www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2017
Peritoneal carcinomatosis: limits of diagnosis and the case for
James R.W. McMullen1, Matthew Selleck2, Nathan R. Wall1 and Maheswari Senthil2
1 Department of Basic Sciences, Center for Health Disparities & Molecular Medicine, Division of Biochemistry, Loma Linda
University Medical Center, Loma Linda, CA, USA
2 Department of Surgery, Division of Surgical Oncology, Loma Linda University Medical Center, Loma Linda, CA, USA
Correspondence to: Nathan R. Wall, email: firstname.lastname@example.org
Correspondence to: Maheswari Senthil, email: email@example.com
Keywords: peritoneal carcinomatosis, liquid biopsy, biomarker, exosomes
Received: January 21, 2017 Accepted: March 15, 2017 Published: March 22, 2017
Peritoneal Carcinomatosis (PC) is a late stage manifestation of several
gastrointestinal malignancies including appendiceal, colorectal, and gastric cancer.
In PC, tumors metastasize to and deposit on the peritoneal surface and often leave
patients with only palliative treatment options. For colorectal PC, median survival
is approximately ve months, and palliative systemic therapy is able to extend this
to approximately 12 months. However, cytoreductive surgery with hyperthermic
intraperitoneal chemotherapy (CRS/HIPEC) with a curative intent is possible in
some patients with limited tumor burden. In well-selected patients undergoing
complete cytoreduction, median survival has been reported as high as 63 month.
Identifying patients earlier who are either at risk for, or who have recently developed
PC may provide them with additional treatment options such as CRS/HIPEC. PC is
diagnosed late by imaging ndings or often times during an invasive procedures such
as laparoscopy or laparotomy. In order to improve the outcomes of PC patients, a
minimally invasive, accurate, and specic PC screening method needs to be developed.
By utilizing circulating PC biomarkers in the serum of patients, a “liquid biopsy,” may
be able to be generated to allow a tailored treatment plan and early intervention.
Exosomes, stable patient-derived nanovesicles present in blood, urine, and many
other bodily uids, show promise as a tool for the evaluation of labile biomarkers.
If liquid biopsies can be perfected in PC, manifestations of this cancer may be more
eectively treated, thus oering improved survival.
Peritoneal Carcinomatosis (PC) is a late stage
manifestation of several gastrointestinal malignancies
characterized by tumor deposition across the peritoneal
surface . This can be entirely asymptomatic in its early
stages, or as the disease progresses, symptoms such as
nausea, diarrhea, abdominal pain, bloating, and weight
loss may develop . The disease is often discovered
when ascites or intestinal obstruction develop, occurring
generally with greater tumor burden which is more
dicult to treat . Early PC detection when there is
limited tumor burden may increase the eectiveness of
current treatment options .
Colorectal cancer (CRC), the third most common
cancer in the world, provides a good case study of PC. In
2016 there will be an estimated 95,270 cases of colorectal
cancer in the United States and nearly 1.4 million cases
worldwide . Synchronous PC is diagnosed around the
time of diagnosis of primary tumor while metachronous
PC is diagnosed at a later time, typically months to
years after the original diagnosis . The incidence
of synchronous isolated peritoneal carcinomatosis in
patients with CRC varies somewhat in the literature from
4%-18% [6-9]. This may even be a low estimate given
the lack of sensitivity of imaging for PC and that it may
not be discovered until surgical exploration. Meanwhile,
metachronous PC has been reported in 5-19% of patients
following denitive treatment.
CYTOREDUCTIVE SURGERY (CRS)
PC used to be considered a lethal disease with
no curative surgical options. However, the growing
acceptance of CRS with hyperthermic intraperitoneal
chemotherapy (HIPEC), has oered the possibility of
improved survival for carefully selected patients .
This method makes use of “cytoreduction” to surgically
remove gross visible tumor deposits followed by direct
contact of heated cytotoxic chemotherapy agents to
aect any residual disease. Given during surgery, this
protocol maximizes potential contact with the peritoneal
surface while minimizing systemic toxicity. Specically,
hyperthermia between 41 and 43 degrees centigrade is
combined with large molecular weight drugs that penetrate
between a few cells deep to 3mm causing cytotoxic eects
. Dr. Paul Sugarbaker is credited with developing this
treatment option by combing these elements into a curative
approach to peritoneal dissemination of gastrointestinal
malignancies [11, 12]. Median survival of CRC PC
without any treatment is approximately 4-7 months, while
palliative systemic therapy may extend this to 12-23
months based on several series [13-15]. Median overall
survival with CRS/HIPEC has been reported to range
from 22 to 63 months with a 5-year survival of 40-51%
in selected patients [13, 15, 16]. The outcomes of CRS/
HIPEC are strongly inuenced by careful patient selection
and complete cytoreduction (CC-0) (see Table 1) .
Survival of patients with colorectal cancer who receive
less than complete cytoreduction (CC-1 or CC-2) or have
a higher burden of disease as indicated by the peritoneal
carcinomatosis index (PCI) (see Figure 1) is signicantly
diminished compared to that of a CC-0 resection [17-19].
Extensive disease burden at identication often leaves
patients with only palliative treatment options .
Despite the benet of CRS/HIPEC, only about 25% of
patients with PC will be eligible for this approach given
the late presentation and burden of disease. In order to
expand patient eligibility and oer treatment with a
curative intent, early detection of PC, before signicant
tumor burden develops, is essential.
