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[30]
Combining immune checkpoint inhibitors (ICIs) with BETi to treat NC is also under investigation . A
PubMed search resulted in 1 article by adding the term “immune checkpoint inhibitor”. Xie et al. performed
a retrospective review of patients with primary pulmonary NC in the First Affiliated Hospital of Guangzhou
[31]
Medical University between Jan 2015 and Dec 2018 . Seven patients were studied and five were treated
with ICIs. One patient who received atezolizumab died after surgery due to severe postoperative
complications (OS 1.5 months); another patient in the series received pembrolizumab following radiation
therapy and had a good clinical response (OS 19.5 months), while another case treated with nivolumab and
paclitaxel-albumin seemed to fail to benefit from treatment (OS of 3 months). Notably, another patient
treated with cetuximab, docetaxel + platinum chemoRT, followed by pembrolizumab and oxaliplatin on the
progression of disease had an OS of 26.7 months. The only patient alive at the time of follow-up (OS
12+ months) had received cetuximab, docetaxel + platinum, nivolumab, and pembrolizumab.

No studies were found using the PubMed search for NUT midline carcinoma and histone methyltransferase
as treatment.

Given that our patient did not have a BRD4-NUT fusion, she was not a candidate for enrolling in a BETi
clinical trial. Instead, our patient was treated with surgical removal of the primary tumor, radiation therapy,
and systemic treatment with weekly carboplatin and paclitaxel and pembrolizumab. In the literature, thus
far, there have been no proposed novel therapeutics that specifically target the fusion protein NSD3-NUT,
likely because this gene combination is less common than BRD4 or BRD3 fusion protein. However, we
would like to propose that additional research should be performed on the addition of HMTis as part of the
therapy for this specific gene mutation. Recently, the HMTi tazemetostat has been approved for metastatic
or locally advanced epithelioid sarcoma. Many other HMTis are in development.

CONCLUSION
NUT midline carcinoma is a rare, devastating, and universally fatal disease within 3 years of diagnosis, with
median overall survival ranging between 6.7 to 9.7 months [4,11] . Chemotherapy, surgery, and radiotherapy
improve survival without providing curative results. By introducing additional agents such as ICIs and
BETis, disease-free survival has been promising. We propose that for patients with NRD3-NUT
translocation, exploring the use of HMTis as adjunctive therapy may provide additional survival benefits.
We also highlight a case of NC mimicking anaplastic thyroid carcinoma with squamous cell differentiation,
where NGS helped expedite an accurate diagnosis. We further propose that diagnostic evaluation of young
patients with CUP and squamous features include NC in the differential diagnosis, given the rapidly
progressive nature of this disease.

DECLARATIONS
Authors’ contributions
Was the main author who wrote the initial draft (Abstract, Introduction, Case Report, Discussion, and
Conclusion) of the manuscript, performed the literature review and edited the manuscript: Neumann M
Reviewed the manuscript and edited the manuscript: Hines A
Provided the figures and their captions: Chang Q
Reviewed each draft of the manuscript, coordinated acquiring the figures, and edited the manuscript in
detail: Seetharamu N
Reviewed the manuscript and edited the manuscript in detail: Lopez C