciences, Tokyo Women’s
Medical University, Tokyo, Japan
James F. Griffin Department of Surgery, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
Julie G. Grossman Section of Hepato-Pancreato-Biliary Surgery,
Department of Surgery and the Alvin J Siteman Cancer Center, Washington

xiii
xiv Contributors

University in Saint Louis, and Barnes-Jewish Hospital, Saint Louis, MO,

USA
Ho-Seong Han Department of Surgery, Seoul National University Bundang
Hospital, Seoul, Republic of Korea
Satoshi Hirano Department of Gastroenterological Surgery II, Hokkaido
University Graduate School of Medicine, Sapporo, Japan
Seiko Hirono Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan
Melissa E. Hogg Division of Surgical Oncology, Department of Surgery,
University of Pittsburgh, Pittsburgh, PA, USA
Yosuke Inoue Department of Hepato-Biliary-Pancreatic Surgery, Cancer
Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
Kyogo Itoh Cancer Vaccine Center, Kurume University, Kurume, Japan
Takao Itoi Department of Gastroenterology and Hepatology, Tokyo Medical
University, Tokyo, Japan
Jakob R. Izbicki Department of General Visceral and Thoracic Surgery,
University of Hamburg Medical Institutions, Hamburg, Germany
Jin-Young Jang Department of Surgery, Seoul National University College
of Medicine, Seoul, Republic of Korea
Keon Wook Kang Department of Nuclear Medicine, Seoul National
University College of Medicine, Seoul, Republic of Korea
Karl-Frederick Karstens Department of General Visceral and Thoracic
Surgery, University of Hamburg Medical Institutions, Hamburg, Germany
Manabu Kawai Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan
Myung-Hwan Kim Department of Internal Medicine, University of Ulsan
College of Medicine, Asan Medical Center, Seoul, Republic of Korea
Song Cheol Kim Division of Hepatobiliary and Pancreatic Surgery,
Department of Surgery, University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Republic of Korea
Sun-Whe Kim Department of Surgery, Seoul National University Hospital,
Seoul, Republic of Korea
Yasuhiro Kodera Department of Gastroenterological Surgery (Surgery II),
Nagoya University Graduate School of Medicine, Nagoya, Japan
Wooil Kwon Department of Surgery, Seoul National University Hospital,
Seoul, Republic of Korea
Huisong Lee Department of Surgery, Mokdong Hospital, Ewha Womans
University School of Medicine, Seoul, Republic of Korea
Contributors xv

Jeong Min Lee Department of Radiology, Seoul National University

Hospital, Seoul, Republic of Korea
Jason C. Maggi Division of Surgical Oncology, Department of Surgery,
University of Pittsburgh, Pittsburgh, PA, USA
Giorvanni Marchegiani Department of Surgery, Pancreas Institute,
University and Hospital Trust of Verona, Verona, Italy
Robert C.G. Martin II Division of Surgical Oncology, University of
Louisville School of Medicine, Louisville, KY, USA
Motoki Miyazawa Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan
Sung-Hoon Moon Department of Internal Medicine, Hallym University
College of Medicine, Hallym University Sacred Heart Hospital, Anyang,
Republic of Korea
Francesca Muffatti Pancreatic Surgery Unit, Pancreas Center, San Raffaele
Hospital, “Vita-Salute” University, Milan, Italy
Akimasa Nakao Department of Surgery, Nagoya Central Hospital,
Nagoya, Japan
Sanjay Pandanaboyana Department of Surgery, Faculty of Medical and
Health Sciences, University of Auckland, Auckland City Hospital, Auckland,
New Zealand
Sang-Jae Park Center for Liver Cancer, Branch of Hepatobiliary Cancer,
National Cancer Center, Goyang, Republic of Korea
Stefano Partelli Pancreatic Surgery Unit, Pancreas Center, San Raffaele
Hospital, “Vita-Salute” University, Milan, Italy
Antonio Pea Department of Surgery, Pancreas Institute, University and
Hospital Trust of Verona, Verona, Italy
Alessandra Pulvirenti Department of Surgery, Pancreas Institute, University
and Hospital Trust of Verona, Verona, Italy
Michelle D. Reid Department of Pathology and Laboratory Medicine,
Emory University Hospital, Atlanta, GA, USA
Ji Kon Ryu Department of Internal Medicine and Liver Research Institute,
Seoul National University College of Medicine, Seoul, Republic of Korea
Akio Saiura Department of Hepato-Biliary-Pancreatic Surgery, Cancer
Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
Roberto Salvia Department of Surgery, Pancreas Institute, University and
Hospital Trust of Verona, Verona, Italy
Jinsil Seong Department of Radiation Oncology, Yonsei University, Seoul,
Republic of Korea
xvi Contributors

Yi-Ming Shyr Department of Surgery, Taipei Veterans General Hospital/

National Yang Ming University, Taipei, Taiwan
Atsushi Sofuni Department of Gastroenterology and Hepatology,
Tokyo Medical University, Tokyo, Japan
Ki Byung Song Division of Hepatobiliary and Pancreatic Surgery,
Department of Surgery, University of Ulsan College of Medicine, Asan
Medical Center, Seoul, Republic of Korea
Gabriele Spoletini HPB and Liver Transplant Surgery, Royal Free Hospital,
NHS Foundation Trust, London, UK
Steven M. Strasberg Section of Hepato-Pancreato-Biliary Surgery,
Department of Surgery and the Alvin J Siteman Cancer Center, Washington
University in Saint Louis, and Barnes-Jewish Hospital, Saint Louis, MO,
USA
Domenico Tamburrino HPB and Liver Transplant Surgery, Royal Free
Hospital, NHS Foundation Trust, London, UK
Masao Tanaka Department of Surgery and Oncology, Shimonoseki City
Hospital, Shimonoseki, Japan
Masaji Tani Division of Gastrointestinal Surgery, Department of Surgery,
Shiga University of Medical Science, Otsu, Japan
Yogesh K. Vashist Department of General Visceral and Thoracic Surgery,
University of Hamburg Medical Institutions, Hamburg, Germany
Caroline Sophie Verbeke Department of Pathology, Oslo University
Hospital, Oslo, Norway
Shin-E Wang Department of Surgery, Taipei Veterans General Hospital/
National Yang Ming University, Taipei, Taiwan
John A. Windsor Department of Surgery, Faculty of Medical and Health
Sciences, University of Auckland, Auckland City Hospital, Auckland,
New Zealand
Christopher L. Wolfgang Department of Surgery, Johns Hopkins University
School of Medicine, Baltimore, MD, USA
Young-Joo Won Department of Cancer Registration and Statistics, National
Cancer Center, Goyang, Republic of Korea
Yue Xue Department of Pathology and Laboratory Medicine,
Emory University Hospital, Atlanta, GA, USA
Hiroki Yamaue Second Department of Surgery, Wakayama Medical
University, School of Medicine, Wakayama, Japan
Akio Yanagisawa Department of Human Pathology, Kyoto Prefectural
University of Medicine, Kyoto, Japan
Contributors xvii

Dong-Sup Yoon Department of Surgery, Yonsei University Gangnam

Severance Hospital, Seoul, Republic of Korea
Jeong Hee Yoon Department of Radiology, Seoul National University
Hospital, Seoul, Republic of Korea
Yoo-Seok Yoon Department of Surgery, Seoul National University Bundang
Hospital, Seoul, Republic of Korea
Shigeru Yutani Cancer Vaccine Center, Kurume University, Kurume, Japan
Herbert J. Zeh Division of Surgical Oncology, Department of Surgery,
University of Pittsburgh, Pittsburgh, PA, USA
Amer H. Zureikat Division of Surgical Oncology, Department of Surgery,
University of Pittsburgh, Pittsburgh, PA, USA
 Part I
Pathology and Tumor Biology
 Epidemiology
Young-Joo Won
1.1  pidemiology of Pancreatic
E data worldwide [1]. A total of 479,436 new pan-
Cancer
Around 95%of pancreatic tumors are adenocar-
cinomas originating from the exocrine (diges-
tive enzyme-producing) region of the pancreas.
Nearly all of these are ductal adenocarcinomas.
Endocrine tumors of the pancreas also exist,
arising from the islets of Langerhans (which
produce several hormones including insulin);
however, endocrine tumors are rare. The dis-
ease is difficult to diagnose, especially in its
early stages. Most pancreatic tumors arise in
the head of the pancreas, often causing bile
duct obstruction that results in clinically evi-
dent jaundice.
1.1.1 Incidence
Pancreatic cancer is the 12th most common can-
cer worldwide, with around 338,000 new cases
diagnosed with the disease in 2012 (2% of the
total number cases). The overall ASR of pancre-
atic cancer increases with age (Table 1.1). Most
patients are between 60 and 80 years of age.
Pancreatic cancer incidence rates are the highest
in Northern America and lowest in Middle Africa;
however, this partly reflects the varying quality of
Y.-J. Won
Department of Cancer Registration and Statistics,
National Cancer Center, Goyang, Republic of Korea
e-mail: astra67@ncc.re.kr
© Springer-Verlag Berlin Heidelberg 2017
S.-W. Kim, H. Yamaue (eds.), Pancreatic Cancer, DOI 10.1007/978-3-662-47181-4_1
1
creatic cancer cases are anticipated in 2025, with
more male (n = 254,874) than female (n = 224,562)
cancer patients expected (Figs. 1.1 and 1.2).
In the United States of America, pancreatic
cancer is the 2nd most common malignant tumor
of the gastrointestinal tract and the 4th leading
cause of cancer-related death in adults. In Europe,
pancreatic cancer is the 8th most common cancer,
with around 104,000 new cases diagnosed with the
disease in 2012 (3% of the total number of cases).
The highest age-­standardized incidence rates for
pancreatic cancer worldwide are in the Czech
Republic for both men and women; the lowest
rates are in Bosnia and Herzegovina for both men
and women. The United Kingdom (UK) pancre-
atic cancer incidence rates are estimated to be the
8th lowest for male patients in Europe and the 20th
highest for female patients [1]. These data are
broadly in line with Europe-specific data available
elsewhere [2].
The highest rates of pancreatic ductal adenocar-
cinoma are recorded among African Americans
(about 12 per 100,000 men and 10 per 100,000
women) and among the indigenous population in
Oceania. The lowest rates (<2 per 100,000 men and
1 per 100,000 women), which may be partly attrib-
utable to underdiagnosis, are recorded in India,
Northern and Central Africa, and Southeast Asia.
3
4 Y.-J. Won

