Clinical Features, Therapy and Long-Term Outcomes of NUT Carcioma in China

Clinical Features, Therapy and Long-Term Outcomes of NUT Carcioma in China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Features, Therapy and Long-Term Outcomes of NUT Carcioma in China Xiaoxiao Wu, Na Shen, Liyan Xue, Zhimin Bian This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3230156/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background NUT carcinoma is a rare, poorly differentiated tumor typically driven by a t(15;19) rearrangement leading to a NUT gene rearrangement event. This uniformly fatal tumor has promoted targeted therapy, yet the clinical characteristics of Chinese patients with NUT carcinoma and the efficacy of all treatment have not been systematically summarized. In order to better understanding the disease characteristic and treatments, correlate them with outcome, we have here compiled findings pertaining to a large population of such patients. Methods A clinical database from all know cases of NUT carcinoma was established. Pathologic, demographic, and survival data of 33 patients were analyzed by questionnaires, the largest cohort studied of NMC patients to data in China. Results Primary tumors sites included nasal cavity (n = 6), maxillary sinus (n = 5),tonsil (n = 1), thyroid (n = 1), lung (n = 16), mediastinum (n = 1), submandibular(n = 1), vulva(n = 1), external auditory canal༈n = 1༉. The patient age ranged from 2 to 69 years with the male/female ratio of 1.3/1,11 of them died, the media overall survival for those patients was 5.5 months. Multivariate analysis proved that the primary site NUT carcinoma was not related to the prognosis, alternative application of different chemotherapy regimen or combination of immunotherapy on the basis of chemotherapy can effectively control the tumor, and combination of radiotherapy on the basis of chemotherapy can benefit the survival of patients, which is the icing on the cake. Radical surgery can help keep the tumor in a stable state and even delay the recurrence of the tumor. Radical surgery combined with chemotherapy, radiotherapy and immunotherapy can benefit the survival of patients. Notably, NUT progresses quickly when therapy is terminated. Unfortunately, radiotherapy alone does not significantly improve outcome in China. Conclusion Breaking the traditional understanding that NUT carcinoma tends to occur in the midline, and not all originate from squamous cell carcinoma. The finding that conventional chemotherapy and radiotherapy have been not sensitively. Chemotherapy combined with immunotherapy or early surgical might improve overall survival. NUT carcinoma treatment outcomes INTRODUCTION Nut carcinoma is a rare but aggressive and poorly differentiated carcinoma characterized by chromosomal rearrangement of the NUT gene ,also known as t(15;19)(q15;p13)[ 1 – 3 ]. This rearrangement lead to NUT in-frame with BRD4, a ubiquitously-expressed transcriptional co-activator, or with BRD3 and other unknown genes, which possess as yet unresolved molecular biology[ 4 , 5 ].Histologically, NUT carcinoma displays undifferentiated carcinoma or poorly differentiated squamous cell carcinoma[ 6 ], which leads to misdiagnosed. Detection of NUT gene translocation by immunohistochemistry, fluorescence in situ hybridization (FISH) or gene sequencing has become the only way to diagnose NUT carcinoma. Large series studies described that NC occurs in the midline, affecting the mediastinum/thymus, upper digestive tract, nasal cavity and sinuses were the most common[ 1 , 7 ] - [ 8 ], however, cases that occur in non-midline structures break traditional cognition[ 8 ],which causing different clinical symptoms. NUT carcinoma is locally aggressive, with early disease progression, extremely poor treatment effect. Recurrence and mortality are high, with a median overall survival in NUT carcinoma is 6.5–6.7 months[ 2 , 9 ] . Treatment approaches have been heterogeneous. There is no standard treatment for NUT carcioma. Chemotherapy and radiotherapy seems to be ineffective[ 10 ] ,the clinical outcomes were variable among patients. Complete resection of tumor may prolong the survival of patient[ 10 , 11 ], which is not always possible because of surgical inaccessibility or metastatic disease[ 10 ].Since its recognition as NUT translocation, and leading to dysregulation of normal differentiation, which promoted many researchers focused on targeted drugs, for example bromodomain and extraterminal (BET) inhibitor. BET inhibitor has been shown in vitro and in vivo to eliminate growth disorders and translate into clinical activity[ 12 , 13 ] , [ 14 ]. Although NUT carcinoma is aggressive, we have noted that response to treatment can be quite variable depend on the patient’s situation[ 10 , 14 ]. The underdiagnosed and rarity have thus far precluded treatment timely, even led to misdiagnosis. In this study, we accessed progression-free survival and overall survival of 33 patients diagnosed with NUT carcinoma, as well as treatment variables including extent of surgical resection, provision of radiotherapy and selected chemotherapeutic agents. Methods and