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\begin{document}

\title{Granulocyte-colony stimulating factor-producing uterine cervical cancer
treated with chemoradiotherapy: A case report with mutation analysis and
literature review}



\author[1]{Shintaro Shiba}%
\author[1]{Takahiro Oike}%
\author[1]{Ken Ando}%
\author[2]{Yuya Yoshimoto}%
\author[3]{Yoshiyasu Takayama}%
\author[4]{Tatsuya Ohno}%
\affil[1]{Gunma University Graduate School of Medicine}%
\affil[2]{Fukushima Medical University}%
\affil[3]{Gunma University Hospital}%
\affil[4]{Gunma University Graduate School of Medicine School of Medicine}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Granulocyte-colony stimulating factor (G-CSF)-producing uterine cervical
cancer (UCC) is a rare aggressive disease. We report a case of
G-CSF-producing UCC treated with chemoradiotherapy. Target-capture
sequencing results indicate that G-CSF-producing UCC is genetically
distinct from other UCCs, warranting further research to establish
specific treatment strategies.%
\end{abstract}%



\sloppy


\textbf{KEYWORDS}

granulocyte-colony stimulating factor, uterine cervical cancer,
radiotherapy, somatic mutations

\textbf{1 \textbar{} INTRODUCTION}

Uterine cervical cancer (UCC) is a common cancer that causes
\textgreater{}311,000 deaths worldwide each year\textsuperscript{1}.
Advances in radiotherapy and chemotherapy have markedly improved the
treatment outcomes of UCC \textsuperscript{2}. Translational research
efforts have provided information on the biological properties of tumors
associated with treatment responses in patients with
UCC\textsuperscript{3--5}, which may help to personalize treatment
strategies.

Although UCC is a common cancer, a subset that produces
granulocyte-colony stimulating factor (G-CSF) is rare. G-CSF-producing
UCCs are highly aggressive\textsuperscript{6--13}. However, specific
patterns of care for G-CSF-producing UCCs have not been established, and
treatment outcomes remain unknown because of the limited number of
reported cases. Moreover, the mutation profile of G-CSF-producing UCC
has not been analyzed. Here, we report a case of G-CSF-producing UCC,
and the results of mutational analysis and literature review.

\textbf{2 \textbar{} CASE REPORT}

A 43-year-old Japanese woman with UCC was referred to the Department of
Radiation Oncology from the Department of Gynecology for definitive
radiotherapy. Histological analysis of the biopsy specimen showed the
presence of tumor cells with enlarged nuclei and pale-to-clear cytoplasm
exhibiting sheet-like growth and stromal infiltration (\textbf{Figure 1}
). Immunohistochemical analysis of the biopsy specimen showed positivity
for p16, p53, and p63, leading to the diagnosis of squamous cell
carcinoma. In line with the pathological diagnosis, the patient showed
high levels of serum squamous carcinoma antigen (SCC, 19.0 ng/ml;
normal, \textless{}1.5 ng/ml). Genotyping of the biopsy specimen showed
positivity for human papillomavirus (HPV) type-31. Bimanual pelvic
examination revealed bilateral parametrium involvement not reaching the
pelvic sidewalls and the absence of vaginal involvement. Magnetic
resonance imaging detected a tumor (61 \selectlanguage{ngerman}× 60 × 75 mm) located in the
uterine cervix with slightly increased intensity on T2-weighted images
extending to the bilateral parametria (\textbf{Figure 2A, B} ). Computed
tomography (CT) showed lymphadenopathy in the external iliac-, common
iliac-, and para-aortic-lymph node (PALN) regions (\textbf{Figure 3A--C}
). 2-deoxy-2-{[}\textsuperscript{18}F{]}fluoro-D-glucose (FDG)-positron
emission tomography (PET) showed abnormal FDG uptake in the primary
tumor (\textbf{Figure 2C} ) and in the involved lymph nodes
(\textbf{Figure 3D--F} ). The CT and FDG-PET examinations showed no
evidence of metastasis to distant organ sites. The patient was diagnosed
as Stage IIB based on the 2008 definition by the International
Federation of Gynecology and Obstetrics.