Table 1.1 Estimated pancreatic incidence by age

Total 0–14 15–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75+ Crude ASR(W)
Both 337,872 0.0 0.2 1.3 3.1 6.1 10.4 16.5 24.0 32.5 55.7 4.8 4.2
Men 178,161 0.0 0.2 1.6 3.9 7.5 12.8 20.1 28.5 37.2 60.6 5.0 4.9
Women 159,711 0.0 0.2 1.0 2.4 4.7 8.0 13.2 20.0 28.6 52.4 4.6 3.6
Crude and age-standardized rates per 100,000

Incidence ASR
a Male

Pancreatic cancer

7.7+

4.7-7.7

2.5-4.7

1.5-2.5

<1.5

No Data

Incidence ASR
b
Female

Pancreatic cancer
5.2+
3.5–5.2
2.2–3.5
0.91–2.2
<0.91
No Data

Fig. 1.1 (a) Incidence of pancreatic cancer in men. (b) Incidence of pancreatic cancer in women
1 Epidemiology 5

World
Pancreas
Year Estimated number of new cancers (all ages) Male Female Both sexes
2012 178161 159711 337872
ages < 65 74063 49149 123212
ages > = 65 104098 110562 214660

2025 254874 224562 479436

ages < 65 96391 63849 160240
ages > = 65 158483 160713 319196

Demographic change 76713 64851 141564

ages < 65 22328 14700 37028
ages > = 65 54385 50151 104536
GLOBOCAN 2012 (IARC) - 19.2.2016

World
Pancreas
Number of new cancers in 2025 (all ages)

Male 254874

Female 224562

0 50000 100000 150000 200000 250000 300000

Incidence in 2012 Demographic effect

World
Pancreas
Number of cancers in 2025 (all ages) - Both sexes

479436

0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000

Incidence in 2012 Demographic effect

GLOBOCAN 2012 (IARC) (19.2.2016)

Fig. 1.2 Incidence prediction of pancreatic cancer in revision. The numbers were computed using age-specific
2025 (Population forecasts were extracted from the rates and corresponding populations for 10 age-groups)
United Nations, World Population prospects, the 2012
6 Y.-J. Won

1.1.2 Mortality in 2012, the highest age-standardized mortality

Pancreatic cancer is the 7th most common cause
of cancer death worldwide, with 330,391 deaths
from pancreatic cancer in 2012 (4% of the total
number of deaths).
It is the 5th most common cause of cancer
death in Europe overall, with more than
104,000 deaths from pancreatic cancer in 2012
(6% of the total number of deaths). In Europe
rates for pancreatic cancer are in Macedonia
for men and in Slovakia for women; the lowest
rates are in Iceland for men and Belarus for
women. The UK pancreatic cancer mortality
rates are estimated to be the 5th lowest for
males in Europe and 17th lowest for females
[1]. These data are broadly in line with Europe-
specific data available elsewhere [2] (Figs. 1.3
and 1.4, Table 1.2).

Mortality ASR
a Male

Pancreatic cancer
7.4+
4.5–7.4
2.5–4.5
1.4–2.5
<1.4
No Data

Mortality ASR
b
Female

Pancreatic cancer
5.1+
3.5–5.1
2.2–3.5
0.88–2.2
<0.88
No Data

Fig. 1.3 (a) Mortality of pancreatic cancer in men. (b) Mortality of pancreatic cancer in women
1 Epidemiology 7

World
Pancreas
Year Estimated number of cancer deaths (all ages) Male Female Both sexes
2012 173827 156564 330391
ages < 65 66117 42108 108225
ages > = 65 107710 114456 222166

2025 249979 220815 470794

ages < 65 86427 54994 141421
ages > = 65 163552 165821 329373

Demographic change 76152 64251 140403

ages < 65 20310 12886 33196
ages > = 65 55842 51365 107207
GLOBOCAN 2012 (IARC) - 19.2.2016

World
Pancreas
Number of cancer deaths in 2025 (all ages)

Male 249979

Female 220815

0 50000 100000 150000 200000 250000 300000

Mortality in 2012 Demographic effect

GLOBOCAN 2012 (IARC) (19.2.2016)

World
Pancreas
Number of cancer deaths in 2025 (all ages) - Both sexes

470794

0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000

Mortality in 2012 Demographic effect

GLOBOCAN 2012 (IARC) (19.2.2016)

Population forecasts were extracted from the United Nations, World Population prospects, the 2012 revision.
The numbers were computed using age-specific rates and corresponding populations for 10 age-groups.

Fig. 1.4 Mortality prediction of pancreatic cancer in revision. The numbers were computed using age-specific
2025 (Population forecasts were extracted from the rates and corresponding populations for 10 age-groups)
United Nations, World Population prospects, the 2012
8 Y.-J. Won

Table 1.2 Estimated pancreatic mortality by age

Total 0–14 15–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75+ Crude ASR(W)
Both 330,391 0.0 0.1 1.0 2.6 5.3 9.3 15.3 22.8 32.2 60.4 4.7 4.0
Men 173,827 0.0 0.2 1.2 3.2 6.5 11.6 18.9 27.3 37.1 66.0 4.9 4.7
Women 156,564 0.0 0.1 0.7 1.9 4.0 7.0 11.9 18.8 28.2 56.6 4.5 3.4
Crude and age-standardized rates per 100,000