Materials Patients A total of 33 patients with NUT carcinoma who were defined as NUT rearrangement demonstrated by fluorescent in situ hybridization(FISH), immunohistochemistry showed abnormal NUT expression, or characteristic t(15;19), or next-generation sequencing(NGS). For 33 cases, a questionnaire was sent to patients, including clinical, demographic, treatment, and outcome variables. Retrospective clinical data were obtained for 33 patients. Collect and summarize patient data, clinical staging was depended on the site of primary tumor, lymph node involvement, and location of metastasis. Initial therapy and relapse or progression were included, and treatment includes surgery and chemotherapy, with either a total or partial excision, chemotherapy with platinum containing or anthracycline containing agents, or immunological drugs. And many people have received combination therapy. For progression-free survival (PFS), time-events are the time between the first diagnosis of cancer at the treating hospital and the first recurrence, progression, or death of the disease, or if these events do not occur, until the last exposure. For overall survival (OS), the time from diagnosis to death or to last follow-up if censored. Clinical responses to initial treatment are classified as complete or partial response, stable disease, or progressive disease. Statistical Analysis Descriptive statistics were used to summarized the demographic and clinical characteristic of patients. Calculation of OS from initial cancer diagnosis to death or to last follow-up. All analyses were performed in SPSS version 24.0, P values less than or equal to .05 were considered statistically significant. Results Clinical Features and Tumor Characteristics The clinical features and tumor characteristics of the 33 patients with NUT carcinoma are summarized in Table 1. The media age at diagnosis was 33.3 years(range = 2-69years), and 51% were male, 48% (16 of 33)of tumors arose from the lung,15% (5 of 33) from nasal cavity,15% (5 of 33) from maxillary sinus, tonsil, thyroid, mediastinum, submandibular, vulva and external auditory canal were one case each. The mean (SD) primary tumor diameter at diagnosis was 5.8cm, lymph node involvement or distant metastasis were found in 56% (19 of 33), and the most common site of metastasis is bone. PD-L1 positivity accounts for approximately 36%. Treatment Outcomes The prognosis of NUT patients is generally poor, and the response to initial treatment was only 21 (54%) of patient having a complete or partial response, most people received multimodality therapy. Three (9%) patients with primary site in the lung underwent initial chemotherapy combined with immunotherapy, among whom two had partial responses and one had stable disease at first but finally died no matter the expression of PD-L1,the first two patients were treated with paclitaxel liposome, cisplatin combined with sintilimab and etoposide, carboplatin combined with nivolumab respectively, and the efficacy evaluation was PR every two cycles. However, the last patient achieved SD with one cycle of paclitaxel liposome, nedaplatin combined with tislelizumab, followed six cycles of bevacizumab combined with paclitaxel and cisplatin, which reduced the primary tumor from 9cm to 3.4cm, and continued with lung radiation therapy only, but also developed abdominal metastasis, so instead of radiation, and the adjustment plan was gemcitabine hydrochloride, nedaplatin and anlotinib with durvalumab, but the patient died after two cycles due to the inability to effectively control the tumor, and the overall survival time was nine months. This seems to prove that early chemotherapy combination of immunotherapy can effectively control tumor progression and even prolong PFS. whereas the other five patients received chemotherapy only, and the response was stable, but it was progressing rapidly. Two patients with primary lung disease received paclitarel with cisplatin only or etoposide with cisplatin, one of which was combined with bevacizumab, but had an overall survival of 4–5 months. The other two patients were 8 and 20 years old and the primary site was tonsil and mediastinum. In patients with mediastinal tumor, the tumor reached stability after 6 cycles of alternating application of doxorubicina, cyclophosphamide combined with vindesil sulfate and ifosfamide combined with etoposide, but the tumor progressed after 3 cycles of irinotecan combined with anlotinib. In patients with primary tonsil disease, the tumor remained under control after alternating 12 cycles of cyclophosphamide, cisplatin combined with pirarubicin and ifosfamide combined with etoposide. The last patient initially diagnosed as lung squamous cell carcinoma, two cycles of paclitaxel combinend with paraplatin were administered, followed by surgery, and the postoperative pathology indicated NUT. After 4 cycles of gemcitabine combined with cisplatin, the tumor progressed. Chemotherapy alone is less effective, but patients can benefit from alternating chemotherapy regiments, and the most impotent is that the incidence of nut was low, pathology in most hospitals were not used as a