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\begin{document}

\title{New protocol for pathological diagnosis and treatment pathway based on
the ``BIOCO'' collector tool in Henan Cancer Hospital}



\author[1]{Wenqun Xing}%
\author[1]{Wenjia Tian}%
\author[1]{Bing wei}%
\author[1]{Jiani Yuan}%
\author[1]{Lingyue Xing}%
\author[1]{Chengzhi Zhao}%
\author[1]{Yuxi Chang}%
\author[1]{Haibo Sun}%
\author[1]{Rui Sun}%
\author[1]{Zhongxian Zhang}%
\author[1]{Yang Yu}%
\author[1]{Jie Ma}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Background. 2018 Guideline from the College of American
Pathologists(CAP), the International Association for the Study of Lung
Cancer (IASLC) , and the Association for Molecular Pathology(AMP)
established a benchmark turnaround time (TAT), according to which the
results were supposed to be available to the treating oncologist within
10 working days. Methods. In this study, we established and validated a
new protocol for pathological diagnosis and treatment pathway that was
tested in the Henan Cancer Hospital, China. Results. Compared with the
routine pathway, the new path adopts a parallel approach to conventional
pathology and molecular pathology, which significantly shortens the TAT
to 4-6 days. Self-designed DNA biology collector ``BIOCO'' tool,
designed by our team to collect specimens that are discarded when the
wax block is trimmed, can effectively save pathological samples, avoid
cross-contamination and reduce the period extension caused by
re-sampling. Most importantly, its accuracy and effectiveness are
consistent with conventional collection methods. Conclusions. Therefore,
the new diagnosis and treatment pathway based on the BIOCO collector can
be used as a practical approach to the molecular diagnostic platform of
the hospital pathology department.%
\end{abstract}%



\sloppy


\textbf{New protocol for pathological diagnosis and treatment pathway
based on the ``BIOCO'' collector tool in Henan Cancer Hospital}

Wenqun Xing\textsuperscript{1*}, Wenjia Tian\textsuperscript{3*}, Bing
Wei\textsuperscript{2}, Jiani Yuan\textsuperscript{3}, Lingyue
Xing\textsuperscript{3},Chengzhi Zhao\textsuperscript{2}, Yuxi
Chang\textsuperscript{2}, Haibo Sun\textsuperscript{1}, Rui
Sun\textsuperscript{2}, Zhongxian Zhang\textsuperscript{2}, Yang
Yu\textsuperscript{3\#}, Jie Ma\textsuperscript{2\#}

{\label{wenqun-xing1-wenjia-tian3-bing-wei2-jiani-yuan3-lingyue-xing3chengzhi-zhao2-yuxi-chang2-haibo-sun1-rui-sun2-zhongxian-zhang2-yang-yu3-jie-ma2}}

* These authors contributed equally to this work.

\textsuperscript{\textbf{\#}} corresponding author

\textbf{Affiliations:}

\subsection*{\texorpdfstring{\textsuperscript{1} Department of Thoracic
Surgery, Henan Cancer Hospital, Zhengzhou, Henan,
China.}{1 Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou, Henan, China.}}

{\label{department-of-thoracic-surgery-henan-cancer-hospital-zhengzhou-henan-china.}}

\subsection*{\texorpdfstring{\textsuperscript{2} Department of Pathology,
Henan Cancer Hospital, Zhengzhou, Henan,
China.}{2 Department of Pathology, Henan Cancer Hospital, Zhengzhou, Henan, China.}}

{\label{department-of-pathology-henan-cancer-hospital-zhengzhou-henan-china.}}

\textsuperscript{3} Novogene Co., Ltd., Beijing, China.

\textsuperscript{\textbf{\#}}\textbf{Correspondence:}

Yang Yu

Novogene Co., Ltd., Beijing, China.

Jiuxianqiao North Road, Chaoyang District, Beijing 100016, China.

E-mail: yuyang@novogene.com

Jie Ma

Department of Pathology, Henan Cancer Hospital, No.127, Dongming Road,
Zhengzhou, Henan 450003, China.

E-mail: majie\_hnzl@163.com

\textbf{Synopsis:}

In order to save the time of tumor NGS detection cycle, Pathology
Department of Henan Cancer Hospital developed an optimized diagnosis and
treatment pathway. Combined with the small sample collector ''BIOCO'',
the new pathway can reduce the patient's detection waiting time by 4-6
days and won valuable treatment time for patients.