The patient had a high-grade fever (39.1°C) with no symptoms of
infection. Blood tests showed a high white blood cell (WBC) count (28.3
× 10\textsuperscript{3}/mm\textsuperscript{3}; normal, 3.0--9.0 ×
10\textsuperscript{3}/mm\textsuperscript{3}) and high levels of serum
C-reactive protein (CRP, 6.21 mg/dl; normal, \textless{} 1.5 mg/dl).
Immature granulocytes suggestive of leukemia were not detected in the
peripheral blood. Serum G-CSF was abnormally high (323 pg/ml; normal,
\textless{}39 pg/ml). Based on these data, the clinical diagnosis was
G-CSF-producing tumor.

The patient received concurrent chemoradiotherapy using cisplatin.
Radiotherapy consisted of external beam radiotherapy (EBRT) and
intracavitary brachytherapy (ICBT). EBRT was administered as follows:
(\emph{i} ) whole pelvic irradiation with 50 Gy in 25 fractions (the
last 20 Gy was delivered using a central shielding technique);
(\emph{ii} ) prophylactic irradiation targeting PALN regions at a dose
of 40 Gy in 20 fractions; and (\emph{iii} ) boost irradiation to the
enlarged lymph nodes (8 Gy in four fractions for pelvic lymph nodes and
16 Gy in eight fractions for PALNs). ICBT was delivered at a dose of 24
Gy in four fractions. Cisplatin (40 mg/m\textsuperscript{2}) was
administered weekly for a total of three cycles starting on day 29 after
improvement of the fever and inflammatory response. The patient
completed the radiotherapy regimen as planned (\textbf{Figure 4} ). The
overall treatment time was 49 days.

After completion of the treatment, the tumor achieved almost complete
response as assessed by the Response Evaluation Criteria in Solid Tumors
(version 1.1) (\textbf{Figure 5} ). Serum G-CSF and SCC levels improved
to within normal limits (36.5 pg/ml and 0.8 ng/ml, respectively). The
patient experienced the following acute adverse effects as assessed by
the Common Terminology Criteria for Adverse Effects (version 4.0):
nausea (Grade 3), leukopenia (Grade 3), neutropenia (Grade 3), diarrhea
(Grade 2), anemia (Grade 2), and thrombocytopenia (Grade 1). These
adverse effects improved to Grade 0 within 2 months after completion of
the treatment.

The patient developed a fever (38.3°C) 2 months after completion of the
treatment. CT examination showed multiple metastases to a left
supraclavicular lymph node, the liver, and the lung (\textbf{Figure 6}
). The patient was considered ineligible for chemotherapy because of the
high inflammatory response (CRP, 18.30 mg/dl) and was provided with best
supportive care. CT performed 4 months after completion of the treatment
showed no evidence of in-field recurrence. Serum G-CSF was not assessed
after the metastases; however, a remarkably high WBC count (104.8 ×
10\textsuperscript{3}/mm\textsuperscript{3}) suggested that the
G-CSF-producing property of the tumor was preserved at the metastatic
sites (\textbf{Figure 7} ). The patient expired from disease progression
5 months after completion of the treatment. Permission for an autopsy
was not granted from the relatives at the time of mortality.

To better understand the biological basis of this aggressive tumor, we
analyzed mutation profiles. DNA was extracted from a pre-treatment
biopsy specimen in which the tumor cell content was higher than 50\%.
The exons of 409 cancer-related genes (\textbf{Supplementary Table 1} )
were sequenced using the Ion AmpliSeq Comprehensive Cancer Panel (Thermo
Fisher Scientific, Waltham, MA, USA). After quality filtering, the
number of sequencing reads per sample was 15.8 million, and the coverage
depth was 945 reads per base (\textbf{Supplementary Table 2} ). Somatic
mutations were identified using the analytical pipeline described
previously\textsuperscript{14}. Sixteen non-synonymous (\textbf{Table 1}
) and four synonymous mutations were identified. The mutation spectrum
in a three-base context did not represent the APOBEC signature (i.e.,
enrichment of substitution of a C preceded by a T into either T, G, or
A) typical of HPV-associated cancers\textsuperscript{15} (\textbf{Figure
8} ). Of the 16 non-synonymous mutations identified,
\emph{PIK3C2B}(T879N), \emph{KDR} (V297I), and \emph{TET2} (P29R) were
registered in the Catalogue of Somatic Mutations in
Cancer\textsuperscript{16} as recurrent mutations.