1.1.3 Survival
It is difficult to perform comparisons of pancreatic
cancer survival between countries due to differ-
ences in methodologies and criteria for including
patients in analyses. Nevertheless, survival rates
following surgical resection for pancreatic cancer
range from 11 to 20 months. The 5-year survival
ranges from 7% to 25% [3]. Patients with unre-
sectable locally advanced disease (stage III) have
a median survival of 6–11 months [4]. Patients
who have metastatic disease have a median sur-
vival of only 2–6 months [5].
In the USA, there has been a steady increase in
the survival rate for most cancers, whereas very
slow advances have been observed for pancreatic
cancer, for which the 5-year relative survival is cur-
rently 7%. These low rates ensue in part because
more than one-half of cases are diagnosed at a dis-
tant stage for which the 5-year survival is 2%. The
distribution of pancreatic cancer by stage is local-
ized, 9%; regional, 28%; and distant, 53% [6].
In general, patients who can be treated with
surgery tend to live longer than those not treated
with surgery. Information from the National
Cancer Database based on individuals diagnosed
with exocrine pancreatic cancer between 1992
and 1998 shows that the 5-year survival rate for
those with stage IA pancreatic cancer is about
14%. For stage IB cancer, the 5-year survival rate
is about 12%. For stage IIA pancreatic cancer, the
5-year survival rate is about 7%. For stage IIB
cancer, the 5-year survival rate is about 5%. The
5-year survival rate for stage III pancreatic can-
cer is about 3%. Patients with stage IV pancreatic
cancer have a 5-year survival rate of about 1%.
Among men with pancreatic cancer, 22% sur-
vive for at least 1 year, and a previous study on the
age-standardized net survival for patients diag-
nosed with pancreatic cancer during 2010–2011 in
England and Wales predicted that this value may
decrease to 4% for patients surviving for 5 years or
more [7]. Survival rates for women are similar,
with 20% surviving for 1 year or more and 3%
predicted to survive for at least 5 years. Survival
rates of pancreatic cancer patients continue to
decline gradually beyond 5 years after diagnosis.
Just 1% of both men and women are predicted to
survive their disease for 10 years or more, as
shown by age-standardized net survival for
patients diagnosed with pancreatic cancer during
2010–2011 in England and Wales [7].
1.1.4 Risk Factors
An individual’s risk of developing pancreatic
cancer depends on many factors, including age,
genetics, and exposure to risk factors (including
some potentially avoidable lifestyle factors).
1 Epidemiology
May increase risk
Increase risk (“sufficient” or (“limited” or “probable”
“convincing” evidence) evidence)
Tobacco, smokeless Alcohol
Tobacco smoking Thorium-232 and its
Body fatness decay products
X-radiation
Gamma radiation
Abdominal fatness
Adult-attained height
Red meat
International Agency for Research on Cancer (IARC) and The World Cancer Research Fund/American Institute for
Cancer Research (WCRF/AICR) classifications. Find out more about IARC and WCRF/AICR classifications
Pancreatic cancer is associated with a number
of risk factors. Smoking is the main risk factor
for pancreatic cancer. Smokeless tobacco also
causes pancreatic cancer. Physical activity, fruits,
and foods containing folate may be associated
with a lower pancreatic cancer risk; however, the
evidence is unclear. Alcohol, red meat, ionizing
radiation, and certain medical conditions and
infections may relate to higher pancreatic cancer
risk; however, the evidence is unclear.
Research from the UK presented that 37% of
pancreatic cancer cases each year are linked to
major lifestyle and other risk factors [8]. Smoking
is the main avoidable risk factor for pancreatic
cancer, linked to an estimated 29% of pancreatic
cancer cases in the UK. An estimated 37% of pan-
creatic cancer cases in the UK are linked to life-
style factors including smoking and overweight
and obesity (12%).
References
1. Ferlay J, Soerjomataram I, Ervik M, et al,
GLOBOCAN. Lyon: International Agency for
Research on Cancer; 2012 [cited 2016 02-13].
Available from: http://globocan.iarc.fr.
9
May decrease risk
Decreases risk (“sufficient” (“limited” or “probable”
or “convincing” evidence) evidence)
Foods containing
folate
Fruits
Physical activity
2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso
S, Coebergh JW, Comber H, et al. Cancer incidence and
mortality patterns in Europe: estimates for 40 countries
in 2012. Eur J Cancer. 2013;49(6):1374–403.
3. Richter A, Niedergethmann M, Sturm JW, Lorenz D,
Post S, Trede M. Long-term results of partial pancre-
aticoduodenectomy for ductal adenocarcinoma of the
pancreatic head: 25-year experience. World J Surg.
2003;27(3):324–9.
4. Amikura K, Kobari M, Matsuno S. The time of occur-
rence of liver metastasis in carcinoma of the pancreas.
Int J Pancreatol: Off J Int Assoc Pancreatol.
1995;17(2):139–46.
5. Kayahara M, Nagakawa T, Ueno K, Ohta T, Takeda T,
Miyazaki I. An evaluation of radical resection for pan-
creatic cancer based on the mode of recurrence as
determined by autopsy and diagnostic imaging.
Cancer. 1993;72(7):2118–23.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics,
2015. CA Cancer J Clin. 2015;65(1):5–29.
7. Cancer Research UK [cited 2016 17-02]. Available
from: http://publications.cancerresearchuk.org/can-
cerstats/statssurvival/surv-data-table.html.
8. Parkin DM, Boyd L, Walker LC. The fraction of can-
cer attributable to lifestyle and environmental factors
in the UK in 2010. Br J Cancer. 2011;105(Suppl
2):S77–81.
 Molecular Alterations in Pancreatic
Cancer
Toru Furukawa
2.1 Introduction
Cancer has somatically mutated genes that con-
tribute to outdrive cellular proliferation and for-
mation of a tumor. To know what genes are
mutated, DNA sequencing is necessary; however
until recently, only a limited number of genes or
portions of genes could have been analyzed in a
routine laboratory practice because of a limited
ability of DNA sequencing in time and cost.
However, there emerged a game changer, the
next-generation sequencer (NGS), in 2009,
which brought a paradigm shift in a way of
genetic studies of diseases [1]. When the human
genome project was conducted, 1987–2003, the
automated Sanger sequencer was a main tool for
analyzing DNA sequence. While the Sanger
sequencer, still considered to be the most accurate
sequencer, can output ~250 k bases per day, NGS
can output 750G bases/3 days, in which the differ-
ence between them is one million times. The
human genome is consisted of 3G base pairs of
DNA; therefore, the output of NGS corresponds
to 250 times of the human haploid genome.
Despite this enormous output, NGS is an error-
prone sequencer that needs redundant reads, usu-
ally 100 times, to get accurate sequencing.
T. Furukawa
Institute for Integrated Medical Sciences, Tokyo
Women’s Medical University, Tokyo, Japan
e-mail: furukawa.toru@twmu.ac.jp
© Springer-Verlag Berlin Heidelberg 2017
S.-W. Kim, H. Yamaue (eds.), Pancreatic Cancer, DOI 10.1007/978-3-662-47181-4_2
2
Nevertheless, NGS has given a revolutionary
impact on sequencing studies primarily because
it enables to sequence individual human genome
in an affordable cost in a few days in a single
laboratory. Alterations in protein-coding genes
can be analyzed by exome that sequences every
exon of human genes. Exons span 45M bases in
total in the human genome, so that the exome
analysis enables much cost- and time-saving
studies than the whole-genome analysis.
Moreover, base alterations in exomes can be
interpreted directly as nonsynonymous or synon-
ymous mutations, which is much more straight-
forward than interpreting variations in noncoding
regions of the genome. For analysis of somatic
mutations in cancer cells, comparison of sequenc-
ing data between cancer cells and normal cells is
necessary; therefore, careful sampling with dis-
tinguishing between cancer cells and normal
cells is needed.
An exome analysis of the pancreatic cancer
has firstly reported by Jones et al. in 2008 [2].
Although this study was by means of Sanger
sequencing, they analyzed 24 cases of pancreatic
ductal adenocarcinoma (PDA). By NGS, Biankin
et al., a team of international collaboration under
International Cancer Genome Consortium, pub-
lished a result of exome combined with a copy
number variation (CNV) analysis of 142 PDAs in