routine examination item, resulting in misdiagnosis and further delay in treatment. However, only one male patient with primary lung tumor, the assessed efficacy was PR after 4 cycles of chemotherapy with paclitaxel combined with cisplatin, followed by 28 times of radiotherapy, and radiotherapy was performed on the lung and metastatic site: left gastric lymph node, followed by 2 cycles of chemotherapy with the original regimen. To our surprised, the tumor recurred 10 months after oral anlotinib monotherapy, which suggests that radiotherapy for primary and metastatic tumors may be beneficial for survival. Radical chemotherapy combined with surgery was shown to be beneficial in delaying tumor recurrence in three patients. The ages of three patients were 27, 27, and 19 years old, respectively. The primary tumors were located in the lungs, sinuses, and vulva. The first patient had tumor recurrence after 17 cycles of alternating vindesine sulfate, epirubicin hydrochloride combined with cyclophosphamide and ifosfamide combined with etoposide regimens after surgery. The second patient was evaluated as PR after 2 cycles of albumin paclitaxel combined with cisplatin, and then underwent surgery. Currently, the tumor is still in a stable state 8 months after surgery. After the third patient underwent surgery, alternating application of cisplatin, vincristine sulfate combined with pirarubicin hydrochloride and cisplatin, cyclophosphamide, vincristine sulfate combined with pirarubicin hydrochloride for 10 cycles resulted in a stable reduction in the size of the inguinal lymph node metastasis from 17mm to 6mm. The above suggests that NUT patients still need early surgical treatment. To our surprised, two patients (6%) received chemotherapy combined with surgery and sintilimab maintenance therapy, however the outcome was quite different. A 34-year-old patient with a primary submandibular tumor of about 2.4*1.6cm before surgery, accompanied by lymph node metastasis in the upper neck, had a tumor recurrence of about 2.4*1.4cm in a half month after surgery. The tumor remained uncontrolled after 4 cycles of alternating cyclophosphamide, doxorubicin hydrochloride liposome combined with vindesine sulfate and ifosfamide combined with etoposide, and was re-operated after 6 cycles of paclitaxel, cisplatin, sintilimab combined with anlotinib. During the postoperative maintenance treatment with sintilimab, the tumor has reached a stable state. However, another 53-year-old male patient with primary lung tumor was treated with paclitaxel combined with cisplatin for two cycles, the tumor increased, forced surgery, and given nedaplatin, gemcitabine hydrochloride combined with sintilimab for one cycle, regrettably the patient died, with an overall survival of about 5 months. Surgery in combination with chemotherapy and radiotherapy seems to benefit patients' survival. The 4 patients with NUT were 47,39,67 and 38, and the primary sites were nasal cavity, nasal cavity, maxillary sinus and frontal sinus, respectively. One of the patients had a recurrence soon after surgery, and was treated with concurrent chemotherapy and oral chidamide maintenance treatment, and now the tumor was in a stable state. Similar to the other patient, the tumor remained stable after surgery by oral administration of chidamide combined with chemoradiotherapy. Another female patient was diagnosed with NUT only when she recurred 2 years after chemoradiotherapy after the malignant transformation of nasal papilloma. She was treated with carboplatin combined with paclitaxel for 2 cycles. So far, the tumor has been stable. Unfortunately, a 38-year-old female patient underwent chemotherapy for 3 cycles after surgery, followed by radiotherapy. Later, the tumor recurred and received radiotherapy again, but she suddenly died of unconsciousness Patients with primary tumors located in the lung were treated with paclitaxel combined with carboplatin for 6 cycles and then treated with 25 radiotherapy for significant tumor shrinkage. The tumors recurred 7 months later and were treated again with paclitaxel, nedaplatin, tislelizumab combined with anlotinib for 4 cycles, and the tumor remained stable now. Another patient at the same site received simultaneous chemoradiotherapy, specifically radiotherapy 25 times, and one cycle of paclitaxel, carboplatin, tislelizumab combined with bevacizumab resulted in tumor shrinkage, unfortunately, the patient died of myelosuppression. Chemotherapy combined with radiotherapy and immunotherapy may be beneficial for the treatment of tumor. Surprisingly, the prognosis for patients after surgery combined with chemotherapy, radiotherapy, and immunotherapy is not ideal. A patient with primary thyroid disease was treated with palliative surgery, postoperative radiotherapy, and chemotherapy with nivolumab, paclitaxel combined with anlotinib after 2 cycles, but the tumor shrank after 3 cycles. The treatment effect of this case was not ideal, and we considered that palliative surgery could not benefit the survival of the patient. The second patient was 9 years old, and the primary tumor site was the right maxillary sinus. Radical