\textbf{3 \textbar{} DISCUSSION}

Production of G-CSF by cancer cells was first reported in 1977 by Asano
et al.\textsuperscript{17} In that report, the diagnostic criteria for
G-CSF-producing cancer were as follows: (\emph{a} ) abnormally high WBC
count in the peripheral blood with no evidence of infection; (\emph{b} )
abnormally high serum G-CSF level; (\emph{c} ) decrease in the WBC count
or G-CSF level after cancer treatment; and (\emph{d} ) G-CSF expression
in tumor tissues. The authenticity of criterion \emph{d} is
controversial because studies indicate that the sensitivity for this
criterion is not high (i.e., approximately 70\%)\textsuperscript{18,19}.
Based on criteria \emph{a} --\emph{c} , a literature search using PubMed
with the search terms ``\emph{uterine cervical cancer} '' AND
``\emph{granulocyte colony stimulating factor} '', followed by
full-manuscript examination, identified only 14 cases of G-CSF-producing
UCC reported to date (\textbf{Table 2} ). The median age of patients was
64 years, and the histopathological type was squamous cell carcinoma in
64\% of the cases. These patient demographics were in line with those
reported for UCC in general\textsuperscript{20,21}. Seventy-five percent
of the patients exhibited elevated serum CRP levels before the initial
treatment. Seventy-five percent of the patients experienced local
recurrence or distant metastasis within 6 months after the initial
treatment, suggesting resistance to conventional treatment and poor
prognosis. The present case had a stage-IIB tumor with PALN involvement
and expired 5 months after completion of chemoradiotherapy because of
multiple distant metastases. Previous studies show that the 5 year
overall survival rate of cohorts predominantly composed of PALN-positive
stage-IIB tumors treated with chemoradiotherapy is approximately
40--60\%\textsuperscript{22,23}, highlighting the aggressive behavior of
the tumor in the present case.

The mutational landscape of G-CSF-producing cancer remains unclear. A
small number of studies have analyzed a few genes of interest in
G-CSF-producing lung cancers. Pre-clinical studies identified
inactivating mutations in \emph{TP53} and\emph{RASSF1A}
\textsuperscript{24}, and reported conflicting results on the presence
of activating mutations in\emph{KRAS} \textsuperscript{24,25}, whereas
activating mutations in\emph{EGFR} were identified in a clinical
tumor\textsuperscript{26}. To the best of our knowledge, this is the
first study reporting the mutation profiles of G-CSF-producing cancer
using a clinically available sequencing panel containing hundreds of
genes. In the present case, the mutation spectrum in a three-base
context was not typical for UCC\textsuperscript{15}. None of the
mutations in \emph{PIK3C2B} ,\emph{KDR} , and \emph{TET2} identified in
the present case were reported in two previous large-scale landmark
studies of UCC-mutation profiles\textsuperscript{27,28}. By contrast,
mutations in genes such as\emph{PIK3CA} , \emph{PTEN} , \emph{STK11} ,
\emph{KRAS} , \emph{ARID1A} ,\emph{EP300} , and \emph{FBXW7} , which
were recurrently identified in previous landmark studies, were absent in
the present case. Taken together, these data suggest that
G-CSF-producing UCC is genetically distinct from other UCCs. Further
compilation of clinical sequencing data is needed to elucidate the
mutational landscape of G-CSF-producing cancer.

G-CSF-producing UCCs show resistance to conventional treatment
(\textbf{Table 2} ). Therefore, treatment strategies specific for this
type of cancer need to be established. One candidate strategy is the use
of molecular targeted drugs selected based on actionable mutation
profiles. \emph{PIK3C2B} and \emph{KDR} encode class II
phosphoinositide-3-kinase isoform C2\selectlanguage{greek}β \selectlanguage{english}and vascular endothelial growth
factor receptor 2, respectively. Therefore, cases such as the present
case, which harbor somatic mutations in these genes, could be treated
with inhibitors of the relevant PI3K/AKT/mTOR
pathway\textsuperscript{29,30}. Another candidate strategy is carbon ion
radiotherapy. Patients with stage-IIB and -IIIB disease treated with
carbon ion radiotherapy survived 108 and 30 months, respectively, with
no evidence of recurrence\textsuperscript{11}. The efficacy of the
precision medicine approach and that of carbon ion radiotherapy for
G-CSF-producing UCCs should be further investigated.

As a limitation of this study, we were unable to assess the expression
of G-CSF in the tumor tissue using immunohistochemistry because of
insufficient sample material.