2012 [3]. Later they published a result of whole-­
genome analysis of 100 PDAs in 2015 [4], and a
result of integrated analysis consisted of whole-­
genome, CNV, transcriptome, and methylome
11
12
analysis of 456 PDAs in 2016 [5]. There also are
some independent studies published elsewhere
including one by Wang et al. regarding exome
analyses of 15 PDA cell lines in 2012 [6] and the
other by Witkiewicz et al. regarding exome anal-
ysis of 109 PDAs in 2015 [7].
2.2 Genetic Alterations in PDAs
Exome analyses of PDAs indicate that one PDA
has approximately 60 nonsynonymous mutations
in average [3, 4]. PDAs with microsatellite insta-
bility that is caused by mismatch repair defi-
ciency have more than 100 mutations/case, often
500 [4]. Spectra of mutations show that C:G>T:A
transition is enriched in PDAs, especially
CpG>TpG mutations are common, which indi-
cates that an aberrant methylation may be a major
cause of the mutations [4]. Smokers usually show
enrichment of C:G>A:T transversion, which is
observed in a fraction of PDAs. On the other
hand, enrichment of C>T transition in TpCpW
site, which is caused by apolipoprotein B mRNA
editing enzyme, catalytic polypeptide-like
(APOBEC), a cytidine deaminase, is not com-
mon in PDAs [4].
Through the exome and CNV analyses, four
commonly altered genes in PDAs, namely, KRAS,
TP53, CDKN2A, and SMAD4, have reemerged
[2–4, 7]. These four genes are altered frequently,
90% of PDAs harbor gain-of-function mutations
in KRAS, 90% harbor mutations or loss of
CDKN2A, 75% harbor TP53 mutations, and 50%
harbor mutations or loss of SMAD4, which has
been well known since the late 1980s; hence,
NGS analyses have reconfirmed alterations of
these “Big 4” genes in PDAs. Next commonly
altered genes are those encoding proteins
involved in chromatin regulation, i.e., KDM6A,
KMT2C/MLL3, KMT2D/MLL2, ARID1A,
ARID2, and PBRM1, which are altered in ~25%
of PDAs [4, 5]. Other genes each altered in ~10%
of PDAs are those functioning in DNA repair
system including BRCA1, BRCA2, PALB2, and
ATM; those functioning in RNA processing and/
or splicing including SF3A1, SF3B1, U2AF1,
U2AF2, RBM6, and RBM10; those functioning in
wingless-type MMTV integration site (Wnt)
T. Furukawa
pathway including CTNNB1; those functioning
in transforming growth factor beta (TGFb) path-
way including SMAD3, TGFBR1, TFGBR2,
ACVR1B, and ACVR2A; and those functioning in
phosphatidylinositol 3-kinase (PI3K) pathway
including PIK3CA and PTEN [4, 5].
2.3 KRAS and the Mitogen-­
Activated Protein Kinase
Pathway
KRAS encodes Kirsten rat sarcoma viral onco-
gene homologue (KRAS) that is a small guano-
sine triphosphate (GTP)-binding protein and one
of three members of rat sarcoma viral oncogene
homologues (RAS) [8]. KRAS is mutated in 90%
of PDAs, and mutations are commonly observed
in codon 12, 13, and 61 as missense mutations, in
which G12D and G12V are most common [5, 9].
G12C mutations that are known to be common in
lung cancer and recently shown as a specific
druggable target [10] are not common in PDAs.
RAS plays a central role in controlling of activi-
ties of numerous signal transduction pathways,
most notably of the mitogen-activated protein
kinase (MAPK) pathway. In the RAS-MAPK
pathway, a membrane-bound enzyme-linked
receptor, e.g., the epidermal growth factor recep-
tor or the platelet-derived growth factor receptor,
activated by ligand binding activates a guanine
nucleotide exchanging factor that facilitates
exchanging guanosine diphosphate (GDP) bound
to RAS with GTP, which makes RAS activated.
The GTP-bound RAS activates the MAPK cas-
cade consisted of the mitogen-activated protein
kinase kinase kinase (MAP3K)/V-Raf oncogene
homologue (RAF), the mitogen-activated
protein kinase kinase (MAP2K)/MAP kinase-
ERK kinase (MEK), and the mitogen-activated
protein kinase 1 (MAPK1)/extracellular signal-
regulated kinase (ERK), in which an activated
signal is passed on by sequential phosphorylating
reactions. RAS has an intrinsic hydrolase activity
that turns bound GTP to GDP, which inactivates
itself; however, the mutations in KRAS cause
decreasing of the hydrolase activity and, hence,
protracting activity of itself as well as down-
stream signal transduction pathways. Active
2 Molecular Alterations in Pancreatic Cancer
MAPK1/ERK translocates into nucleus and acti-
vates transcription factors that induce expression
of effector genes functioning in DNA replication,
RNA maintenance, transcription and translation,
cell cycle and mitosis, transporting, and cell pro-
liferation [11]. Activity of MAPK1/ERK is nega-
tively regulated by dual specificity phosphatases
(DUSPs), most directly by DUSP6 [12]. DUSP6
forms a negative feedback loop with MAPK1/
ERK, i.e., an activation of MAPK1/ERK induces
expression of DUSP6 that inactivates MAPK1/
ERK; therefore, MAPK1/ERK activity is tightly
regulated through this negative feedback loop
[13]. However in some PDAs, expression of
DUSP6 is downregulated mostly by aberrant
methylation; hence, the negative feedback loop
between MAPK1/ERK and DUSP6 is abrogated,
which results in constitutive activation of
MAPK1/ERK and expression of genes impli-
cated in malignant phenotypes of PDAs [14].
BRAF encodes B-Raf proto-oncogene, serine/
threonine kinase that functions as a MAP3K in
MAPK pathway. BRAF is mutated in some of
PDAs that harbor the wild-type KRAS; therefore,
mutations in BRAF and KRAS are mutually
exclusive in PDAs [15]. Most mutations of
BRAF in human cancers including PDAs are
observed as a V600E mutation, which turns the
kinase constitutively active [16]. Vemurafenib is
developed to target cancers with the BRAFV600E
mutation [17].
2.4 TP53
TP53 encodes p53, a transcription factor involved
in DNA damage response [18]. DNA damage
provoked by irradiation and/or reactive oxygen
species is sensed by and activates the ataxia tel-
angiectasia mutated (ATM), a serine/threonine
protein kinase, that phosphorylates p53. The
phosphorylated p53 dissociates from the mouse
double minute 2 homologue (MDM2), an
E3-ubiquitin ligase, and binds DNA to induce
expression of target genes that have a consensus
binding sequence in their promoters. Most of
these target genes of p53 encode proteins involved
in cell cycle arrest, DNA repair, and apoptosis
including p21, p27, BAX, PUMA, etc., which
13
plays an important role in determining cells’ fate
whether they survive through DNA repair or die
by apoptosis to avoid accumulation of mutations
caused by DNA damage [19]. Mutations in TP53
are found in 60–75% of PDAs. Mutations in
TP53 are either frameshift mutations or missense
mutations within a DNA-binding domain of p53.
The missense mutation in p53 abrogates DNA-­
binding activity, which results in dysfunction of
its transcription-activating activity. These muta-
tions have been thought as loss-of-function muta-
tions, which definitely is the case in frameshift
mutations; however, a recent investigation indi-
cates that missense mutations in p53, at least
some of them, can modulate functions of chro-
matin remodeling proteins and then enhance
transcriptions of certain genes that promote
malignant phenotypes of cancer, which indeed
are gain-of-function mutations [20]. p53 proteins
with missense mutations are refractory to
MDM2-mediated proteasomal destruction and,
therefore, accumulate in the nucleus and appeared
as overexpressed by immunohistochemistry [21].
2.5 CDKN2A
CDKN2A encodes the cyclin-dependent kinase
inhibitor 2A (CDKN2A)/p16. CDKN2A/p16
plays a role in attenuation of cell cycle progres-
sion from G1 phase to S phase. For progression
of the cell cycle, the cyclin-dependent kinase 4
(CDK4) is activated by binding with cyclin D;
subsequently the activated CDK4 phosphorylates
retinoblastoma protein (RB), and then, the phos-
phorylated RB dissociates from the E2F tran-
scription factor 1 (E2F1), which facilitates
nuclear translocation of E2F1 and expression of
target genes necessary for the cell cycle progres-
sion [22]. CDKN2A inhibits the activation of
CDK4 by hampering its binding to cyclin D and,
therefore, attenuates cell cycle progression.
CDKN2A is mutated and deleted homozygously
in 25% and 10% of PDAs, respectively [4].
Moreover, CDKN2A is epigenetically silenced by
aberrant hypermethylation in 50–60% of PDAs;
hence, CDKN2A is functionally disrupted in
almost all PDAs, which presumably contributes
to uncontrolled cell cycle progression [23].
14 T. Furukawa