radiotherapy was followed by 2 cycles of lobaplatin chemotherapy, the evaluated efficacy was PR. After 2 cycles of chemotherapy with paclitaxel, lobaplatin combined with nimtotuzumab, surgery was performed, and the tumor recurred after surgery, unfortunately, we did not track the time from surgery to recurrence. The last 5-year-old patient, whose primary site was the maxillary sinus, was treated with 6 cycles of paclitaxel, etoposide combined with cisplatin after surgery, followed by radiotherapy, and concurrent immunotherapy. The patient died due to infection, and the overall survival was 9 months. The patient was MIER1-NUTM1 fusion, which was the reason for the poor treatment effect of the patient. A 13-year-old patient with primary nasal cavity tumor was treated with 30 radiotherapy after surgery, followed by maintenance therapy with toripalizumab, and is now in a stable state. Maintenance of immunotherapy can improve the survival of patients In addition, there were 4 patients who received oral BET inhibitors, which quickly controlled the tumor, but had high blood toxicity, such as thrombocytopenia that caused the patient to be intolerant. To sum up, we concluded that the alternative application of different chemotherapy regimen or combination of immunotherapy on the basis of chemotherapy can effectively control the tumor, and combination of radiotherapy on the basis of chemotherapy can benefit the survival of patients, which is the icing on the cake. Radical surgery can help keep the tumor in a stable state and even delay the recurrence of the tumor. Radical surgery combined with chemotherapy, radiotherapy and immunotherapy can benefit the survival of patients. However, palliative surgery does not benefit patients, either in tumor control or in survival, and immune drugs may be used to maintain treatment. MIER1-NUTM1 gene fusion leads to more malignant tumors. BET inhibitors can be very effective in tumor control and can even change the status quo of NUT treatment. We call on hospital pathology departments to establish routine NUT testing programs to reduce the rate of misdiagnosis. Detailed patient data are shown in Table 2. Discussion In order to better describe the clinical outcomes of NUT cancer patients, we conducted a retrospective analysis of the results of all known cases, which representing the most comprehensive collection of reports to date. Although we have included all known cases, the sample size is still very small, and the results should be interpreted with caution. We found that the incidence of NUT diagnosis and the age of diagnosis seem to be increasing, however we recognize that this may reflect reporting bias in this still rare and potentially underappreciated disease. So we recommend using immunohistochemistry to detect NUT expression in all poorly differentiated carcinomas with or without squamous cell differentiation, as the number of patients may continue to increase. NUT is a rare tumor characterized by the presence of a fusion gene between NUT (testicular nucleus) and BRD4 (encoding the dual bromodomain and the ET-containing protein) and its variants[ 15 , 16 ] ,and usually has a poor prognosis. Because they lack specific clinicopathological features, NUT cancer is often misdiagnosed as squamous cell carcinoma, Ewing’s sarcoma, and lymphomas[ 17 ], leading to delayed treatment, which requires IHC and FISH, because NUT is pathologically characterized by translocation of NUT gene (also known as NUTM1 or chr15orf55) on chromosome 15q14, and in about two-thirds of cases, NUT is balanced translocation with the BET family gene BRD4 on chromosome 19p13.1 [t(15;19)(q14; p13.1)], forming an in-frame BRD4-NUT fusion oncogene whose product is driven by the BRD4 promoter [ 18 ], and the partner gene is either BRD3 on chromosome 9 (25%) [t(9;15) (q34.2; q14)], either another BRD-free gene, such as histone methyltransferase NSD3 on chromosome 8 [t(8;15) (p11.23;q14)], or ZNF532 t(15; 18)(q14; q23) [ 19 ]. Only specific FISH and immune structure tests can support the correct diagnosis of this rare tumor and FISH detects potential NUT variants. Previous statistics have shown that the survival time of BRD4-NUT fusion is about 28 weeks[ 20 ], while in the other variants, the overall survival appears to be longer, about 96 weeks[ 17 ], both are equally lethal, but there are also conflicting reports. NUT rearrangement is a key driver of tumor initiation, and BRD3-NUT is a catastrophic event in cell tumor transformation[ 21 , 22 ].NUT is most common in the mediastinum (56%) and head and neck (21%), while sinonasal (57%) account for more than half of head and neck cases, followed by nasopharynx, oropharynx, hypopharynx, larynx and salivary glands [ 11 ]. However, rare cases occur below the diaphragm (e.g., bladder) or in the parotic gland, iliac bone, adrenal gland, and pancreas[ 23 ]. The malignant degree of NUT is very high, and two-thirds of patients have already developed distant metastasis when diagnosed. The most common metastatic sites are lymph nodes, bone, lung and pleura, while metastasis to the liver and brain is rare[ 20 ]. The head and neck are often accompanied