\textbf{4 \textbar{} CONCLUSIONS}

We reported a case of G-CSF-producing UCC that showed rapid disease
progression after definitive chemoradiotherapy leading to an overall
survival period of 5 months. The aggressive behavior of this tumor
against conventional treatment was in line with the findings described
in previous reports on G-CSF-producing UCCs. This study is the first
report describing the somatic mutation profile of G-CSF-producing UCC.
The data presented will expand our biological understanding of this
cancer subset, which warrants further investigation.

\textbf{INFORMED CONSENT}

The enrollment of the patient was approved by the Institutional Ethical
Review Committee of Gunma University Hospital (approval number: 1109).
The Institutional Ethical Review Committee waived the requirement for
written informed consent from the patient because of the retrospective
and non-invasive design of the study. The study was conducted in
accordance with the ethical principles of the Declaration of Helsinki.

\textbf{ACKNOWLEDGMENTS}

We thank Dr. Yasushi Sasaki and Dr. Takashi Tokino of Sapporo Medical
University, and Ms. Yuka Hirota of Gunma University, for technical
support. This study was supported by Gunma University Heavy Ion Medical
Center and by JSPS KAKENHI Grant Number 16H06279 (PAGS).

\textbf{CONFLICT OF INTEREST}

None declared.

\textbf{AUTHOR CONTRIBUTIONS}

SS and KA: treated the patient and drafted the manuscript; YY: analyzed
sequencing data; YT: performed pathological review; T. Oike: analyzed
sequencing data and finalized the manuscript; T. Ohno: supervised the
study.

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\end{enumerate}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Table 1. Somatic non-synonymous mutations identified in this
study.} & \textbf{Table 1. Somatic non-synonymous mutations identified
in this study.} & \textbf{Table 1. Somatic non-synonymous mutations
identified in this study.}\tabularnewline
\midrule
\endhead
Gene & Mutation & Mt count in COSMIC\tabularnewline
\emph{IGF2R} & L252V & 0\tabularnewline
\emph{} & S1194L & 0\tabularnewline
\emph{} & L2008V & 0\tabularnewline
\emph{KDR} & V297I & 16\tabularnewline
\emph{MTR} & N919G & 0\tabularnewline
\emph{NOTCH4} & L13\_L16del & 0\tabularnewline
\emph{PIK3C2B} & T879N & 2\tabularnewline
\emph{PLEKHG5} & I156T & 0\tabularnewline
\emph{PTPRT} & D530A & 0\tabularnewline
\emph{RNF213} & H5074T & 0\tabularnewline
\emph{SAMD9} & V549L & 0\tabularnewline
\emph{SYNE1} & A2795V & 0\tabularnewline
\emph{TET1} & D162G & 0\tabularnewline
\emph{TET2} & P29R & 8\tabularnewline
\emph{} & V218M & 0\tabularnewline
\emph{UBR5} & A1245S & 0\tabularnewline
MT, mutation; COSMIC, Catalogue Of Somatic Mutations In Cancer. & MT,
mutation; COSMIC, Catalogue Of Somatic Mutations In Cancer. & MT,
mutation; COSMIC, Catalogue Of Somatic Mutations In
Cancer.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} &
\textbf{Table 2. Summary of reports on G-CSF producing
UCC.}\tabularnewline
\midrule
\endhead
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.}
\textbf{Table 2. Summary of reports on G-CSF producing UCC.} Age Stage
Histology G-CSF (pg/ml) WBC (x10\textsuperscript{3}/ul) CRP (mg/dl)
Initial Tx PFS (M) Rec site Rec Tx OS (M) Reference 56 IB2 Sq 197 12.9
7.0 Surgery 0.5 Parametrium BSC 2 6 39 IB2 Sq 50 13.9 1.8 Surgery-RT
0.25 Brain, skin, lung CT 5 7 72 IB2 Sq 248 20.6 4.8 CCRT 6 Uterus. lung
S-CT 15 7 64 IIA2 Cs 1500 48.0 NA RT 0.25 Skin, bone RT 2 8 64 IIB Ad
148 11.8 3.8 RT 0.25 SCLN, liver,lung BSC 3 9 43 IIB Sq 323 28.3 6.2
CCRT 2 SCLN, liver,lung BSC 5 Present case 58 IIB Sq 58 22.5 6.6 CCRT NA
NA NA 24 10 75 IIB NA 223 31.7 2.6 CIRT - - - 108+ 11 41 IIIB Sq 106
34.4 1.5 CCRT 3 Liver CT 9 7 76 IIIB Sq 642 31.1 5.4 CIRT - - - 30+ 11
71 IIIB Sq 195 30.0 NA RT - - - 8+ 12 59 IVB Sq 875 13.7 0.6 RT-AC 1
Lung, LN BSC 3 7 70 IVB Sm 269 17.1 0.8 CT-RT-CT 0 Liver BSC 11 13
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
G-CSF, granulocyte-colony stimulating factor; UCC, uterine cervical
cancer; Sq, squamous cell carcinoma; Cs, carcinosarcoma; Ad,
adenocarcinoma; NA, not available; Sm, small cell carcinoma; WBC, white
blood cell count before initial treatment; CRP, serum C-reactive protein
before initial treatment; Tx, treatment; RT, radiotherapy; CCRT,
concurrent chemo-radiotherapy; CIRT, carbon ion radiotherapy; CT,
chemotherapy; PFS, progression free survival; M, months; Rec,
recurrence; LN, lymph node; SC, supraclavicular; BSC, best supportive
care; OS, overall survival; +, still alive. Laboratory test results
before initial treatment are shown. G-CSF, granulocyte-colony
stimulating factor; UCC, uterine cervical cancer; Sq, squamous cell
carcinoma; Cs, carcinosarcoma; Ad, adenocarcinoma; NA, not available;
Sm, small cell carcinoma; WBC, white blood cell count before initial
treatment; CRP, serum C-reactive protein before initial treatment; Tx,
treatment; RT, radiotherapy; CCRT, concurrent chemo-radiotherapy; CIRT,
carbon ion radiotherapy; CT, chemotherapy; PFS, progression free
survival; M, months; Rec, recurrence; LN, lymph node; SC,
supraclavicular; BSC, best supportive care; OS, overall survival; +,
still alive. Laboratory test results before initial treatment are shown.
& & & & & & & & & & &\tabularnewline
\bottomrule
\end{longtable}