\textbf{Data Availability Statement}

The data used to support the findings of this study are available from
the corresponding author upon request.

\subsection*{Abstract}

{\label{abstract}}

\textbf{Background} . 2018 Guideline from the College of American
Pathologists(CAP), the International Association for the Study of Lung
Cancer (IASLC)~, and the Association for Molecular Pathology(AMP)
established a benchmark turnaround time (TAT), according to which the
results were supposed to be available to the treating oncologist within
10 working days\textbf{.} \textbf{Methods} . In this study, we
established and validated a new protocol for pathological diagnosis and
treatment pathway that was tested in the Henan Cancer Hospital,
China.\textbf{Results} . Compared with the routine pathway, the new path
adopts a parallel approach to conventional pathology and molecular
pathology, which significantly shortens the TAT to 4-6 days.
Self-designed DNA biology collector ``BIOCO'' tool, designed by our team
to collect specimens that are discarded when the wax block is trimmed,
can effectively save pathological samples, avoid cross-contamination and
reduce the period extension caused by re-sampling. Most importantly, its
accuracy and effectiveness are consistent with conventional collection
methods. \textbf{Conclusions.} Therefore, the new diagnosis and
treatment pathway based on the BIOCO collector can be used as a
practical approach to the molecular diagnostic platform of the hospital
pathology department.

\emph{\textbf{Keywords:} New diagnosis and treatment pathway; TAT;
``BIOCO'' collector}

\subsection*{Introduction}

{\label{introduction}}

With the widespread application of Next Generation Sequencing (NGS)
molecular pathology in clinical work, a large number of genetic
aberrations have been identified, thus permitting the development of new
targeted therapy for patients with cancer, including an advanced
non-small cell lung cancer (NSCLC)\textsuperscript{1}. Over recent
years, new-targeted drugs, molecular markers, and detection methods have
been constantly emerging\textsuperscript{2}. For example, the recent
treatment guidelines of the National Comprehensive Cancer Network (NCCN)
in the United States has suggested that nine driving genes
(EGFR/KRAS/HER2/ALK/ROS1/MET/BRAF/RET/NTRK) should be routinely detected
in lung cancer to provide more detailed genetic mutation information for
the precise treatment of lung cancer\textsuperscript{3}.

As an advanced genetic testing method, NGS has the advantages of high
sensitivity and comprehensive detection. However, compared to
traditional methods like fluorescence in situ hybridization (FISH),
immunohistochemistry (IHC), and reverse transcription-polymerase chain
reaction (RT-PCR), NGS has longer detection cycle (results are usually
obtained within 4-10 natural days). Recent guideline recommendations by
AMP, CAP, and ASLC~established a benchmark turnaround time (TAT). Based
on the guideline, the results were supposed to be available to the
treating oncologist within 10 working days\textbf{.}
\textsuperscript{4,5}. In a retrospective analysis of all NSCLC cases
within one year from a large academic institution, DiStasio\emph{et al}
found that 81.5\% of the test results were presented within ten working
days as recommended by the guidelines, which proved the feasibility of
TAT recommended by CAP, IASLC, and AMP guideline\textsuperscript{6}.

With the development of precision medicine, both patients and clinicians
expect to benefit from precise timely treatment, so a rapid and accurate
diagnosis and genotyping workflow for lung cancer are required.
Currently, many hospitals are still using routine clinical diagnosis and
treatment pathways, which imply TAT of about 10-16 days. In this study,
we established and validated a new protocol for pathological diagnosis
and treatment pathway that was tested in the Henan Cancer Hospital,
China.