Traditional imaging, such as CT and MRI lack
sensitivity to both detect and estimate disease burden
in PC. Classic computed tomography (CT) signs of PC
such as “omental caking,” thickening of the omentum,
and peritoneal nodules are not common radiographic
ndings in “early” disease states. Several studies designed
to determine the specicity and accuracy of CT scans in
assessing tumor burden for PC found that CT signicantly
underestimated the amount of disease present in the
peritoneal cavity [21-24]. Sensitivity for CT detection
of tumor nodules less than 0.5 cm and 1cm had been
reported to be 11% and 25-50% respectively . This
is particularly important in colorectal PC, where PCI is
a critical determinant of complete cytoreduction and
Figure 1: Peritoneal Cancer Index (PCI) scoring system. PCI is a diagnostic and prognostic tool that is a sum of scores in thirteen
abdominal regions. Each receives a score of 0-3 based on the largest tumor size in each region. Scores range from 0 to 39. Higher scores
indicate more widespread and/or larger tumors in the peritoneal cavity.
long-term outcomes . In a study by Koh et al looking
specically at CRC PC they determined CT signicantly
underestimated clinical PCI . In fact sensitivity of
small bowel involvement in each region ranged from
8-17%. Despite this, the Fifth International Workshop on
Peritoneal Surface Malignancy in Milan, identied CT as
the principal imaging modality to assess suitability for
CRS . Ultrasound also has very limited sensitivity
for detecting PC nodules [27-29]. Magnetic resonance
imaging (MRI), and particularly diusion weighted
images, has been demonstrated in prospective studies to
have increased accuracy in detection of carcinomatosis
within certain areas of the abdomen . This however
carries its own limitations due to the motion artifacts
of peristalsis, cost, and the need for radiologists trained
in their interpretation and inter-observer variation.
Additionally, positron emission technology (PET) may
have increased sensitivity, but similar limitations and
absence of added clinical value often precludes its use for
determining resectability [24, 31-33]. These diculties,
especially limited sensitivity, lack of meaningful clinical
correlation and high cost, reduce the utility of non-
invasive imaging in the early detection of PC. With the
current technology, laparoscopy or exploratory surgery is
often necessary to conrm the diagnosis and extent of PC
(see Table 2) .
Given the narrow subset of patients who are oered
CRS/HIPEC, a potentially life-saving treatment, we are
in need of a paradigm change. Patients who are either at
risk for developing PC or who are in the earliest stage
of this disease process may signicantly benet from
expanded treatment options. The term “liquid biopsy” has
reached prolic use as large-scale investigations seek to
identify tumor markers in the serum. This usually refers to
molecular diagnostic studies that are performed on blood
or body uid as opposed to cancerous tissue itself .
Multiple serum tumor markers: carcinoembryonic antigen
(CEA), carbohydrate antigen CA 19-9, and CA 125, are
commonly elevated in patients with PC and the degree of
elevation tends to correlate with the extent of PC .
However, these serum tumor markers are inadequate for
early detection of PC. Moreover, they lack specicity to
predict the presence or risk of PC in patients with CRC.
There is a critical clinical need to identify circulating
tumor biomarkers of aggressiveness, likelihood of
recurrence, risk of metastasis such as PC, or even the
presence of a malignancy to better tailor therapy for
patients. For example, if a patient with a newly diagnosed
stage III colorectal cancer is known to be at signicant risk
for peritoneal recurrence due to the presence of a specic
set of biomarkers in their serum, they may benet from
prophylactic HIPEC. This is just one example of how this
Table 1: CC is the completeness of cytoreduction score. It indicates the size of the largest tumor that remains after
Completeness of Cytoreduction scores
Score Size of largest post-surgery residual tumor
CC-0 No visible tumor
CC-1 Less than 0.25 cm
CC-2 Between 0.25 cm and 2.5 cm
CC-3 > 2.5 cm or conuent
Table 2: This table summarizes the pros and cons of each non-invasive imaging modality in assessing PC
Non-Invasive Imaging Utility in PC Detection
Modality Pros Cons
compared to surgical analysis References
Limited PC nodule
sensitivity, highly operator
Non-specic  [24, 25]
Limited small PC nodule
25-100%/78-100% with only 11-
48% sensitivity for tumors less
than 5 mm  [18-21]
Relatively Expensive, slight
peristalsis motion artifact,
90%/95.5% (diusion weighted)
Peristalsis motion artifact 78-97%/55-90%  [27, 28]
technology may be applied.
If blood-borne biomarkers for PC with high
sensitivity and specicity are discovered, patients
developing PC may be quickly identied with a blood test,
a liquid biopsy. One such type of biomarker, microRNAs
(miRs), short, non-coding RNAs that regulate mRNAs, has
demonstrated diagnostic utility by correctly identifying
several cancers of unknown primary with reasonable
accuracy . The diagnostic miR prole that was used
in this study was generated from miR analysis in well
dierentiated primary tumors . Several miRs, such as
miR-21, have been linked to gastrointestinal cancers as
potential diagnostic targets and prognostic indicators .
However these miRs and other types of RNAs are rapidly
degraded in the plasma [39-41].