2.6 SMAD4 MLL2 encode the lysine-specific histone methyl-

transferase 2C (KMT2C) and the lysine-specific
SMAD4 encodes the Sma and Mad protein homo- histone methyltransferase 2D (KMT2D), respec-
logue 4 (SMAD4). SMAD4 plays a role in signal tively, which are members of the ASC-2/NCOA6
transduction of the transforming growth factor β complex (ASCOM) that are involved in tran-
(TGFβ) pathway. TGFβ, a ligand, binds and facil- scriptional coactivation [27, 28]. Because
itates formation of a heterodimer between TGFβ KDM6A is associated with KMT2C and
receptor (TGFBR) type 1 and TGFBR type 2 and, KMT2D, alterations of KDM6A, KMT2C, and
then, induces phosphorylation of the receptors at KMT2D are mutually exclusive [5]. ARID1A
each other. The phosphorylated TGFBR type 1 encodes the AT-rich interactive domain 1A (SWI-­
recruits and phosphorylates the Sma and Mad like), a member of the SWI/SNF family, whose
protein homologue 2 (SMAD2) or the Sma and members have helicase and ATPase activities and
Mad protein homologue 3 (SMAD3). The phos- are able to restructure the nucleosome to make its
phorylated SMAD2/SMAD3 oligomerizes with DNA accessible during transcription, replication,
SMAD4, and the SMAD2/SMAD3-SMAD4 and DNA repair [29]. ARID2 encodes the AT-rich
oligomer translocates into nucleus and activates interactive domain 2/BAF200, an integral com-
transcription factors, which induces expression ponent of the polybromo-associated BAF (PBAF)
of target genes that harbor TGFβ-responsive ele- chromatin remodeling complex of the SWI/SNF
ment in their promoters. The target genes include family, which facilitates a ligand-dependent tran-
MMP3 and ADAM19, which encode matrix scriptional activation by nuclear receptors [30].
metalloproteinases; ARHGAP5 and ARHGAP10, PBRM1 encodes the polybromo 1/BAF180 that is
which encode Rho-GTPase-activating proteins; another subunit of PBAF complex [31]. ARID2/
CSNK1A1, DKK1, and FRAT1, which encode BAF200 and PBRM1/BAF180 are mutually
proteins associated with Wnt pathway; CASP8 exclusive in constitution of the PBAF complex,
that encodes a caspase; HDAC9 that encodes a which contributes to distinct selection of remod-
histone deacetylase; and CAMK2D that encodes eled genetic elements [30]. Mutations of these
a protein associated with calcium signaling [24]. genes are largely loss-of-function mutations,
SMAD4 is mutated and homozygously deleted in which is thought to cause dysfunction of chroma-
around 20% and 10% of PDAs, respectively [4, tin regulation and aberrant expression of target
25]. Many of the mutations are nonsense or genes although detail of dysfunction of these
frameshift mutations, which indicates that molecules in PDA is waited to be elucidated [5].
SMAD4 alterations in PDAs are virtually loss-of-­
function alterations. SMAD4 alterations in PDAs
can be detected by immunohistochemistry as 2.8 DNA Repair-Associated
complete loss of its protein product in cancer Genes
cells [21].
DNA repair-associated genes including BRCA1,
BRCA2, PALB2, and ATM are altered in ~10% of
2.7 Chromatin Modification PDAs. BRCA1 and BRCA2 encode the breast can-
Genes cer 1 (BRCA1) and the breast cancer 2 (BRCA2),
respectively, both of which are involved in repair
Chromatin remodeling genes, KDM6A, KMT2C/ of a double-strand break of DNA by homologous
MLL3, KMT2D/MLL2, ARID1A, ARID2, and recombination. When DNA suffers from a dou-
PBRM1, are altered in ~25% of PDAs. KDM6A/ ble-strand break caused by ionizing radiation and/
UTX encodes the lysine-specific demethylase 6A or reactive oxygen species, BACA1 associates
(KDM6A) that contains a Jumonji C domain and with a broken end and helps to process the end
catalyzes the demethylation of tri-/dimethylated being ready for the homologous recombination
histone H3 [26]. KMT2C/MLL3 and KMT2D/ [32]. BRCA2 binds a single-­ strand DNA and
2 Molecular Alterations in Pancreatic Cancer
helps to bring RAD51, a RecA homologue in
eukaryotes, and plays a vital role in strand inva-
sion in the homologous recombination, to damag-
ing sites in DNA for its proper function [33]. ATM
encodes the ataxia telangiectasia mutated (ATM)
that is a kinase and functions in sensing of a DNA
damage. ATM associates with a damaged site and
phosphorylates some proteins including the
checkpoint kinase 1 (CHK1) and the checkpoint
kinase 2 (CHK2), which eventually results in cell
cycle arrest for DNA repair. PALB2 encodes the
partner and localizer of BRCA2 (PALB2) that, as
this name suggests, is co-expressed with
BRCA2 in nuclear foci when cells are irradiated,
which indicates that PALB2 also participats in
DNA repair [34]. Since most of mutations of these
genes are loss-of-function mutations, a proper
repair of DNA cannot be pursued, and, therefore,
secondary mutations accumulate in cells with
mutations of these genes.
2.9 RNA Processing Genes
Genes encoding RNA processing and/or splicing
factors including SF3A1, SF3B1, U2AF1,
U2AF2, RBM6, and RBM10 are mutated in ~16%
of PDAs [5]. SF3A1, SF3B1, U2AF1, and U2AF2
encode components of U2AF, a small nuclear
ribonucleoprotein (snRNP) essential for proper
splicing of pre-messenger RNA. Most of muta-
tions in these genes are missense mutations in a
functional domain and are demonstrated to func-
tion as a dominant negative protein that facilitates
immature splicing [35]. RBM6 and RBM10
encode RNA-binding molecules implicated in
alternative splicing. Mutations of these genes are
mostly loss-of-function mutations, which is dem-
onstrated to be implicated in dysfunction of alter-
native splicing of some key molecules for
oncogenesis like NUMB [36].
2.10 Wnt Pathway Genes
Wnt pathway is an important signaling pathway in
development of multicellular organisms. One of
important mediators in Wnt pathway implicated in
15
pancreatic cancer is beta catenin. The gene
encoding beta catenin is CTNNB1, which is
mutated in ~10% of PDAs. Beta catenin is a
cadherin-­ associated protein in the adherence
complex that mediates cell-cell junction. Beta
catenin is also a cytoplasmic protein that can
function as a signal mediator, which is tightly
regulated through formation of a complex with
axin and the adenomatous polyposis coli (APC)
protein. The complex of beta catenin-axin-APC
associates with glycogen synthase kinases that
phosphorylate and render beta catenin for
ubiquitin-­proteosomal destruction. Wnt signal-
ing suppresses the complex formation and facil-
itates free beta catenin. The free beta catenin
translocates into the nucleus and functions as a
transcriptional coactivator [37]. Mutations in
CTNNB1 cause to generate a protein refractory
to the ubiquitin-mediated destruction, which
results in facilitation of the transcriptional
coactivator activity of beta catenin [38]. By
immunohistochemistry, a mutated beta catenin
is often found as an overexpressed protein in the
nucleus.
2.11 Phosphatidylinositol
3-Kinase (PI3K) Pathway
Genes
Genes encoding molecules implicated in PI3K
pathway including PIK3CA and PTEN are
mutated in ~5% of PDAs. PI3K pathway
plays a fundamental role in cell growth.
Phosphatidylinositol (PI) is a glycerophospho-
lipid molecule sitting in the cell membrane. PI is
phosphorylated by kinases on specific hydroxyl
groups, PI-3, PI-4, and PI-5, and functions as a
signal mediator. PIK3CA encodes the
phosphatidylinositol-­4,5-bisphosphate 3-kinase,
catalytic subunit alpha. Mutations in PIK3CA
mostly affect codon 545 or 1047, which causes
upregulation of kinase activity of its protein
product. PTEN encodes the phosphatase and ten-
sin homologue, a phosphatase specific for PI-3.
Mutations in PTEN are mostly frameshift or non-
sense mutations that result in loss of function of
its product.
16
2.12 Molecular Mechanism
of Development of PDA
Pancreatic cancer has been hypothesized to
develop from ductal cells, in which normal ductal
cells would give rise to full-brown cancer cells
via gradual dysplastic changes of themselves.
PDA tissues usually have dysplastic ductal
lesions in close vicinity of invasive carcinoma
[39, 40], and studies on these dysplastic lesions
have elucidated that dysplastic cells have varying
grades of atypia, from low-grade to high-grade,
and the high-grade lesions can be found fre-
quently in a pancreatic tissue specimen with inva-
sive cancer while extremely infrequently in that
without invasive cancer [40]. Molecular studies
have uncovered that low-grade dysplastic cells
harbor KRAS mutations and CDKN2A inactiva-
tion, while high-grade dysplastic cells have aber-
rations of TP53 and SMAD4 in addition to the
KRAS mutation and CDKN2A inactivation [21].
These results indicate that molecular aberrations
indeed accumulate along with the progression of
dysplastic grade of ductal cells. Now these dys-
plastic lesions are termed pancreatic intraepithe-
lial neoplasia (PanIN) [41], i.e., PanIN is a
noninvasive proliferative lesion of dysplastic
ductal cells, which develops as a low-grade lesion
and progresses to a high-grade lesion with an
association with molecular alterations. This mul-
tistep hypothesis is known as the progression
model for the pancreatic cancer [42].
The progression model for the pancreatic can-
cer seems to be further endorsed by studies of
genetically engineered mouse models (GEMM)
of pancreatic cancer. GEMM with lox-Stop-lox
(LSL)-KrasG12D and Pdx1-Cre induces the mutant
Kras, KrasG12D, the most common type of mutant
KRAS in human PDAs, in a pancreas-specific
manner during development. This mouse is born
without any abnormality; however, it gradually
develops microscopic proliferative lesions in the
pancreatic duct that closely mimic PanIN and,
eventually, although rarely, invasive ductal carci-
noma in the pancreas in 2 years [43]. Detailed
examinations of this model indicate that PanINs
in early phase are with low-grade dysplasia,
while those in late phase harbor high-grade
T. Furukawa
dysplasia. GEMM with pancreas-specific expres-
sion of KrasG12D and Trp53R172H (mutant p53)
shows facilitation of development of invasive
ductal carcinoma with frequent metastasis, which
indicates that an accumulation of genetic altera-
tions, the mutated Kras and the mutated Trp53 in
this case, accelerates pancreatic cancer develop-
ment [44]. Moreover, GEMM with pancreas-spe-
cific expression of KrasG12D and Trp53R172H and
complete loss of Smad4 develops a rapidly grow-
ing pancreatic tumor with metastasis and shows
shorter survival than a mouse with KrasG12D and
Trp53R172H, in which overexpression of Runx3 is
associated with the metastatic phenotype [45].
2.13 Genetic Alterations
in Intraductal Papillary
Mucinous Neoplasms
Intraductal papillary mucinous neoplasms
(IPMNs) are characterized by manifestation of
dilated duct filled with mucin. The dilated duct is
lined with neoplastic cells growing in papillae
with varying grades of atypia [46]. The papillae
show diverse architectural variations termed gas-
tric, intestinal, pancreatobiliary, and oncocytic
subtypes [47]. The atypia ranges from low-grade
to high-grade, which often intermingles with
each other. Occasionally the neoplastic cells
invade into parenchyma, which forms invasive
mucinous colloid carcinoma or invasive ductal
adenocarcinoma [48]. These features of IPMNs
are quite distinctive from PDAs, a conventional
type of pancreatic cancer; however, molecular
alterations specific for IPMNs had been unknown
until just recently. In 2011, two groups of
researchers independently reported that IPMNs
exclusively harbored somatic mutations in GNAS,
which has uncovered a specific molecular path-
way implicated in IPMNs [49, 50]. Somatic
mutations in GNAS are observed in 50–70% of
IPMNs while, strikingly, none of PDAs exam-
ined. GNAS encodes the guanine nucleotide-­
binding protein (G protein) stimulating alpha
subunit (Gsα) that functions as a mediator in the
G protein-coupled receptor (GPCR) pathway.
GDP-bound Gsα forms a heterotrimeric G protein
Another random document with
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 But the inspection was not too encouraging. We were distinctly
short of water. Qway thought we should have just enough to take us
out to his “Valley of the Mist,” and back again to Dakhla, if all went
well, but he pointed out that we had one lame camel and another
limping slightly, and that at that season it was quite possible that we
might get some hot days with a simum blowing, and he consequently
thought that it would be far better to be on the safe side and go
straight back to Dakhla, rest the camels, and then come out and go
on to the valley on the next journey.
As this was obviously sound advice, we struck camp, packed up
and prepared to set off at once towards Dakhla, leaving several
sacks of grain behind us, which greatly eased the burden of the
camels and allowed us to leave the two limping beasts unloaded.
The wady in which the camp had been pitched evidently lay on
the southern fringe of the plateau, and opened out on its eastern
side down a sandy slope on to the lower ground beyond. The
plateau, I knew, did not extend much farther to the east, so with two
damaged camels in the caravan, I thought it best to avoid a return
over the very rough road we had followed on our outward journey,
and to strike instead in an easterly direction, round the south-east
corner of the tableland, over the smooth sandy desert lying at the
foot of the scarp of the plateau.
This road, though somewhat longer than the one we had followed
on our outward journey, proved to be excellent going; it lay almost
entirely over smooth hard sand. We continued to follow an easterly
course till the middle of the next morning, when, on reaching the
edge of the dune belt that runs along the western boundary of
Dakhla, we turned up north towards Mut, and coasted along it.
The road was almost featureless. A few low rocky hills were seen
on the lower ground for a while after leaving the “Valley of the Rat,”
but even these soon ceased. From this point onwards we saw
nothing of interest, with the exception of some pieces of petrified
wood, lying on a greenish clay, until we reached our destination at
Mut, in Dakhla Oasis. In the desert round about Kharga and Dakhla
we several times came across the petrified remains of trees, though
they never occurred in large patches.
Qway proved to be right in his forebodings of hot weather, and we
had two days of fairly warm simum wind. We, however, managed to
get in without suffering unduly from thirst—but I felt rather glad that
we had not tried to reach that valley.
The state of my caravan necessitated my giving them some days’
rest, to enable them to recover their condition, and to allow their feet
to get right again after the hard usage they had received on the
sharp rocks of the plateau, before setting out again into the desert.
In the meantime I conducted an experiment to try and locate the
position of the place from which the palm doves—the kimri sifi—were
said to come. Their migration was just at its height, and several
times, while on the plateau, we put them up from the rocks on which
they had alighted to rest during their flight.
The kimri sifi always arrived in the oasis just before sunset, and
as they generally made for a particular well to the south-west of Mut,
I went there one evening with a compass and gun to wait for them. I
took the bearing with my compass to the direction in which a number
of them came. These bearings tallied very closely, the average of
them being 217° mag.
I then shot a few of them just as they were alighting, and cut them
open. They had all been feeding on seeds—grass seeds apparently
—and olives. The seeds were in an almost perfect condition, but the
olives were in such an advanced state of digestion as to be hardly
recognisable.
I next bought some doves of the ordinary kind kept in the oasis
from the villagers, and confined them in a cage. At sunrise the
following morning I fed them on olives and then, towards midday,
took them out one by one, at intervals of an hour, killed them, and
cut them open to see the state of the olives. Those of the one killed
at three o’clock seemed in the state most resembling those taken
from the kimri sifi I had shot, showing that it required about nine
hours’ digestion to reduce them to that condition.
 The kimri sifi is a weak-flighted bird, and, judging from the
numbers we put up in the desert from places where they had settled
down to rest, spends a considerable part of the day during the flight
to Mut from the oasis where the olives grow, resting upon rocks in
the desert. I consequently concluded that its average speed,
including the rests, during its journey from the olive oasis, would be
about twenty-five miles an hour.
Applying the principles of Sherlock Holmes to the case I deduced
—I believe that to be the correct word—that the oasis the kimri came
from lay in the direction of the mean of the bearings I had taken, viz.
217° mag., at a distance of nine times twenty-five, or two hundred
and twenty-five miles, and that it contained olive trees. Some years
later an Arab told me that there was an oasis off there that contained
large quantities of olive trees. Boy scouts will, I trust, copy!
 CHAPTER VIII