\textbf{FIGURE LEGENDS}

\textbf{FIGURE 1} . \selectlanguage{ngerman}\textbf{Hematoxylin-eosin staining of biopsied tumor
tissue (×400).}

\textbf{FIGURE 2.} \textbf{Magnetic resonance imaging (MRI)
and\textsuperscript{18}fluoro-2-deoxyglucose-positron emission
tomography (FDG-PET) showing the primary tumor before the initiation of
chemoradiotherapy. (A)} MRI axial plane. \textbf{(B)} MRI sagittal
plane. \textbf{(C)} FDG-PET axial plane.

\textbf{FIGURE 3.} \textbf{Computed tomography (CT)
and\textsuperscript{18}fluoro-2-deoxyglucose-positron emission
tomography (FDG-PET) showing multiple lymphadenopathy before the
initiation of chemoradiotherapy.} \textbf{(A--C)} CT image showing
enlarged lymph nodes in the external iliac-, common iliac-, and
para-aortic-lymph node regions, respectively. \textbf{(D--F)} FDG-PET
images corresponding to A--C.

\textbf{FIGURE 4.} \textbf{Schematic presentation of the treatment
protocol.} CS, central shielding; CRP, serum C-reactive protein; fr,
fractions; G-CSF, serum granulocyte-colony stimulating factor; ICBT,
intracavitary brachytherapy; LN, lymph node; PALN, para-aortic lymph
node; Prophyl, prophylactic; RT, radiotherapy; WBC, white blood cell
count in the peripheral blood; WP, whole pelvis.

\textbf{FIGURE 5. Magnetic resonance imaging (MRI) and computed
tomography (CT) after completion of chemoradiotherapy.} \textbf{(A,
B)}MRI of axial and sagittal planes, respectively, showing the uterine
cervix. \textbf{(C--E)} CT image showing the external iliac-, common
iliac-, and para-aortic-lymph node regions, respectively.

\textbf{FIGURE 6. Computed tomography (CT) at 2 months after completion
of chemoradiotherapy.} Metastatic tumors (arrows) in \textbf{(A)} the
left supraclavicular lymph node, \textbf{(B)} the liver, and \textbf{(C,
D)} the lung.

\textbf{FIGURE 7. Kinetics of laboratory markers during the clinical
course.} CRP, serum C-reactive protein; G-CSF, serum granulocyte-colony
stimulating factor; SCC, serum squamous cell carcinoma antigen; and WBC,
white blood cell count in the peripheral blood.

\textbf{FIGURE 8. Mutation spectrum in a three-base
context\textsuperscript{15}.}\selectlanguage{english}
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