Exosomes, small cell-derived vesicles (Figure 2),
can protect RNAs and miRNAs, from being degraded [42-
46]. When researchers exposed miRs to RNase, the miRs
that were in exosomes and cells were protected while the
free RNAs were degraded . When exosomes were
exposed to RNase the contained RNAs were protected
from degradation while cellular RNA was degraded by the
same RNase . Exosomes hold great potential for both
diagnosis and prognosis of diseases and are exceptionally
useful as cancer biomarkers . When a panel of lung
cancer associated miRs was examined in solid tumors and
tumor exosomes from patient plasma, most of the miRs
were found to have highly comparable expression levels
(see Table 3 for the miRs) [48, 49]. Cervical cancer cell
line tumor derived exosomes (TEXs) contain survivin,
which contributes to cancer aggressiveness and metastatic
potential [50, 51]. In a study of ovarian cancer, greater
numbers of cancer exosomes were found in the serum
as more advanced cancer stages were examined .
Furthermore, approximately four times more serum
exosomes were discovered in lung cancer patients as
compared to cancer free controls and the exosomes
contained more than twice the miRs . In our research,
we found increased serum exosome levels in patients with
prostate and breast cancers as compared to disease free
controls [53-55]. TEXs are prevalent in patient serum from
Table 3: These lung cancer associated miRs were discovered in both solid tumor and in tumor exosomes.
miR-17-3p miR-21 miR-106a miR-146 miR-155 miR-191
miR-192 miR-203 miR-205 miR-210 miR-212 miR-214
Table 4: Gastric Cancer PC associated exosomal miRs and their prevalence in various cancers.
Gastric Cancer Lung
Cancer Adrenal Cancer
uid, cell culture
 XX↑Ø tumor tissue 
uid, cell culture
, ↓tNm tumor
↓ tumor tissue 
 ↑ serum 
lavage uid ,
↓ cancer tissue  X↓ blood
↑ blood ,
↓ solid tumor
↓ multiple types of
solid tumors 
uid, cell culture
 X X X X X
uid, cell culture
 X X X
All data is from human studies
↑, ↓-increased/decreased expression associated with cancer
↑tnM, ↓tnM -increased/decreased expression associated with metastatic cancer
↑tNm, ↓tNm -increased/decreased expression associated with lymph node metastasis
↑ Ø, ↓Ø -increased/decreased expression associated with shorter patient survival
↔-present but no signicant dierential regulation
X -no research discovered in literature
multiple cancer types and protect labile biomarkers from
degradation [42, 45, 48, 53-55].
Exosomes have not been extensively studied in
PC diagnostics. Andre and colleagues examined ascites
exosomes from patients with PC and found that the tumor
specic markers Her2/Neu, TRP1, and Mart1 were present
in ascites tumor exosomes . Tokuhisa and colleagues
have identied several RNAs present in exosomes within
peritoneal ascites, peritoneal lavage, and PC metastatic
cell lines . After exosome miR screening, 5 miRNAs
were selected as a panel of signicantly dierentially
regulated RNAs: miR 1202, 1207-5p, 1225-5p, 320c, and
4270 . miR 21 had the strongest signal intensity in
malignant ascites . Exosomes from peritoneal lavage
were probed for miR 21, 1225-5p, and 320c; miR 21 and
1225-5p were found to be upregulated in later stages of
gastric cancer and correlated with serosal invasion . In
a study on primary gastric cancer tissue, miR 1255-5p was
generally downregulated and was found to inhibit cancer
cell growth, motility, as well as cancer invasion . This
apparently contradictory result suggests that miR 1225-
5p in peritoneal lavage either is being released by non-
cancerous tissue in an attempt to stop abnormal growths
or is being used by cancers in order to facilitate better
attachment to the peritoneum. In apparently contradictory
results to the above study, in gastric cancer cell lines and
in vivo, miR 1255-5p was generally downregulated and
was found to inhibit cell growth and motility as well as
cancer invasion .
The prospective gastric PC miR biomarkers
described in the study by Tokuhisa and colleagues 
have been found to be associated with other cancers as
well (see Table 4). Notably, miR 1202, 1207-5p, 1225-5p,
and 4270, were found circulating in the blood of breast
cancer patients . In human bladder cancer tissue
samples, miR 320c was signicantly downregulated .
In hepatocellular carcinoma tissue samples, miR 1207-
5p was found to be signicantly downregulated .
In adrenocortical carcinoma tissue samples, increased
miR 1202 expression was found to be associated with
signicantly reduced patient lifespan . The gaps in our
knowledge of RNA signaling in cancer are immediately
apparent from Table 4. The observation that these miRs,
either individually or in a group, are associated with
multiple types of cancer and are found in exosomes from
the peritoneal cavity suggest the potential of exosomal
diagnosis of PC.