H AVING given my caravan sufficient time to recover from their

previous journey, I set out again into the desert. On this
occasion the camels were much more heavily loaded, as I had
determined to cover as much ground as possible.
But we had not proceeded for more than four hours from Mut
when one of the camels fell dead lame again. As it was obviously
hopeless to think of taking him along with us, and we had proceeded
such a short distance, I decided to turn back and make a fresh start.
On reaching Mut we fired the camel and then the poor brute was
cast loose. He hobbled painfully about for a few minutes, and then
with a grunt knelt down on the ground. Musa, with the idea perhaps
of relieving his sufferings, squatted on his heels in front of him, and
proceeded to warble to him on his flute.
This was an expedient to which he often resorted in order to
soothe the beasts under his charge. Frequently, after an unusually
heavy day in the desert, when the camels had been fed, he would
squat down among them and discourse wild music from his reed
flute to them, till far into the night. As this generally had the effect of
keeping me awake, I rather objected to the proceeding.
On this occasion his musical efforts seemed curiously to take
effect. The camel for some time remained shuffling uneasily on the
ground, probably in considerable pain. But after a time he became
quieter, and before long he stretched his long neck out upon the
ground and apparently went to sleep.
The day after our operation on the camel we started off again for
the “Valley of the Mist” and Qway’s high black mountain.
The weather at the beginning of April is always variable. A strong
northerly wind sprang up towards evening, on the third day out, and
made things rather uncomfortable. The sky at dusk had a curious
silvery appearance that I had noticed often preceded and followed a
sand storm. It was presumably caused by fine sand particles in the
upper reaches of the atmosphere. The wind dropped after dark, as it
frequently does in the desert, but it sprang up again in the morning
with increased strength. During the night it worked round from north
towards the east, and by morning had got round still farther, and was
blowing a gale from the south, right into our teeth.
Soon after our start, we found considerable difficulty in making
any headway against it, and before long we were marching into a
furious gale. One of the beasts, which was perhaps rather
overloaded, was several times brought to a standstill by a violent
gust. An unusually powerful one that struck him fairly brought him
down on his knees. We got him on his feet again, but had gone but a
short way when another camel followed his example. Then the first
one came down again and this time threw his load.
It was obviously useless to attempt to proceed, so having
reloaded the camel, we retraced our steps to a hill at the foot of
which we had camped. It was, of course, quite out of the question to
pitch the tent, so it was left tied up in a bale, together with the other
baggage, while we climbed up on to a ledge that ran round the hill,
about twenty feet above its base. Here we were above the thickest of
the clouds of sand that swept over the surface of the ground so
densely that it was hardly possible to see more than a few yards in
any direction.
Towards the afternoon the wind increased if anything in force, and
small stones could be heard rattling about among the rocks on the
hill. It veered round once more till it was blowing again from the
north. The gale had considerably fallen off by sunset. I accordingly,
rather to my subsequent regret, decided to spend the night at the
bottom of the hill.
When I got out my bedding, I picked up a woollen burnus and
shook it to get rid of the sand. It blazed all over with sparks. I put the
end of my finger near my blankets, and drew from them a spark of
such strength that I could very faintly feel it. When I took off the hat I
was wearing I found that my hair was standing on end—this I hasten
to state was only due to electricity.
The wind died out towards morning. I had, however, to get up
several times before midnight to shake off the sand that had
accumulated on my blankets, to prevent being buried alive, for it
drifted to an extraordinary extent round the flanks of the hill.
We had started off some time the following morning before it
struck me that there was something wrong with the baggage, and I
found that the tent had been left behind. We found it at the foot of the
hill completely buried by the sand that must have banked up during
that gale to the height of two or three feet against the hill.
The horrors of a sand storm have been greatly overrated. An
ordinary sand storm is hardly even troublesome, if one covers up
one’s mouth and nose in the native fashion and keeps out of the
sand. A certain amount of it gets into one’s eyes, which is
unpleasant, but otherwise there is not much to complain about. On
the other hand, there is an extraordinarily invigorating feeling in the
air while a sand storm is blowing—due perhaps to the electrified
condition of the sand grains, which, from some experiments I once
made on the sand blown off a dune, carry a fairly high charge of
positive electricity.
The storm I have described was certainly unpleasant, but it had
one compensation—Musa left his reed flute lying on the sand, and
my hagin promptly ate it! That camel seemed to be omnivorous.
Feathers, tent pegs and gun stocks all figured at various times in his
bill of fare. But bones were his favourite delicacy; a camel’s skeleton
or skull by the roadside invariably drew him off the track to
investigate, and he seldom returned to his place without taking a
mouthful. In consequence, among the numerous names by which he
was known in the caravan—they were all abusive, for his habits were
vile—was that of the ghul, or cannibal.
We got off at five in the morning the day following the sand storm,
and, after a six hours’ march, reached the sacks of grain in the
“Valley of the Rat.” As the day was rather warm, we rested the
camels here for four hours and then pushed on for Qway’s “high
black mountain” and the “Valley of the Mist.”
I had hoped great things from Qway’s description of them, but
unfortunately I had not taken into account the want of proportion of
the bedawin Arabs. The “high black mountain” was certainly black,
but it was only seventy feet high!
From the top of this “mountain” we were able to look down into the
“Valley of the Mist.” Here, too, great disappointment met me. The
wady was there all right—it was an enormous depression, about two
hundred and fifty feet lower than the plateau. But the vegetation and
the huge oasis, that I had been expecting from Qway’s account of
the “mist,” were only conspicuous by their absence. The wady was
as bare as the plateau; and considering the porous nature of the
sand that covered its floor, and the height above sea-level as
compared with the other oases, it could hardly have been otherwise.
It was clearly, however, of enormous size, for it stretched as far as
we could see south of an east and west line, as a vast expanse of
smooth sand, studded towards the south and east by a few low
rocky hills, but absolutely featureless to the south-west and west.
The “mist,” upon which Qway laid such stress, I found was not
due to moisture at all, but to refraction, or rather to the absence of it.
The hot sun blazing down on to a flat stony desert, such as the
plateau over which we had been travelling, causes a hazy
appearance in the nature of a mirage on the distant horizon. But,
when looking from the top of a tableland over a deep depression
some distance away, this hazy appearance is absent, as the line of
sight of the spectator lies the height of the cliff above the floor of the
depression, instead of being only a few feet above it. Though the
“Valley of the Mist” was invisible from the point where Qway had first
seen his “high black mountain,” his experienced eye had seen that a
depression lay beyond it, owing to the absence of this haze, which,
however, is only to be seen under certain conditions.
With some difficulty we managed to get the caravan down from
the plateau on to the lower ground, and then coasted along towards
the west, under the cliff, in order to survey it. This scarp ran
practically due east and west, without a break or indentation until we
came to a belt of dunes which poured over it, forming an easy ascent
on to the plateau, up which we proceeded to climb.
At the top the sand belt passed between two black sandstone
hills, from the summit of one of which a very extensive view over the
depression was obtainable. It was at once clear that there was no
prospect of finding water—still less an oasis—for at least two days’
journey farther to the south, for there was nothing whatever to break
the monotony of the sand-covered plain below us. As the water
supply was insufficient to warrant any further advance from Mut, we
had to return—always a depressing performance.
We found, however, one hopeful sign. The pass that led over the
dune belt on to the plateau—the “Bab es Sabah,” or “gate of the
morning,” as the poetical Khalil called it, because we first sighted it
soon after dawn—had at its foot an ’alem. When I plotted our route
on the map, I found that this ’alem lay almost exactly in line with the
old road we had followed on our first journey out from Mut, showing
that the pass had been the point for which it had been making. The
place to which this road led would consequently be sure to lie near,
or on the continuation of the bearing from the pass to the place
where we had seen the two first ’alems. This was a point of
considerable importance, as there seemed to be little chance of
finding any remains of the road itself on the sandy soil of the
depression, unless we should happen to land on another ’alem. The
bearing we had been marching on before was such a short one that
there was always the risk that, owing to the obstruction to the direct
road of some natural feature, the short section of it, along which the
bearing was taken, was not running directly towards its ultimate
destination.
While hunting round about the camp, I found embedded in the
sand two pieces of dried grass, much frayed and battered. So on
leaving the camp next day, we followed the line of the sand belt to
the north, as showing the direction of the prevailing wind, in hopes of
finding the place from which the dried grass embedded in the dune
had come.
 View near Rashida.
Note the wooded height in the background and the scrub-lined stream in foreground
from the well under the large tree on the right. (p. 49).

