\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[polish,ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{A Case of Thoracic SMARCA4-Deficient Undifferentiated Tumor Successfully
Treated with Combination Ipilimumab-Nivolumab}



\author[1]{Yoshio NAKANO}%
\author[1]{Daisuke Sekinada}%
\author[1]{Yusuke Kuze}%
\author[1]{Norio Okamoto}%
\author[1]{Iwao GOHMA}%
\author[1]{Yumiko Yasuhara}%
\affil[1]{Sakai City Medical Center}%


\vspace{-1em}



  
  \date{June 02, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Thoracic SMARCA4-deficient undifferentiated tumors are rare, with poor
prognosis. A 73-year-old man presented to our hospital with dyspnea.
Computed tomography-guided biopsy revealed a SMARCA4-deficient
undifferentiated tumor. The patient was treated with combination
ipilimumab-nivolumab. The tumor reduced in size after two courses.%
\end{abstract}%



\sloppy


\textbf{A Case of Thoracic \emph{SMARCA4}-Deficient Undifferentiated
Tumor Successfully Treated with Combination Ipilimumab-Nivolumab}

Yoshio Nakano\textsuperscript{a*}, Daisuke Sekinada\textsuperscript{a},
Yusuke Kuze\textsuperscript{a}, Norio Okamoto\textsuperscript{a}, Iwao
Gohma\textsuperscript{a}, Yumiko Yasuhara\textsuperscript{b}

\textsuperscript{a}Department of Respiratory Medicine, Sakai City
Medical Center, 1-1-1, Ebaraji-cho, West Ward, Sakai City, Osaka
Prefecture, 593-8304, Japan; Email:

\textsuperscript{b}Department of Pathology, Sakai City Medical Center,
1-1-1, Ebaraji-cho, West Ward, Sakai City, Osaka Prefecture, 593-8304,
Japan

\textsuperscript{*}Correspondence: Yoshio Nakano

Department of Respiratory Medicine Sakai City Medical Center, 1-1-1,
Ebaraji-cho, West Ward, Sakai City, Osaka Prefecture, 593-8304, Japan

Email:\emph{methylemon@yahoo.co.jp}

\textbf{Data availability statement:} Data will be made available on
request.

\textbf{Funding statement:} This research did not receive any specific
grants from funding agencies in the public, commercial, or
not-for-profit sectors.

\textbf{Conflict of interest statement:} none.

\textbf{Ethics approval statement:} We adhere to the journal's code of
ethics.

\textbf{Patient consent statement:} Written informed consent was
obtained from the patient for the publication of this case report.

\textbf{Key Clinical Message} The present case indicated that 1)
combination ipilimumab-nivolumab successfully showed clinical benefits
in the treatment of thoracic \emph{SMARCA4} -deficient undifferentiated
tumors ,and 2) the good tolerability of combination
ipilimumab-nivolumab.

\textbf{Abstract}

Thoracic \emph{SMARCA4} -deficient undifferentiated tumors are rare,
with poor prognosis. A 73-year-old man presented to our hospital with
dyspnea. Computed tomography-guided biopsy revealed a\emph{SMARCA4}
-deficient undifferentiated tumor. The patient was treated with
combination ipilimumab-nivolumab. The tumor reduced in size after two
courses.

\textbf{Keywords:} \emph{SMARCA4} , undifferentiated tumors, case report

\textbf{Introduction}

Thoracic \emph{SMARCA4} -deficient undifferentiated tumors are
high-grade tumors of the thoracic region in adults, characterized by an
anaplastic or rhabdoid phenotype and defective \emph{SMARCA4}
expression. These tumors occur more commonly in young to middle-aged men
with a history of heavy smoking and are often centered in the
mediastinum or hilar regions. The prognosis is poor, with a median
survival of 4--7 months due to poor response to treatment and high-grade
malignancy.\textsuperscript{1,2} In general, cytotoxic chemotherapy is
not effective; however, case reports of significant response to immune
checkpoint inhibitors have been
published.\textsuperscript{3--6}Combination ipilimumab-nivolumab
reportedly significantly prolongs overall survival (OS) compared with
chemotherapy in patients wtih non-small cell lung
cancer,\textsuperscript{7} although no cases of\emph{SMARCA4} -deficient
undifferentiated tumors treated with combination ipilimumab-nivolumab
have been reported.