RNAS AND GASTRIC CANCER
RNAs are found to be globally downregulated in
cancer . Upregulated RNAs and miRs are likely to
be related to cancer growth and function or the body’s
response to cancer. miR 320c inhibited cell growth and
motility in bladder cancer . miR 1207-5p functioned
to inhibit cell growth and invasion in liver cancer but
functions to increase stemness in colorectal cancer [61,
63]. Since these exosomal-associated miRs have known
functions in tumors, the possibility emerges of tailoring
PC treatment based on what biomarkers are discovered
in a patient’s exosomes. miR 320c inhibited cell growth
and motility and miR 1207-5p functioned to inhibit cell
Figure 2: Tumor Cells release nanovesicles called exosomes which carry RNAs, including microRNAs and messenger
RNAs, and proteins.
growth and invasion. The observation that these exosomal-
associated miRs have known functions in tumors opens
up the possibility of utilizing these biomarkers to tailor an
individual patient’s treatment. [60, 61]
Additional research is needed to identify biomarkers
in peritoneal carcinomatosis. Distinguishing metastatic
disease of peritoneal origin from solid organ metastases
should be both biologically feasible and clinically
useful. As we look to exosomes to provide insight into
the eld, shared challenges in nanovesicle isolation and
validation will need to be addressed. Reliable and ecient
methods as well as recognized standards will need to be
established for clinical use. Future clinical work in this
eld should include the prospective collection of samples
for retrospective investigation. This will be instrumental
in establishing clinical validity and utility. We are hopeful
that the shared work of many will continue to yield
advances in reducing the burden of life lost from this
Recently, TEXs have been implicated in facilitating
metastasis. TEXs can be taken up by multiple cell types,
including endothelial cells, bone marrow progenitor
cells, and other cancer cells [64-67]. These exosomes
demonstrated the ability to deliver functional RNAs
and proteins to recipient cells, modifying their growth
patterns to be pro-oncogenic [65, 66]. Further, TEXs have
demonstrated the ability to greatly increase metastatic
tumor burden in a mouse model . Studying TEXs
in the context of metastasis is a promising eld. PC is
currently dicult to detect at its onset. Late PC detection
usually leaves the disease incurable. PC must be detected
sooner for better patient outcomes. Non-invasive imaging
is impractical for early PC detection. Detection of PC by
means of markers within a patient’s biouids, such as a
serum “liquid biopsy” would be ideal. Both serum and
ascites contain biomarkers released by PC. Exosomes
are released into serum by multiple types of cancers and
protect their contents from degradation in the blood. These
provide us with a likely source of a sensitive and specic
diagnostic modality to detect PC in its earliest most
The authors would like to thank the Center for
Health Disparities & Molecular Medicine for its support.
They would also like to thank members of the Wall
Laboratory for careful review of this manuscript.
Research reported in this publication was supported
by NIH award P20MD006988 (NRW).
CONFLICTS OF INTEREST
The Authors declare no conicts of interest.
1. Levy AD, Shaw JC, Sobin LH. Secondary Tumors and
Tumorlike Lesions of the Peritoneal Cavity: Imaging
Features with Pathologic Correlation. RadioGraphics. 2009;
29: 347-73. doi: 10.1148/rg.292085189.
2. Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire
M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure
JL, Porcheron J, Peix JL, François Y, et al. Peritoneal
carcinomatosis from non-gynecologic malignancies.
Cancer. 2000; 88: 358-63. doi: 10.1002/(SICI)1097-
0142(20000115)88:2 < 358::AID-CNCR16 > 3.0.CO;2-O.
3. Chia CS, You B, Decullier E, Vaudoyer D, Lorimier G,
Abboud K, Bereder JM, Arvieux C, Boschetti G, Glehen
O, Group tBIGR. Patients with Peritoneal Carcinomatosis
from Gastric Cancer Treated with Cytoreductive Surgery
and Hyperthermic Intraperitoneal Chemotherapy: Is Cure
a Possibility? Annals of Surgical Oncology. 2016: 1-9. doi:
4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016.
CA: A Cancer Journal for Clinicians. 2016; 66: 7-30. doi:
5. Mekenkamp LJM, Koopman M, Teerenstra S, van Krieken
JHJM, Mol L, Nagtegaal ID, Punt CJA. Clinicopathological
features and outcome in advanced colorectal cancer
patients with synchronous vs metachronous metastases.
British Journal of Cancer. 2010; 103: 159-64. doi: 10.1038/
6. Klaver YLB, Lemmens VEPP, Nienhuijs SW, Luyer MDP,
de Hingh IHJT. Peritoneal carcinomatosis of colorectal
origin: Incidence, prognosis and treatment options. World
Journal of Gastroenterology : WJG. 2012; 18: 5489-94. doi:
7. Klaver CEL, Musters GD, Bemelman WA, Punt CJA,
Verwaal VJ, Dijkgraaf MGW, Aalbers AGJ, van der Bilt
JDW, Boerma D, Bremers AJA, Burger JWA, Buskens
CJ, Evers P, et al. Adjuvant hyperthermic intraperitoneal
chemotherapy (HIPEC) in patients with colon cancer at
high risk of peritoneal carcinomatosis; the COLOPEC
randomized multicentre trial. BMC Cancer. 2015; 15. doi:
8. Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J,
Bouvier A-M. Epidemiology, management and prognosis
of colorectal cancer with lung metastases: a 30-year
population-based study. Gut. 2010; 59: 1383-8. doi:
9. Quere P, Facy O, Manfredi S, Jooste V, Faivre J, Lepage
C, Bouvier AM. Epidemiology, Management, and Survival
of Peritoneal Carcinomatosis from Colorectal Cancer: A
Population-Based Study. Diseases of the Colon & Rectum.
2015; 58: 743-52. doi: 10.1097/DCR.0000000000000412.
10. Yan TD, Cao CQ, Munkholm-Larsen S. A pharmacological
review on intraperitoneal chemotherapy for peritoneal
malignancy. World J Gastrointest Oncol. 2010; 2: 109-16.