The current protocol in Henan Cancer Hospital relays on two primary
specimen sources: 1) in-hospital analyses and delivery of the specimen;
2) analyses and delivery of the specimen from Henan Cancer Hospital
branches. The puncture specimens from the hospital undergo paraffin
embedding, sectioning, hematoxylin-eosin (H\&E) staining, IHC\selectlanguage{ngerman}±FISH, and
NGS detection in sequence, which take approx.7-16 days for the entire
molecular pathology detection of lung cancer (\textbf{Figure 1a} ). H\&E
staining, morphological diagnosis and release of the test report require
approximately 1-3 days. The molecular pathology testing for lung cancer
can be started only when the H\&E report is sent back to the Department
of Molecular Pathology. Consequently, 5-8 natural days are required for
NGS testing, which is then sent back by mail to the clinic. Above all,
it takes 8-14 natural days for the FFPE specimens from the consortium,
the shipment by routine diagnosis and treatment pathway to issuing of
the molecular pathological report of lung cancer (\textbf{Figure 1b} ).
Through routine detection pathways, a detection cycle for some patients
in the hospital lasts about 15 days, while some get discharged, which
prevents them from timely obtaining the treatment plan or even makes
them miss the best treatment time. Therefore, the optimization of the
diagnosis and treatment pathway, and shortening of the detection cycle
have become issues of the utmost importance.

During the actual operation of the lung-cancer based on 6 genes NGS
testing kit (Novogene Co., Ltd., Beijing, China) in hospital, we found
that the main factors affecting TAT included: specimen type, transport
link, clinical diagnosis and treatment pathway, molecular pathology
detection duration and report release route. In response to the above
problems, Henan Cancer Hospital proposed a new diagnosis and treatment
protocol. For the cycle problem, we used the Life sequencing platform,
which has the fastest detection cycle compared to other sequencers. At
the same time, we optimized the diagnosis and treatment path to shorten
unnecessary waiting times in the process. For the problem of
insufficient sample size, we designed a small sample collector
``BIOCO'', which is used to collect waste samples when constructing wax
blocks, and as a supplement when the sample is insufficient. The new
clinical diagnosis and treatment approach based on Life sequencer and
BIOCO collector for public hospitals can provide patients with more
timely test reports and accurate treatment.

\subsection*{Materials and Methods}

{\label{materials-and-methods}}

\subsection*{New Clinical Diagnosis and Treatment
Pathway}

{\label{new-clinical-diagnosis-and-treatment-pathway}}

TAT refers to the time from when samples are received by pathology
laboratory to when the test results are sent back to the
clinicians\textsuperscript{4,5}. In order to ensure better treatment
decisions for patients in a timely manner, histopathological diagnosis,
clinical staging, and molecular typing of lung cancer must be carried
out quickly and efficiently. The Molecular Pathology Department of Henan
Cancer Hospital summed up experience during the operation using the NGS
platform and tested the pattern of parallel development in routine
pathological diagnosis and molecular pathological diagnosis, developing
new and more efficient diagnosis and treatment pathway with shorter TAT
that are suitable for public hospitals. The protocol (\textbf{Figure 2}
) is presented as follows:

Day 1: according to the relevant examinations and preliminary diagnosis
of patients (medical history, routine blood testing, blood coagulation
test, electrocardiogram, tumor markers testing, and a contrast chest
computed tomography data), clinicians propose a pathological and genetic
diagnosis \textsuperscript{7}. The patient's puncture specimen is sent
to the pathology laboratory for registration and entry system. The
molecular pathology department checks the doctor's recommendation,
communicates with the patient, signs the supplementary application form
for lung cancer-related 6 genes testing, and confirms the pathological
diagnosis and genetic diagnosis prescribed at the same time.

Day 2: puncture specimens in the pathology department are fixed,
dehydrated, embedded in paraffin, cut into the paraffin section,~and
stained with H\&E. At the same time, part of the sample is sent to the
molecular pathology department by the medical coordinator. At the
department of pathology, the diagnosis of IHC and FISH is judged
according to the preliminary pathological diagnosis results. If further
diagnosis of IHC or FISH is needed, the pathological results are
uploaded into the electronic system on the 6th day, and the clinicians
are informed. BIOCO paraffin rolls and unstained white paraffin slides
are sent to the Department of Molecular Pathology, checked and
registered in the system. BIOCO samples and white films, which are sent
to the Department of Molecular Pathology, are also subjected to H\&E
staining and morphological diagnosis, and the results are checked. When
the tumor cell content is greater than 10\%, the next detection step is
performed.