\textbf{Case presentation}

A 73-year-old man with a 10-year history of diabetes and heart failure
and a 50 pack-year smoking history underwent computed tomography (CT) in
November of year X-1 and was suspected to have lung cancer.
Subsequently, the patient's respiratory distress worsened on
approximately January X and he visited our hospital on January 18th the
same year, and the following vital signs were documented: oxygen
saturation (SpO\textsubscript{2}, 95\%); respiratory rate, 16
breaths/min; blood pressure, 110/83 mmHg; and heart rate, 122 beats/min.
Endobronchial ultrasound-guided transbronchial needle aspiration was
performed on lymph nodes \#7 and \#4R with a 21-gauge puncture needle,
although the cytology results were inconclusive. CT-guided biopsy was
performed for metastatic lesions in the right adrenal gland with an
18-gauge puncture needle. Histopathological examination revealed diffuse
sheets of proliferating and highly atypical epithelioid cells with
coagulation necrosis.

The tumor cells were relatively monotonous, with eosinophilic cytoplasm,
vesicular chromatin, 1--2 prominent nucleoli, and a partial rhabdoid
appearance (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1. Histopathology of adrenal gland metastasis}

The biopsy specimen shows diffuse sheets of proliferating and highly
atypical, epithelioid cells with coagulation necrosis. The tumor cells
are relatively monotonous, with eosinophilic cytoplasm, vesicular
chromatin, 1--2 prominent nucleoli, and partial rhabdoid appearance.

Immunohistochemically, the tumor cells totally lacked \emph{SMARCA4} and
BRM (\emph{SMARCA2} ); were negative for AE1/3, Claudin4, desmin, MyoD1,
myogenin, CD99, CD56, and WT-1 proteins; and were weakly positive for
synaptophysin. Based on these results, the tumor was classified as a
thoracic \emph{SMARCA4} -deficient undifferentiated tumor. Driver gene
screening showed negative results for \emph{EGFR, ALK, ROS-1, KRAS,}
and\emph{BRAF.} Immunohistochemical expression of programmed
death-ligand 1 (PD-L1) was found to be 10--20\%. Positron emission
tomography-CT showed a 3.4-cm primary tumor in the right upper lobe of
the lung and metastases to the mediastinal lymph nodes, multiple bones,
and bilateral adrenal glands (Figure 2). The tumor was thus staged as
clinical stage IVB (cT2aN2M1c).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2. PET CT scan}

(A) A 3.4-cm primary tumor in the right upper lobe; (B) mediastinal
lymph node metastases; (C) large metastatic lesion in the right adrenal
gland; and (D) multiple bone metastases. CT, computed tomography; PET,
positron emission tomography

On February 22nd of year X, the patient's condition deteriorated and he
was admitted due to respiratory distress with an SpO\textsubscript{2} of
88\%. He was assigned performance status 2 (PS2) because of his
inability to walk owing to right femoral bone metastasis. After
obtaining informed consent, combination ipilimumab-nivolumab (nivolumab
at a dose of 360 mg every 3 weeks plus ipilimumab at a dose of 1 mg/kg
every 6 weeks) were initiated on February 24th of same year. Thereafter,
home oxygen therapy was initiated, and combination ipilimumab-nivolumab
was administered on an outpatient basis. On June 1st of the same year at
the end of the second course, a repeat CT scan showed that the primary
tumor and metastases had shrunk (Figure 3). The tumor progression was
judged to have stabilized, according to the revised ``Response
Evaluation Criteria in Solid Tumors'' guidelines (version
1.1).\textsuperscript{8}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3. Comparison of pre- and post-therapy CT scans}

(1) Mediastinal lymph node metastases at the beginning of treatment; (2)
right adrenal gland metastasis at the beginning of treatment; (3)
mediastinal lymph node metastases at the end of the treatment second
course; and (4) right adrenal gland metastasis at the end of the second
treatement course.

Clinically, the patient's dyspnea improved because the tumor had shrunk
and the tracheal stenosis had resolved. The patient had severe heart
failure before the cancer diagnosis, and the echocardiographic
evaluation revealed a decreased ejection fraction of 42.9\% and
decreased wall motion in all circumferential regions, especially from
the septum to the anterior wall. On June 12th of same year, his
underlying heart failure worsened and he died suddenly. Our request to
perform a clinical/pathological autopsy was denied by the patient's
family. Because immune checkpoint inhibitor-associated myocarditis is a
rare adverse event, the incidence rate ranges between 0.27\% and
1.14\%,\textsuperscript{9} and our patient's chronic heart failure was
severe enough to be the cause of death in this case, we opined that the
worsening chronic heart failure was a result of its pre-existing
severity and was not directly related to the administration of
combination ipilimumab-nivolumab.