11. Goodman MD, McPartland S, Detelich D, Saif MW.
Chemotherapy for intraperitoneal use: a review of
hyperthermic intraperitoneal chemotherapy and early post-
operative intraperitoneal chemotherapy. J Gastrointest
Oncol. 2016; 7: 45-57. doi: 10.3978/j.issn.2078-
12. Sugarbaker PH, Kern K, Lack E. Malignant pseudomyxoma
peritonei of colonic origin. Natural history and presentation
of a curative approach to treatment. Dis Colon Rectum.
1987; 30: 772-9. doi:
13. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal
F, Classe J-M, Ferron G, Guilloit J-M, Meeus P, Goéré
D, Bonastre J. Complete Cytoreductive Surgery Plus
Intraperitoneal Chemohyperthermia With Oxaliplatin for
Peritoneal Carcinomatosis of Colorectal Origin. Journal
of Clinical Oncology. 2009; 27: 681-5. doi: 10.1200/
14. Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD,
Goldberg RM, Pitot HC, Grothey A, Alberts SR, Sargent
DJ. Treatment of Colorectal Peritoneal Carcinomatosis
With Systemic Chemotherapy: A Pooled Analysis of North
Central Cancer Treatment Group Phase III Trials N9741
and N9841. Journal of Clinical Oncology. 2012; 30: 263-7.
15. Verwaal VJ, Ruth Sv, Bree Ed, Slooten GWv, Tinteren
Hv, Boot H, Zoetmulder FAN. Randomized Trial
of Cytoreduction and Hyperthermic Intraperitoneal
Chemotherapy Versus Systemic Chemotherapy
and Palliative Surgery in Patients With Peritoneal
Carcinomatosis of Colorectal Cancer. Journal of
Clinical Oncology. 2003; 21: 3737-43. doi: 10.1200/
16. Chua TC. Progress in the combined modality management
of peritoneal carcinomatosis. Journal of Surgical Oncology.
2010; 102: 728-9. doi: 10.1002/jso.21748.
17. Sugarbaker PH. Successful management of microscopic
residual disease in large bowel cancer. Cancer
Chemotherapy and Pharmacology. 1999; 43: S15-S25. doi:
18. Harmon RL, Sugarbaker PH. Prognostic indicators in
peritoneal carcinomatosis from gastrointestinal cancer.
International Seminars in Surgical Oncology. 2005; 2: 3.
19. Verwaal VJ, Ruth Sv, Witkamp A, Boot H, Slooten Gv,
Zoetmulder FAN. Long-Term Survival of Peritoneal
Carcinomatosis of Colorectal Origin. Annals of Surgical
Oncology. 2004; 12: 65-71. doi: 10.1007/s10434-004-
20. Verwaal VJ, Kusamura S, Baratti D, Deraco M. The
eligibility for local-regional treatment of peritoneal surface
malignancy. Journal of Surgical Oncology. 2008; 98: 220-3.
21. Dromain C, Leboulleux S, Auperin A, Goere D, Malka D,
Lumbroso J, Schumberger M, Sigal R, Elias D. Staging
of peritoneal carcinomatosis: enhanced CT vs. PET/CT.
Abdominal Imaging. 2007; 33: 87-93. doi: 10.1007/s00261-
22. Esquivel J, Chua Tc, Stojadinovic A, Melero JT, Levine Ea,
Gutman M, Howard R, Piso P, Nissan A, Gomez-Portilla
A, Gonzalez-Bayon L, Gonzalez-Moreno S, Shen P, et al.
Accuracy and clinical relevance of computed tomography
scan interpretation of peritoneal cancer index in colorectal
cancer peritoneal carcinomatosis: A multi-institutional
study. Journal of Surgical Oncology. 2010; 102: 565-70.
23. Koh J-L, Yan TD, Glenn D, Morris DL. Evaluation
of Preoperative Computed Tomography in Estimating
Peritoneal Cancer Index in Colorectal Peritoneal
Carcinomatosis. Annals of Surgical Oncology. 2008; 16:
327-33. doi: 10.1245/s10434-008-0234-2.
24. Low RN, Barone RM, Lucero J. Comparison of MRI
and CT for predicting the Peritoneal Cancer Index
(PCI) preoperatively in patients being considered for
cytoreductive surgical procedures. Annals of Surgical
Oncology. 2015; 22: 1708-15. doi: 10.1245/s10434-014-
25. da Silva RG, Sugarbaker PH. Analysis of prognostic
factors in seventy patients having a complete cytoreduction
plus perioperative intraperitoneal chemotherapy for
carcinomatosis from colorectal cancer. J Am Coll Surg.
2006; 203: 878-86. doi: 10.1016/j.jamcollsurg.2006.08.024.
26. Baratti D, Kusamura S, Deraco M. The Fifth International
Workshop on Peritoneal Surface Malignancy (Milan, Italy,
December 4-6, 2006): methodology of disease-specic
consensus. Journal of Surgical Oncology. 2008; 98: 258-
62. doi: 10.1002/jso.21056.