Day 3-7: NGS can deliver results in the fastest 4 days. on the third
day, tissue specimens are dewaxed and digested, and DNA and RNA
extraction are performed, followed by RNA reverse transcription. Library
construction is done on day 4; after RNA reverse transcription, the cDNA
and extracted DNA are amplified by multiple PCR, followed by primer
digestion, amplicons ligation, magnetic beads purification, and library
quantification. Consequently, emulsion PCR will be performed. On day 5,
templates enrichment, sequencer cleaning, on-line sequencing, and
automatic analysis of biological information are conducted. The
generation and check of lung cancer-related 6 genes tests are performed
on day 6. The report is then fed back to the clinic on day 7. If there
is insufficient sample size or other circumstances, the NGS detection
period will be extended.

For small biopsy specimens in our hospital, the clinicians prescribe the
lung cancer related 6 genes test that can be done within 1 day and NGS
test that takes 4-7 days. The test report is reviewed and fed back to
the clinic in one day. So the entire process lasts 6-9 days. Clinicians
make treatment plans according to the test results for the patient
harboring specific mutations, referring to NCCN Guidelines and Chinese
Guidelines.

\subsection*{Real-world TAT data obtained by using new diagnostic and
therapeutic
pathway}

{\label{real-world-tat-data-obtained-by-using-new-diagnostic-and-therapeutic-pathway}}

The NGS platform used in the hospital is DA8600. The platform is based
on the principle of semiconductor sequencing and is the first domestic
sequencer approved by National Medical Products Administration (NMPA)
for tumor genetic testing. Its main advantages are small sample
requirements, short testing period, and moderate throughput. Therefore,
the platform is integral part of the novel diagnosis and treatment
pathway.

''Human EGFR, KRAS, BRAF, PIK3CA, ALK and ROS1 Gene Mutation Detection
Kit (semiconductor sequencing)''(Novogene Co., Ltd., Beijing, China)
were used to detect lung cancer-related 6 genes. From January 1, 2019 to
November 30, 2019, 384 specimens of lung cancer-related 6 genes tests
were detected on the hospital platform, all of which were puncture
biopsy specimens. The lung cancer-related 6 genes test was carried out
by the new clinical diagnosis and treatment pathway in the hospital. The
proportion of in-hospital reports with TAT\textless{}5 days was 72.40\%,
and the report with TAT of 5-7 days was 14.84\%. The test report with
TAT within 7-10 days was 12.76\%. Therefore, all reports could be issued
within 10 days, which gives additional 4-6 days for patients treatment
compared with a routine pathway\selectlanguage{english}(Table 1\selectlanguage{english}).

\subsection*{\texorpdfstring{Small puncture specimens collector
``BIOCO''}{Small puncture specimens collector BIOCO}}

{\label{small-puncture-specimens-collector-bioco}}

In our hospital, most of the specimens for genetic testing in clinic are
small biopsy specimens. In addition, the samples used for genetic
testing are usually the remaining material from the routine pathological
diagnosis, so, sometimes, sample size or the amount of extracted DNA may
be insufficient. Through the analysis of the above real-world data, we
found that the reasons for TAT \textgreater{} 5 days mainly include
insufficient specimens in the initial stage of the project or samples
being re-send due to failed extraction of nucleic acid. To solve these
problems, the new type biopsy specimen collector
BIOCO\textsuperscript{TM} was designed.

Design principle and device diagram of BIOCO collector

BIOCO was made of polyvinyl chloride (PVC) material using a one-time
pressing (patent application number is 201820902335.6). It is a small
device used to collect waste sample during sectioning; the collected
samples can be used as a supplement when there are insufficient
samples.\textbf{Figure 3} shows a schematic diagram of BIOCO from
different angles. The BIOCO tool consists of two round magnets on the
collector that can be adsorbed on the microtome blade holder, thus
making it to move arbitrarily. Before slicing, the prepared FFPE
specimen is fixed on the microtome. The BIOCO collector is then adsorbed
on the knife holder, and the leading edge is aligned with the knife.
When slicing, the cut tissue will directly enter the collector, without
contaminating the knife holder. After the specimen enters the collector,
the upper cover with a buckle is fastened to the collector, and the
cover is numbered with a marker. The specimen can be processed in the
laboratory, after which samples will be stored or shipped. When the
laboratory specimen processing starts, the lower piston of the collector
is pull out and tightly connected to the 1.5 mL centrifuge tube, the
upper cover is flicked to make the wax roll enter the centrifuge tube.
If there is a residual specimen on the wall, the tube connecting the
collector is vertically placed on the test tube rack, dewaxing liquid is
directly added into the collector, and specimen is dissolved into the
centrifuge tube for nucleic acid extraction.