A Conspicuous Road—to an Arab.

Two small piles of stone, or ’alems can, with difficulty, be seen. Arabs can march for
hundreds of miles through a waterless desert, relying on landmarks such as these.
(p. 86).
 Battikh.
A type of sand erosion, known as battikh or “watermelon” desert. (p. 308).

We left the camp about half-past seven. Soon after four we

entered what is known as a redir—that is to say, a place where water
will collect after one of the rare desert rains. It was a very shallow
saucer-like hollow, a few feet in depth, the floor of which consisted of
clay. The farther side of this was covered with sand, and here we
found the grass for which we had been searching.
It was very thinly scattered over an area a few hundred yards in
diameter. It was quite shrivelled and to all appearances completely
dead. But it was the first vegetation we had seen on the plateau to
the south-west of Dakhla. This redir showed a noticeable number of
tracks of the desert rats, and was probably one of their favourite
feeding grounds.
Having solved the problem of the grass, as our water supply was
getting low, we turned off in a north-easterly direction, making for
Dakhla. The plateau surface changed for the worse, and a
considerable amount of sofut had to be crossed; but fortunately the
camels held out. We crossed two old roads running up north,
apparently to Bu Mungar and Iddaila. Here and there along these old
disused roads we saw circles, four or five feet in diameter, sparsely
covered with stones about the size of a hen’s egg, scattered on the
sandy surface, that obviously had been placed there by human
agency. Qway explained that these were the places where the old
slave traders, who used these roads, had been in the habit of laying
their water-skins. A gurba, raised slightly off the ground in this way,
so that the air can circulate round it, keeps the water much cooler
than when laid with a large part of its surface in contact with the
ground.
Other evidence of the old users of these roads were to be seen in
an occasional specimen of an oval, slightly dished stone about two
feet long, known as a markaka, on which they used to grind, or
rather crush, their grain with the help of a smaller hand stone, and
also in the quantities of broken ostrich shells that were frequently
seen. These shells can be found in many parts of the desert, and are
said to be the remains of fresh eggs brought by old travellers from
the Sudan to act as food on the journey. It has been argued, from
their existence, that ostriches ran wild in these deserts. But it is
difficult to see upon what food such a large bird could have
subsisted.
On the second day after leaving the redir, we got on to another
old road, and continued to follow it all day. This road eventually took
us to a clump of four or five green terfa bushes, and a second one of
about the same size was reached soon afterwards. These little
clusters of bushes proved afterwards to be of the greatest assistance
to us, as they not only afforded the camels a bite of green food, but
were the source from which came most of the firewood that we used
in the desert. Evidently others had found them useful too in the past,
for no less than four old roads converged on to them—a striking
instance of the value of green food and firewood in the desert. Some
broken red pottery was found amongst these bushes.
Shortly after leaving them we found the track of a single camel
going to the west—obviously to Kufara. But beyond this single track,
and that of the five camels we had seen on our first journey from
Mut, we never saw any modern traces of human beings on the
plateau.
The weather, which had been very hot, fortunately grew suddenly
cool, and once or twice a few drops of rain fell. This change in the
temperature was most welcome, as the camels were becoming
exhausted with their long journey away from water, and showing
unmistakable signs of distress. The change to colder weather,
however, revived them wonderfully.
The road, unluckily, became much worse, and we got on to a part
of the plateau thickly covered by loose slabs of purplish-black
sandstone, many of which tinkled like a bell when kicked.
On the day before we reached Dakhla there was a slight shower
in the morning just after we started, and the weather remained cool,
with a cold north wind and overcast sky all day. We were
consequently able to make good progress, and by the evening had
reached the north-east corner of the plateau and were within a day’s
journey of Mut.
Just before camping there was a sharp shower accompanied by
thunder and lightning, enough rain falling during the few minutes it
lasted to make my clothing feel thoroughly damp.
The tent was pitched on a sandy patch, and had hardly been
erected before the rain, for about a quarter of an hour, came down in
torrents, with repeated flashes of vivid lightning, which had a very
grand effect over the darkened desert.
I was just going to turn in about an hour afterwards when my
attention was attracted by a queer droning sound occurring at
intervals. At first I thought little of it, attributing it to the wind blowing
in the tent ropes, which the heavy rain had shrunk till they were as
taut as harp strings. The sound died away, and for a few minutes I
did not hear it.
Then again it swelled up much louder than before and with a
different note. At first it sounded like the wind blowing in a telegraph
wire; but this time it was a much deeper tone, rather resembling the
after reverberation of a great bell.
 I stepped out of the tent to try and discover the cause. It was at
once clear that it could not be due to the wind in the tent ropes, for it
was a perfectly calm night. The thunder still growled occasionally in
the distance and the lightning flickered in the sky to the north. After
the hot scorching weather we had experienced, the air felt damp and
chilly enough to make one shiver.
The sound was not quite so distinctly audible outside the tent as
inside it, presumably owing to the fact that the rain had so tightened
the ropes and canvas that the tent acted as a sounding board. At
times it died away altogether, then it would swell up again into a
weird musical note.
Thinking that possibly it might be due to a singing in my ears, I
called out to my men to ask if they could hear anything.
Abd er Rahman, whose hearing was not so keen as his eyesight,
declared that he could hear nothing at all. But Khalil and Qway both
said they could hear the sound, Qway adding that it was only the
wind in the mountain. It then flashed across me that I must be
listening to the “song of the sands,” that, though I had often read of, I
had never actually heard.
This “song of the sands” was singularly difficult to locate. It
appeared to come from about half a mile away to the west, where
the sand came over a cliff. It was a rather eerie experience
altogether.
Musical sands are not very uncommon. The sound they emit is
sometimes attributed, by the natives, to the beating of drums by a
class of subterranean spirits that inhabit the dunes. In addition to
those sands that give out a sound of their own accord, there is
another kind that rings like a bell when struck. A patch of sand of this
kind is said to exist on the plateau to the north of Dakhla Oasis. I
never personally came across any sand of this description, but much
of the Nubian sandstone we found on the plateau to the south-west
of Dakhla Oasis gave out a distinctly musical sound when kicked,
and in the gully that leads up to the plateau at the Dakhla end of the
’Ain Amur road, I passed a shoulder of rock that emitted a slight
humming sound as a strong south wind blew round it.
 The following day we reached Mut without any further incident.
We, however, only just got in in time as our water-tanks were
completely empty, after our journey of eleven days in the desert.
Knowing that many of the natives in Dakhla suspected me of
being engaged on a treasure hunt, and of looking for the oasis of
Zerzura, I had played up to the theory by continually asking for
information on the subject. On our return from such a long journey
into the desert several natives, assuming that we must have found
something, came round to enquire whether I had actually found the
oasis.
Khalil, who had heard the account in the “Book of Treasure,”
called my attention to the fact that the road we had followed on our
return journey, until it lost itself in the sand dunes on the outskirts of
Dakhla, at that time was leading straight for the Der el Seba’a Banat,
and gave it as his opinion that, if we only followed the road far
enough in the opposite direction, it would be bound to lead us to
Zerzura. For the benefit of any treasure seekers who wish to look for
that oasis, to embark on a treasure hunt, I will mention another and
still more significant fact—that road exactly follows the line of the
great bird immigration in the spring—showing that it leads to a fertile
district, and moreover—most significant fact of all—many of those
birds are wild geese!
 CHAPTER IX