27. Repiso A, Gómez-Rodríguez R, López-Pardo R, Lombera
MM, Romero M, Aranzana A, Abad S, Rodríguez-Merlo
R, López L, Carboles JM. Usefulness of endoscopic
ultrasonography in preoperative gastric cancer staging:
diagnostic yield and therapeutic impact. Revista Española
De Enfermedades Digestivas: Organo Ocial De La
Sociedad Española De Patología Digestiva. 2010; 102: 413-
28. Savelli L, De Iaco P, Ceccaroni M, Ghi T, Ceccarini M,
Seracchioli R, Cacciatore B. Transvaginal sonographic
features of peritoneal carcinomatosis. Ultrasound in
Obstetrics and Gynecology. 2005; 26: 552-7. doi: 10.1002/
29. Patel CM, Sahdev A, Reznek RH. CT, MRI and PET
imaging in peritoneal malignancy. Cancer Imaging. 2011;
11: 123-39. doi: 10.1102/1470-7330.2011.0016.
30. Fehniger J, Thomas S, Lengyel E, Liao C, Tenney M, Oto
A, Yamada SD. A prospective study evaluating diusion
weighted magnetic resonance imaging (DW-MRI) in
the detection of peritoneal carcinomatosis in suspected
gynecologic malignancies. Gynecol Oncol. 2016; 142: 169-
75. doi: 10.1016/j.ygyno.2016.04.018.
31. De Vos N, Goethals I, Ceelen W. Clinical Value of (18)
F-FDG- PET-CT in the Preoperative Staging of Peritoneal
Carcinomatosis from Colorectal Origin. Acta Chirurgica
Belgica. 2014; 114: 370-5. doi:
32. Klumpp BD, Schwenzer N, Ascho P, Miller S, Kramer U,
Claussen CD, Bruecher B, Koenigsrainer A, Pfannenberg
C. Preoperative assessment of peritoneal carcinomatosis:
intraindividual comparison of 18F-FDG PET/CT and MRI.
Abdominal Imaging. 2012; 38: 64-71. doi: 10.1007/s00261-
33. Low RN, Barone RM, Lacey C, Sigeti JS, Alzate GD,
Sebrechts CP. Peritoneal tumor: MR imaging with dilute
oral barium and intravenous gadolinium-containing
contrast agents compared with unenhanced MR imaging
and CT. Radiology. 1997; 204: 513-20. doi: 10.1148/
34. Yonemura Y, Canbay E, Endou Y, Ishibashi H, Mizumoto
A, Miura M, Li Y, Liu Y, Takeshita K, Ichinose M, Takao
N, Hirano M, Sako S, et al. Peritoneal cancer treatment.
Expert Opinion on Pharmacotherapy. 2014; 15: 623-36. doi:
35. Kin C, Kidess E, Poultsides GA, Visser BC, Jerey SS.
Colorectal cancer diagnostics: biomarkers, cell-free
DNA, circulating tumor cells and dening heterogeneous
populations by single-cell analysis. Expert Review
of Molecular Diagnostics. 2013; 13: 581-99. doi:
36. Wagner PL, Austin F, Sathaiah M, Magge D, Maduekwe
U, Ramalingam L, Jones HL, Holtzman MP, Ahrendt SA,
Zureikat AH, Pingpank JF, Zeh HJ, Bartlett DL, et al.
Signicance of Serum Tumor Marker Levels in Peritoneal
Carcinomatosis of Appendiceal Origin. Annals of surgical
oncology. 2013; 20. doi: 10.1245/s10434-012-2627-5.
37. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J,
Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando
AA, Downing JR, Jacks T, Horvitz HR, et al. MicroRNA
expression proles classify human cancers. Nature. 2005;
435: 834-8. doi: 10.1038/nature03702.
38. Yin C, Zhou X, Dang Y, Yan J, Zhang G. Potential Role
of Circulating MiR-21 in the Diagnosis and Prognosis of
Digestive System Cancer: A Systematic Review and Meta-
Analysis. Medicine (Baltimore). 2015; 94: e2123. doi:
39. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J,
Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, et al.
Characterization of microRNAs in serum: a novel class of
biomarkers for diagnosis of cancer and other diseases. Cell
Research. 2008; 18: 997-1006. doi: 10.1038/cr.2008.282.
40. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman
SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom
J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher
CW, et al. Circulating microRNAs as stable blood-based
markers for cancer detection. Proceedings of the National
Academy of Sciences. 2008; 105: 10513-8. doi: 10.1073/
41. Tsui NBY, Ng EKO, Lo YMD. Stability of Endogenous
and Added RNA in Blood Specimens, Serum, and Plasma.
Clinical Chemistry. 2002; 48: 1647-53. doi:
42. Koga A, Aoyagi K, Imaizumi T, Miyagi M, Shirouzu K.
Comparison between the Gastric Cancer Cell Line MKN-
45 and the High-Potential Peritoneal Dissemination Gastric
Cancer Cell Line MKN-45P. The Kurume Medical Journal.
2011; 58: 73-9. doi: 10.2739/kurumemedj.58.73.
43. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van
Eijndhoven MAJ, Hopmans ES, Lindenberg JL, de Gruijl
TD, Würdinger T, Middeldorp JM. Functional delivery of
viral miRNAs via exosomes. Proceedings of the National
Academy of Sciences of the United States of America.
2010; 107: 6328-33. doi: 10.1073/pnas.0914843107.
44. Skog J, Wurdinger T, van Rijn S, Meijer D, Gainche L,
Sena-Esteves M, Curry WT, Carter RS, Krichevsky AM,
Breakeeld XO. Glioblastoma microvesicles transport
RNA and protein that promote tumor growth and provide
diagnostic biomarkers. Nature cell biology. 2008; 10: 1470-
6. doi: 10.1038/ncb1800.
45. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ,
Lötvall JO. Exosome-mediated transfer of mRNAs and
microRNAs is a novel mechanism of genetic exchange
between cells. Nature Cell Biology. 2007; 9: 654-9. doi:
46. Cheng L, Sharples RA, Scicluna BJ, Hill AF. Exosomes
provide a protective and enriched source of miRNA for
biomarker proling compared to intracellular and cell-
free blood. J Extracell Vesicles. 2014; 3. doi: 10.3402/jev.
47. Khan S, Bennit HF, Wall NR. The emerging role of
exosomes in survivin secretion. Histol Histopathol. 2015;
30: 43-50. doi: 10.14670/hh-30.43.
48. Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD,
Kloecker GH. Exosomal MicroRNA: A Diagnostic Marker
for Lung Cancer. Clinical Lung Cancer. 2009; 10: 42-6. doi:
49. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto
K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T,
Calin GA, Liu CG, Croce CM, et al. Unique microRNA
molecular proles in lung cancer diagnosis and
prognosis. Cancer Cell. 2006; 9: 189-98. doi: 10.1016/j.
50. Khan S, Aspe JR, Asumen MG, Almaguel F, Odumosu
O, Acevedo-Martinez S, De Leon M, Langridge WH,
Wall NR. Extracellular, cell-permeable survivin inhibits
apoptosis while promoting proliferative and metastatic
potential. Br J Cancer. 2009; 100: 1073-86. doi: 6604978
51. Khan S, Jutzy JM, Aspe JR, McGregor DW, Neidigh
JW, Wall NR. Survivin is released from cancer cells via
exosomes. Apoptosis. 2011; 16: 1-12. doi: 10.1007/s10495-
52. Taylor DD, Gercel-Taylor C. MicroRNA signatures of
tumor-derived exosomes as diagnostic biomarkers of
ovarian cancer. Gynecologic Oncology. 2008; 110: 13-21.
53. Khan S, Bennit HF, Turay D, Perez M, Mirshahidi S, Yuan
Y, Wall NR. Early diagnostic value of survivin and its
alternative splice variants in breast cancer. BMC Cancer.
2014; 14: 176. doi: 10.1186/1471-2407-14-176.
54. Khan S, Jutzy JM, Valenzuela MM, Turay D, Aspe JR,
Ashok A, Mirshahidi S, Mercola D, Lilly MB, Wall NR.
Plasma-derived exosomal survivin, a plausible biomarker
for early detection of prostate cancer. PLoS One. 2012; 7:
e46737. doi: 10.1371/journal.pone.0046737.
55. Turay D, Khan S, Diaz Osterman CJ, Curtis MP, Khaira
B, Neidigh JW, Mirshahidi S, Casiano CA, Wall NR.
Proteomic Proling of Serum-Derived Exosomes from
Ethnically Diverse Prostate Cancer Patients. Cancer Invest.
2016; 34: 1-11. doi: 10.3109/07357907.2015.1081921.
56. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P,
Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier
T, Tursz T, Amigorena S, Raposo G, et al. Malignant
eusions and immunogenic tumour-derived exosomes.
Lancet. 2002; 360: 295-305. doi: S0140-6736(02)09552-1
57. Tokuhisa M, Ichikawa Y, Kosaka N, Ochiya T, Yashiro M,
Hirakawa K, Kosaka T, Makino H, Akiyama H, Kunisaki C,
Endo I. Exosomal miRNAs from Peritoneum Lavage Fluid
as Potential Prognostic Biomarkers of Peritoneal Metastasis
in Gastric Cancer. PLoS One. 2015; 10: e0130472. doi:
58. Zheng H, Zhang F, Lin X, Huang C, Zhang Y, Li Y, Lin J,
Chen W, Lin X. MicroRNA-1225-5p inhibits proliferation
and metastasis of gastric carcinoma through repressing
insulin receptor substrate-1 and activation of β-catenin
signaling. Oncotarget. 2015; 7: 4647-63. doi: 10.18632/
59. Hamam R, Ali AM, Alsaleh KA, Kassem M, Alfayez M,
Aldahmash A, Alajez NM. microRNA expression proling
on individual breast cancer patients identies novel panel
of circulating microRNA for early detection. Scientic
Reports. 2016; 6: 25997. doi: 10.1038/srep25997.
60. Wang X, Wu J, Lin Y, Zhu Y, Xu X, Xu X, Liang Z, Li S,
Hu Z, Zheng X, Xie L. MicroRNA-320c inhibits tumorous
behaviors of bladder cancer by targeting Cyclin-dependent
kinase 6. Journal of Experimental & Clinical Cancer
Research : CR. 2014; 33: 69. doi: 10.1186/s13046-014-
61. Zhao G, Dong L, Shi H, Li H, Lu X, Guo X, Wang J.
MicroRNA-1207-5p inhibits hepatocellular carcinoma
cell growth and invasion through the fatty acid synthase-
mediated Akt/mTOR signalling pathway. Oncology
Reports. 2016. doi: 10.3892/or.2016.4952.