\subsection*{\texorpdfstring{\emph{Comparison between BIOCO and Routine
Collection (ROUCO)
method}}{Comparison between BIOCO and Routine Collection (ROUCO) method}}

{\label{comparison-between-bioco-and-routine-collection-rouco-method}}

Randomly selected biopsy specimens were collected from 163 patients with
advanced NSCLC between January 1, 2019 and November 30, 2019. At the
same time of H\&E sectioning, each specimen was collected by the BIOCO
method and stored until further analysis. When the patient was diagnosed
with NSCLC, the ROUCO collection method was used to obtain paraffin
samples from the same patient. Finally, 39 paired specimens were
obtained for subsequent experiments. DNA extraction was performed using
QIAamp DNA FFPE Tissue Kit (Qiagen, Germany, \#56404) and DNA
concentration; the quality was determined using Nanodrop2000 and Qubit.
Quantitative mutation detection was carried out using ACCBio's human
EGFR gene mutation quantitative detection kit (Beijing ACCB Biotech Ltd.
\#180626). SPSS software (version 19.0, SPSS Ins) was used to analyze
the data from the two groups of samples. A P value \textless{}0.05 was
considered to be statistically significant.

\textbf{Results}

\textbf{DNA extraction efficiency between BIOCO and ROUCO}

When using the Nanodrop2000, the median DNA concentration of the samples
collected by BIOCO was 13.8ng/\selectlanguage{greek}μ\selectlanguage{english}l (1.4-68.5ng/\selectlanguage{greek}μ\selectlanguage{english}l); the median DNA
concentration measured by the ROUCO method was 25.7ng/\selectlanguage{greek}μ\selectlanguage{english}l (2.5-200ng/\selectlanguage{greek}μ\selectlanguage{english}l).
When using the Qubit test, the median DNA concentration of the samples
collected by BIOCO was 3.5ng/\selectlanguage{greek}μ\selectlanguage{english}l (0.3-34.0ng/\selectlanguage{greek}μ\selectlanguage{english}l), while the median DNA
concentration measured by the ROUCO method was 4.3ng/\selectlanguage{greek}μ\selectlanguage{english}l (0.2-27.0ng/\selectlanguage{greek}μ\selectlanguage{english}l).
There was no significant difference (p \textgreater{} 0.05) in DNA
extraction efficiency between BIOCO group and ROUCO group under the same
elution volume (\textbf{Figure 4} ), which suggested that BIOCO could
meet the needs of subsequent testing.

\textbf{The equivalent experiment of pollution prevention by BIOCO and
ROUCO method}

Ten paraffin blocks with a known high abundance of EGFR exon 21 L858R
mutation (A1-10) and 10 paraffin blocks (B1-10) of EGFR wild type
specimens were selected. Alternate section of mutant and wild-type
paraffin blocks
(A1-B1-A2-B2-A3-B3\ldots{}\ldots{}\ldots{}\ldots{}.A10-B10) was
performed. ROUCO method was used for the A1-10, and BIOCO method for
B1-10. Each paraffin block was replaced with disposable blades and
tweezers before slicing, and the tool holder was not processed. The cut
paraffin was collected into a 1.5 mL centrifuge tube, and DNA was
extracted from all 20 specimens according to the standard nucleic acid
extraction process, followed by qualitative detection of EGFR gene by
fluorescence quantitative PCR. As shown in \textbf{Table 2} , all
samples obtained the expected results, and no cross-contamination
occurred.

\textbf{Extraction of DNA by BIOCO and ROUCO for EGFR mutation
detection}

A total of 39-paired specimens were tested for EGFR by amplification
refractory mutation system (ARMS-PCR), and the positive rate was 51.3\%
in both groups (\textbf{Table 3} ). The results were completely
consistent in the mutant subtypes of EGFR between the two groups. We
defined 0-10\% as low abundance, 10-20\% as medium abundance,
\textgreater{}20\% as high abundance. The consistencies of mutation with
high abundance, medium abundance, and low abundance in the two groups
were 85.7\%, 100\%, and 83.3\%, respectively. Although the two patients'
abundance results were inconsistent, the difference between the two
groups was not obvious (P\textgreater{}0.05).