\textbf{Discussion}

The present case highlights two clinical issues (3.1 and 3.2) related to
combination ipilimumab-nivolumab therapy in a patient with a
thoracic\emph{SMARCA4} -deficient undifferentiated tumor.

First, in our case, combination ipilimumab-nivolumab successfully showed
clinical benefits in the treatment of thoracic \emph{SMARCA4} -deficient
undifferentiated tumors (3.1). Thoracic \emph{SMARCA4} -deficient
undifferentiated tumors are unresponsive to chemotherapy and have a poor
prognosis, with a median life expectancy of 4--7
months.\textsuperscript{1,2} Recently, case reports of these tumors
responding to immune checkpoint inhibitors both alone
(pembrolizumab\textsuperscript{3,4} or nivolumab\textsuperscript{6}) and
in combination with chemotherapy (pembrolizumab plus carboplatin and
pemetrexed,\textsuperscript{10} atezolizumab with bevacizumab,
paclitaxel, and carboplatin\textsuperscript{11}) have been published.
However, no reports of response to ipilimumab-nivolumab combination
exist. Only one case of combination therapy with two immune checkpoint
inhibitors has been reported, in which ipilimumab was added some time
after the onset of pembrolizumab administration.\textsuperscript{12} The
Checkmate 227 study demonstrated that treatment with combination
ipilimumab-nivolumab in patients with non-small cell lung cancer was
associated with a significant advantage in OS compared with
chemotherapy, regardless of PD-L1 expression. In the same study, 2-year
OS tended to be better with combination ipilimumab-nivolumab than that
with nivolumab alone in patients with PD-L1 expression [?]1\% (22C3) and
[?]50\%, respectively.\textsuperscript{7} In our case, the patient was
able to receive combination ipilimumab-nivolumab without any apparent
adverse events and had a successful response with symptom improvement.
Unfortunately, the patient died from worsening chronic heart failure;
however, we believe that a long-term positive response might have been
possible because the tumor had shrunk and his respiratory distress
symptoms and general condition had improved.

The second clinical issue is the good tolerability of combination
ipilimumab-nivolumab (3.2). At the time of diagnosis, the patient was at
PS2 (could not walk and required oxygenation,) making cytotoxic
chemotherapy difficult to administer. In addition, combination
ipilimumab-nivolumab was administered on an outpatient basis without any
adverse events. The efficacy of PD-1/PD-L1 inhibitor monotherapy in the
primary treatment of stage IV non-small cell lung cancer in patients at
PS2 is currently unclear, as the KEYNOTE-024 and IMpower110 trials
enrolled only patients at PS0--1 as eligibility
criteria.\textsuperscript{13,14} A study on pembrolizumab in patients at
PS2 (PePS2 study) reported that pembrolizumab could be safely
administered even in patients with PS2.\textsuperscript{15} Because the
patient had a thoracic \emph{SMARCA4} -deficient undifferentiated tumor
that was not expected to respond to chemotherapy, and his general
condition was poor (PS2), we discussed the best supportive care or
immunotherapy with him. After an intense discussion, we decided to use
both ipilimumab and nivolumab instead of a single agent to achieve a
better response. Further studies will be conducted in similar cases to
investigate the use of ipilimumab-nivolumab combination.

\textbf{Conclusion}

Combination ipilimumab-nivolumab was successfully administered to a
patient with thoracic \emph{SMARCA4} -deficient undifferentiated tumor.
These findings may be further validated in trials when chemotherapy is
not possible owing to patient or tumor factors.

\textbf{Acknowledgements}

The authors thank the patient and his family members. We would like to
thank Editage (www.editage.com) for English language editing.

\textbf{Funding}

This research did not receive any specific grants from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Consent}

Written informed consent was obtained from the patient for the
publication of this case report.

\textbf{Author contributions}

Yoshio Nakano: Conceptualization, Methodology, Data curation, Writing-
Original draft preparation

Daisuke Sekinada: Visualization, Investigation

Yusuke Kuse: Writing- Reviewing and Editing

Norio Okamoto: Supervision

Gohma Iwao: Supervision

Yumiko Yasuhara: Diagnosis of pathology.

\textbf{References}

1. Le Loarer F, Watson S, Pierron G, et al. SMARCA4 inactivation defines
a group of undifferentiated thoracic malignancies transcriptionally
related to BAF-deficient sarcomas. \emph{Nat Genet} .
2015;47(10):1200-1205. doi:\emph{10.1038/ng.3399}.