I N the journey from which we had just returned, we had been a

rather long time away from water for that time of year, and the
camels were in a very exhausted condition from the hard travelling in
the heat on a short allowance of water. It was then May, and March
is usually considered in Egypt as being the last month for field work,
so I decided to give them a rest to recover their condition, and then
go back to Kharga Oasis and the Nile Valley.
The men, with the exception of Khalil, had all settled down to the
routine of desert travelling, and were working well. The mainstay of
the caravan was Qway. He was a magnificent man in the desert, and
was hardly ever at fault.
Finding that the caravan was rather overloaded at our start for our
third journey, I left, on our second day out, a tank of water and two
sacks of grain in the desert, to be picked up on our way back to Mut.
From that point we had gone three days to the south. We had then
gone two days south-west; then two days west; another day towards
the north-west, and then three days north-east. All but the first four
days of this journey had been over ground which was quite unknown
to him; but when at the end of this roundabout route I asked him to
point out to me where our tank and sacks had been laid, he was able
to indicate its position without the slightest uncertainty.
At first sight the faculty that a good desert guide has of finding his
way about a trackless desert seems little short of miraculous. But he
has only developed to an unusual degree the powers that even the
most civilised individual possesses in a rudimentary state.
Anyone, for instance, can go into a room that he knows in the
dark, walk straight across from the door to a table, say, from there to
the mantelpiece, and back again to the door without any difficulty at
all, thus showing the same sense of angles and distances that
enabled Qway, after a circuitous journey of a hundred and sixty
miles, to find his way straight back to his starting-point. The Arabs,
however, have so developed this faculty that they can use it on a
much larger scale.
The bedawin, accustomed to travelling over the wide desert
plains, from one landmark to another, keep their eyes largely fixed
on the horizon. You can always tell a desert man when you see him
in a town. He is looking towards the end of the street, and appears to
be oblivious of his immediate surroundings. This gives him that “far-
away” look that is so much admired by lady novelists.
It would be rash, however, to assume that a desert guide does not
also notice what is going on around him, for there is very little indeed
that he does not see. He may be looking to the horizon to find his
next landmark during a great part of his time, but he also scans most
closely the ground over which he is travelling, and will not pass the
faintest sign or footprint, without noticing it and drawing his own
conclusions as to who has passed that way and where they were
going. He may say nothing about them at the time; but he does not
forget them.
Nor will he forget his landmarks, or fail to identify them when he
sees them a second time; a good guide will remember his landmarks
sufficiently well to be able to follow without hesitation, a road that he
has been over many years before, and has not seen in the interval.
Frequently, after passing a conspicuous hill, I have seen Qway
glance over his shoulder for a second or two, to see what it would
look like when he approached it again on the return journey, and to
note any small peculiarities that it possessed.
In addition to this sense of angles and distances, these desert
men have in many cases a wonderfully accurate knowledge of the
cardinal points of the compass. This seems at first sight to amount
almost to an instinct. It is, however, probably produced by a
recollection of the changes of direction in a day’s march which has,
through long practice, become so habitual as to be almost
subconscious.
 A good guide can not only steer by the stars and sun, but is able
to get on almost equally well without them. On the darkest and most
overcast night, Qway never had the slightest doubt as to the
direction in which our road lay—and this too in a part of the desert
which he had previously never visited.
I often tested the sense of direction possessed by my men when
we got into camp, by resting a rifle on the top of a sack of grain and
telling them to aim it towards the north, afterwards testing their
sighting by means of my compass.
Qway and Abd er Rahman were surprisingly consistent in their
accuracy, and there was very little indeed to choose between them.
There was considerable rivalry between them on this point in
consequence. They were very seldom more than two degrees wrong
on one side or the other of the true north.
Qway was an unusually intelligent specimen of the bedawin Arabs
—a race who are by no means so stupid as they are sometimes
represented. There was little that he did not know about the desert
and its ways, and he was extraordinarily quick to pick up any little
European dodges, such as map-making to scale, that I showed him;
but on questions connected with irrigation, cultivation, building, or
anything that had a bearing on the life of the fellahin, he was—or
professed to be—entirely ignorant. He regarded them as an inferior
race, and evidently considered it beneath his dignity to take any
interest at all in them or their ways. He seldom alluded to them to me
without adding some contemptuous remark. He never felt at home in
the crowded life of the Nile Valley, declared that he got lost whenever
he went into a town—this I believe to be the case with most bedawin
—that the towns were filthy, the inhabitants all thieves, liars,
“women” and worse, and that the drinking water was foul, and even
the air was damp, impure, and not to be compared with that of his
beloved desert.
The opinion of the Egyptians of the Nile Valley is equally
unfavourable to the Arabs. They regard them as an overbearing,
lawless, ignorant set of ruffians whom they pretend to despise—but
they stand all the same very much in awe of them. After all, their
views of each other are only natural; their characters have practically
nothing in common, and criticism usually takes the form of “this man
is different from me, so he must be wrong.”
Qway, in the caravan, was invariably treated with great respect.
He was usually addressed to as “khal (uncle) Qway,” and he was not
the man to allow any lapses from this attitude, which he considered
his due as an Arab and as the head-man of the caravan. Any falling
off in this respect was immediately followed by some caustic
reference on his part to the inferiority of slaves, “black men,” or
fellahin, as the case required.
Abd er Rahman and the camel men all did their work well, and the
difficulties due to the sand and the attitude of the natives that I had
been warned that I should have to face, all appeared to be greatly
exaggerated. With Qway as my guide, I hoped with the experience I
had already gained, to make an attempt the next year, with a
reasonable prospect of success, to cross the desert, or at any rate to
penetrate much farther into it than I had already done, and reach
some portion that was inhabited.
But just when I was preparing to return to Egypt, an event
happened that put an entirely new complexion upon things, and
upset the whole of my plans.
During our absence in the desert, a new mamur arrived in Dakhla
Oasis and came round to call on me. He was rather a smart-looking
fellow, dressed in a suit considerably too tight for him, of that peculiar
shade of ginger so much affected by the Europeanised Egyptians.
He had the noisy boisterous manner common to his class, but he
spoke excellent English and was evidently prepared to make himself
pleasant.
Before he left, he informed me that the postman had just come in,
and that news had arrived by the mail of the revolution in Turkey.
This revolution had long been simmering, with the usual result that
the scum—in the form of Tala’at and the Germanised Enver—had
come up to the top. The Sultan had been deposed, and it was
considered likely that he would be replaced by some sort of republic.
The whole Moslem community was in a very excited state in
consequence.
A day or two later the Coptic doctor dropped in. He told me that
he had just seen Sheykh Ahmed, from the zawia at Qasr Dakhl—
whose guest I had been at his ezba—who had told him that if the
revolution in Turkey succeeded and the Sultan really were deposed,
the Senussi Mahdi would reappear and invade Egypt. The Mahdi, it
may be mentioned, is the great Moslem prophet, who according to
Mohammedan prophecies, is to arise shortly before the end of the
world, to convert the whole of mankind to the faith of Islam.
This, if it were true, was important news. The position was one
fraught with considerable possibilities. In order to understand the
situation some explanation may perhaps be useful to those
unacquainted with Mohammedan politics.
Egypt at that time was a part of the Turkish Empire—our position
in the country being, at any rate in theory, merely that of an
occupation, with the support of a small military force. The Sultan of
Turkey was consequently, nominally, still the ruler of the country.
But in addition to being Sultan of Turkey, Abdul Hamid was also
the Khalif of Islam—an office that made him a sort of Emperor-Pope
of the whole of the Mohammedans. His claim to be the holder of this
title was in reality of a somewhat flimsy character; but whatever his
rights to it may have been according to the strict letter of the Moslem
law, he was almost universally regarded by the members of the
Sunni Mohammedans as their Khalif, that is to say, as the direct
successor, as the head of Islam, of the Prophet Mohammed himself,
in the same way that the Pope is regarded as the direct successor to
St. Peter.
A revolution always loosens the hold that the central Government
has over the outlying parts of a country, and in a widespread and
uncivilised empire like that subject to the Sultan of Turkey, where
centuries of misgovernment have produced a spirit—it might almost
be said a habit—of revolt, serious trouble was bound to follow, if the
Sultan should be deposed and his place be taken by a republic. Not
only would Egypt and Tripoli be deprived of the ruler to whom they
owed their allegiance, but the whole native population of North
Africa, with the exception of an almost negligible minority, would be
left without a spiritual head. This would have been clearly a situation
that opened endless possibilities to such an enterprising sect as the
Senussia, whose widespread influence through North Africa is
shown by the numerous zawias they have planted in all the countries
along the south of the Mediterranean and far into the interior of the
continent.
Egypt, as the richest of these countries, was likely to offer the
most promising prize. The fellahin of Egypt, when left to themselves,
are far too much taken up in cultivating their land to trouble
themselves about politics, and though of a religious turn of mind, are
not fanatical. But, as recent events have shown, they are capable of
being stirred up by agitators to a dangerous extent.
I several times heard the Senussi question discussed in Egypt.
Opinions on its seriousness varied greatly. Some loudly and
positively asserted that the threat of a Senussi invasion was only a
bugbear, and, like every bugbear, more like its first syllable than its
second. But there were others who relapsed into silence or changed
the subject whenever it was mentioned. It was, however, certain that
with the small force we at that time possessed in the country, an
attempt to invade Egypt by the Senussi accompanied, as it was
almost certain it would have been, by a rising engineered by them
among the natives of the Nile Valley, would have caused a
considerable amount of trouble.
The appearance of a Mahdi—if he is not scotched in time—may
set a whole country in a ferment. Not infrequently some local
religious celebrity will proclaim himself the Mahdi and gain perhaps a
few followers; but his career is usually shortlived. Occasionally,
however, one arrives on the scene, who presents a serious problem
—such, for instance, as the well-known Mahdi of the Sudan, and the
lesser known, but more formidable, Mahdi of the Senussi sect.
The latter, though he seems to have been a capable fellow, was a
theatrical mountebank, who preferred to surround himself with an