\subsection*{Discussion}

{\label{discussion}}

The new diagnosis and treatment pathway at our hospital is based on the
Thermo DA8600 platform. The new pathway relies on a simple operation
steps and short detection cycle. From the perspective of the sample
amount, BIOCO collector improves the success rate of molecular
detection. Our study showed that for about 12\% of cases, it was not
possible to obtain enough specimens, thus many patients needed to
undergo a second biopsy. The lack of samples may increase the
probability of secondary biopsy, the risk of puncture complications, and
additional financial burden, as well as reduce the availability of
clinical examinations, thus missing the best time for targeted
therapy\textsuperscript{8}. DNA contamination between specimens is also
one of the key factors affecting the accuracy of
detection\textsuperscript{9}. According to the requirements of LASCA
guidelines, the slicing knife should be replaced when slicing the
specimen and the knife holder and utensils should be wiped with alcohol
to prevent cross-contamination. This further increases the burden of
experimenters in practical work. The design of BIOCO solves the problem
of sample collection and preservation during the trimming of paraffin
blocks, simplifies the follow-up workflow of molecular pathology
detection, and reduces cross-contamination.

Compared to the ROUCO collection method, our new BIOCO approach showed
similar DNA extraction efficiency. The qualitative results of 39 cases
found that one high-abundance patient got a medium-abundance result, and
one medium-abundance patient got a low-abundance result. which may be
due to the differences in the total amount of DNA collected or the
heterogeneity of the tumor. Overall, about 95\% (37/39) of the samples
obtained consistent abundance, and 100\% (39/39) of the samples obtained
consistent mutation detection results; which suggested that the results
obtained by BIOCO collected samples were reliable.

However, this study has a few limitations. In order to shorten the
period of molecular pathology detection, molecular pathology H\&E
staining was simultaneously performed with the overnight digestion of
the sample. If H\&E staining showed no tumor cells or the content of
tumor cells was less than 10\%, it did not meet the criteria of
pathological quality control, and the samples, reagents, and labor went
to waste. However, in practical applications, this occurs very rarely.

\subsection*{}

{\label{section}}

\subsection*{Conclusions}

{\label{conclusions}}

The new diagnosis and treatment pathway accelerates the reporting period
of molecular pathology detection, shortens the TAT to 4-6 days, and
provides the opportunity for rapid and precise treatment of patients,
which has far-reaching implications for each patient and his family. At
the same time, the rapid and accurate molecular pathology detection
report accelerated the turnover of the hospital beds, improved the
efficiency of the use of hospital beds, and reduced the medical
expenses. DA8600 platform and BIOCO collector showed to be effective
tools for clinical-pathological diagnosis, which can be used by
pathology and related departments.

\textbf{Disclosure}

None declared for all authors.

\textbf{Acknowledgment}

This study was supported by the Construction of big data platform for
precision medical treatment of common tumors such as lung cancer in
Henan Province, Henan Province Major Science and Technology Project
(161100311500). We also thank MedSci (https://www.mjeditor.com/) for
proofreading the manuscript.

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\verb`FIG.4.docx`  available at \url{https://authorea.com/users/342121/articles/469000-new-protocol-for-pathological-diagnosis-and-treatment-pathway-based-on-the-bioco-collector-tool-in-henan-cancer-hospital}

\textbf{Hosted file}

\verb`TABLE 1.docx`  available at \url{https://authorea.com/users/342121/articles/469000-new-protocol-for-pathological-diagnosis-and-treatment-pathway-based-on-the-bioco-collector-tool-in-henan-cancer-hospital}

\textbf{Hosted file}

\verb`TABLE 2.docx`  available at \url{https://authorea.com/users/342121/articles/469000-new-protocol-for-pathological-diagnosis-and-treatment-pathway-based-on-the-bioco-collector-tool-in-henan-cancer-hospital}

\textbf{Hosted file}

\verb`TABLE 3.docx`  available at \url{https://authorea.com/users/342121/articles/469000-new-protocol-for-pathological-diagnosis-and-treatment-pathway-based-on-the-bioco-collector-tool-in-henan-cancer-hospital}

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