62. Özata DM, Caramuta S, Velázquez-Fernández D, Akçakaya
P, Xie H, Höög A, Zedenius J, Bäckdahl M, Larsson C,
Lui W-O. The role of microRNA deregulation in the
pathogenesis of adrenocortical carcinoma. Endocrine-
Related Cancer. 2011; 18: 643-55. doi: 10.1530/ERC-11-
63. Farhana L, Antaki F, Anees MR, Nangia‐Makker P,
Judd S, Hadden T, Levi E, Murshed F, Yu Y, Van Buren
E, Ahmed K, Dyson G, Majumdar APN. Role of cancer
stem cells in racial disparity in colorectal cancer. Cancer
Medicine. 2016; 5: 1268-78. doi: 10.1002/cam4.690.
64. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G,
Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di
Giannatale A, Ceder S, Singh S, Williams C, Soplop N,
et al. Tumour exosome integrins determine organotropic
metastasis. Nature. 2015; 527: 329-35. doi: 10.1038/
65. Paggetti J, Haderk F, Seiert M, Janji B, Distler U,
Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E,
Berchem G, Moussay E. Exosomes released by chronic
lymphocytic leukemia cells induce the transition of stromal
cells into cancer-associated broblasts. Blood. 2015; 126:
1106-17. doi: 10.1182/blood-2014-12-618025.
66. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-
Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams
C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A,
Homan C, Badal K, et al. Melanoma exosomes educate
bone marrow progenitor cells toward a pro-metastatic
phenotype through MET. Nat Med. 2012; 18: 883-91. doi:
67. Franzen CA, Simms PE, Van Huis AF, Foreman KE,
Kuo PC, Gupta GN. Characterization of uptake and
internalization of exosomes by bladder cancer cells. Biomed
Res Int. 2014; 2014: 619829. doi: 10.1155/2014/619829.
68. Huang K-H, Lan Y-T, Fang W-L, Chen J-H, Lo S-S, Li
AF-Y, Chiou S-H, Wu C-W, Shyr Y-M. The Correlation
between miRNA and Lymph Node Metastasis in Gastric
Cancer. BioMed Research International. 2015; 2015. doi:
69. Chen L, Lü MH, Zhang D, Hao NB, Fan YH, Wu YY,
Wang SM, Xie R, Fang DC, Zhang H, Hu CJ, Yang SM.
miR-1207-5p and miR-1266 suppress gastric cancer growth
and invasion by targeting telomerase reverse transcriptase.
Cell Death & Disease. 2014; 5: e1034. doi: 10.1038/
70. Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L,
Stöppler H, Simko J, Hilton JF, Carroll P, Blelloch R.
Microuidic based multiplex qRT-PCR identies diagnostic
and prognostic microRNA signatures in sera of prostate
cancer patients. Cancer research. 2011; 71: 550-60. doi:
71. Zhu J, Chen L, Zou L, Yang P, Wu R, Mao Y, Zhou H,
Li R, Wang K, Wang W, Hua D, Zhang X. MiR-20b,
-21, and -130b inhibit PTEN expression resulting in
B7-H1 over-expression in advanced colorectal cancer.
Human Immunology. 2014; 75: 348-53. doi: 10.1016/j.
72. Fricke A, Ullrich PV, Heinz J, Pfeifer D, Scholber J, Herget
GW, Hauschild O, Bronsert P, Stark GB, Bannasch H,
Eisenhardt SU, Braig D. Identication of a blood-borne
miRNA signature of synovial sarcoma. Molecular Cancer.
2015; 14. doi: 10.1186/s12943-015-0424-z.
73. Leidinger P, Hart M, Backes C, Rheinheimer S, Keck B,
Wullich B, Keller A, Meese E. Dierential blood-based
diagnosis between benign prostatic hyperplasia and prostate
cancer: miRNA as source for biomarkers independent of
PSA level, Gleason score, or TNM status. Tumor Biology.
2016; 37: 10177-85. doi: 10.1007/s13277-016-4883-7.
74. He H-c, Han Z-d, Dai Q-s, Ling X-h, Fu X, Lin Z-y,
Deng Y-h, Qin G-q, Cai C, Chen J-h, Jiang F-n, Liu X,
Zhong W-d. Global analysis of the dierentially expressed
miRNAs of prostate cancer in Chinese patients. BMC
Genomics. 2013; 14: 757. doi: 10.1186/1471-2164-14-757.
75. Bartley AN, Yao H, Barkoh BA, Ivan C, Mishra BM,
Rashid A, Calin GA, Luthra R, Hamilton SR. Complex
Patterns of Altered MicroRNA Expression during the
Adenoma-Adenocarcinoma Sequence for Microsatellite-
Stable Colorectal Cancer. Clinical cancer research : an
ocial journal of the American Association for Cancer
Research. 2011; 17: 7283-93. doi: 10.1158/1078-0432.
76. Velázquez-Fernández D, Caramuta S, Özata DM, Lu M,
Höög A, Bäckdahl M, Larsson C, Lui W-O, Zedenius
J. MicroRNA expression patterns associated with
hyperfunctioning and non-hyperfunctioning phenotypes
in adrenocortical adenomas. European Journal of
Endocrinology. 2014; 170: 583-91. doi: 10.1530/EJE-13-
77. Lei T, Zhu Y, Jiang C, Wang Y, Fu J, Fan Z, Qin H.
MicroRNA-320 was downregulated in non-small cell
lung cancer and inhibited cell proliferation, migration
and invasion by targeting fatty acid synthase. Molecular
Medicine Reports. 2016; 14: 1255-62. doi: 10.3892/