2. Rekhtman N, Montecalvo J, Chang JC, et al. SMARCA4-deficient thoracic
sarcomatoid tumors represent primarily smoking-related undifferentiated
carcinomas rather than primary thoracic sarcomas. \emph{J Thorac Oncol}
. 2020;15(2):231-247. doi:\emph{10.1016/j.jtho.2019.10.023}.

3. Henon C, Blay JY, Massard C, et al. Long lasting major response to
pembrolizumab in a thoracic malignant rhabdoid-like SMARCA4-deficient
tumor. \emph{Ann Oncol} . 2019;30(8):1401-1403.
doi:\emph{10.1093/annonc/mdz160}.

4. Takada K, Sugita S, Murase K, et al. Exceptionally rapid response to
pembrolizumab in a SMARCA4-deficient thoracic sarcoma overexpressing
PD-L1: A case report. \emph{Thorac Cancer} . 2019;10(12):2312-2315.
doi:\emph{10.1111/1759-7714.13215}.

5. Naito T, Umemura S, Nakamura H, et al. Successful treatment with
nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a
high tumor mutation burden: A case report. \emph{Thorac Cancer} .
2019;10(5):1285-1288. doi:\emph{10.1111/1759-7714.13070}.

6. Iijima Y, Sakakibara R, Ishizuka M, et al. Notable response to
nivolumab during the treatment of SMARCA4-deficient thoracic sarcoma: A
case report. \emph{Immunotherapy} . 2020;12(8):563-569.
doi:\emph{10.2217/imt-2019-0142}.

7. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus
ipilimumab in advanced non--small-cell lung cancer. \emph{N Engl J Med}
. 2019;381(21):2020-2031. doi:\emph{10.1056/NEJMoa1910231}.

8. Eisenhauer EA, Therasse P, Bogaerts J, et al.New response evaluation
criteria in solid tumours: Revised RECIST guideline (version
1.1).\emph{Eur J Cancer} . version 1.1. 2009 January;45(2):228-247.
doi:\emph{10.1016/j.ejca.2008.10.026}.

9. Hu J-R, Florido R, Lipson EJ, et al. Cardiovascular toxicities
associated with immune checkpoint inhibitors. \emph{Cardiovasc Res} .
2019 April 15;115(5):854-868. doi:\emph{10.1093/cvr/cvz026}.

10. Tanaka S, Hayashi S, Isobe Y, et al. Positive outcome of first-line
therapy for a SMARCA4-deficient thoracic sarcomatoid tumor. \emph{Int
Cancer Conf J} . 2021;10(2):112-115.
doi:\emph{10.1007/s13691-021-00472-4}.

11. Kawachi H, Kunimasa K, Kukita Y, et al. Atezolizumab with
bevacizumab, paclitaxel, and carboplatin was effective for patients with
SMARCA4-deficient thoracic sarcoma. \emph{Immunotherapy} .
2021;13(10):799-806. doi:\emph{10.2217/imt-2020-0311}.

12. An\selectlanguage{polish}Ž\selectlanguage{english}i\selectlanguage{polish}č \selectlanguage{english}N, Krasniqi F, Eberhardt AL, Tzankov A, Haslbauer JD.
Ipilimumab and pembrolizumab mixed response in a 41-year-old patient
with SMARCA4-deficient thoracic sarcoma: An interdisciplinary case
study, Case. \emph{Case Rep Oncol} . 2021;14(2):706-715.
doi:\emph{10.1159/000515416}.

13. Reck M, Rodr\selectlanguage{ngerman}íguez-Abreu D, Robinson AG, et al. Pembrolizumab versus
Chemotherapy for PD-L1--Positive non--small-Cell Lung Cancer. \emph{N
Engl J Med} . 2016;375(19):1823-1833. doi:\emph{10.1056/NEJMoa1606774}.

14. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for
first-line treatment of PD-L1--selected patients with NSCLC. \emph{N
Engl J Med} . 2020;383(14):1328-1339. doi:\emph{10.1056/NEJMoa1917346}.

15. Middleton G, Brock K, Savage J, et al. Pembrolizumab in patients
with non-small-cell lung cancer of performance status 2 (PePS2): A
single arm, phase 2 trial. \emph{Lancet Respir Med} . 2020;8(9):895-904.
doi:\emph{10.1016/S2213-2600(20)30033-3}.

\selectlanguage{english}
\FloatBarrier
\end{document}