by distant lymph node metastasis (26%), while distant metastasis is uncommon (6%). The main reason is that head and neck symptoms occur early. Despite multiple treatment modalities, the outcome of patient with NUT is poor, the median overall survival was 6.7 months, and the overall survival rate of 19% at 2 years, and more than 80% of patients died within 1 year of their diagnosis [ 10 ]. Surprisingly, the overall survival of patients with head and neck tumors is better than that of lung tumors. This suggests that early diagnosis can help improve survival [ 11 ]. In the largest series so far reported which enrolled 63 NMC patients, which suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS, and no chemotherapeutic regimen was associated with improved outcome[ 10 ]. A similar retrospective study in 40 NUT patients found that surgery with or without chemoradiation or radiation (P = 0.04), as well as resection of negative margins (P = 0.01) improved the progression free survival(PFS) and overall survival(OS) of patients significantly[ 11 ]. While these are only for patients diagnosed early, most patients are already at an advanced stage by the time they are diagnosed. Studies so far have shown that chemotherapy or radiotherapy alone has no effect on survival. Moreover, studies have shown that no specific chemotherapy regimen is superior, and the combination of platinum-based regimen with Ewing's sarcoma regimen (vincristine, doxorubicin and cyclophosphamide, alternating with ifosfamide and etoposide) is the most commonly used treatment combination when necessary[ 10 , 11 ] Paclitaxel has also been used as an alternative [ 24 ]. Most patients respond to chemotherapy, but soon the tumor progresses and no remedial chemotherapy has been shown to be effective. Given no better treatment options to date, and new treatment strategies are urgently needed to challenge NUT tumors. Conventional chemotherapy is difficult to achieve good therapeutic effects, leading to the emergence of molecular targeted drugs. BET inhibitors are acetyl-histone mimetics compounds that target BRD4-NUT by competitively inhibiting its binding to chromatin. Recently, regarding the use of BET inhibitors OTX015/MK-8628 in 4 patients with advanced NUT, 2 patients achieved partial response and 4 had stable disease, more interestingly, the two patients achieved an OS of 18 and 19 months which is the longest so far described in the literature. CDK inhibitors are selected from a large number of kinase inhibitors, LDC67 mediates impaired cell viability by inducing apoptosis and DNA damage, and CDK9 is a promising drug target. NUT is an epigenetic-driven tumor due to an ectopic NUT gene, insensitivity to conventional chemotherapy, radiation and rapid tumor progression leading to a very poor survival. Recently, the nut fusion protein has been a small analytical inhibition target to identify this rare patient population and has broader prospects in the clinic. Future clinical treatment is to study targeted drugs combined with multimodal treatment strategies. Correct and timely diagnosis of NUT is the key to improve patients’ outcome. Clinical and molecular analysis of 33 NUT patients confirms the generally poor outcomes in this disease, which provides the most comprehensive understanding of the natural history of NUT and highlights the desperate need for effective therapies. The prognosis of NUT is very poor, traditional chemotherapy is not enough, targeted therapy is imminent, and local treatment, such as surgery may improve the survival rate of patients. Declarations Acknowledgements This work was supported by the National Natural Science Foundation of China (Youth Program, grant No.81172252). We thank everyone who participated in this article. Author’s contributions Xiaoxiao Wu and Na Shen collected clinical data; Liyan Xue and Zhimin Bian designed research, and Xiaoxiao Wu wrote the paper. Funding No funding Availability of data and materials All data is obtained from the clinical diagnosis and treatment data of each patient. Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and approved by Institutional Ethics Committee of the National Clinical Research Center for Cancer/Cancer Hospital. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all individuals or individuals’ guardians. Consent for publication Written informed consent for publication was obtained from all participants. Competing interest The authors have declared no competing interests. Availability of Data and Materials The datasets used during the current study available from the corresponding author on reasonable request. Author details 1 Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2 Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 3 Department of Hematology, Affiliated Hospital of Hebei Engineering University, Hebei, China. *Corresponding author: Liyan Xue Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Email: [email protected] *Corresponding author: Zhimin Bian Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Email: [email protected] References Shah AA, Jeffus SK, Stelow EB: Squamous cell carcinoma variants of the upper aerodigestive tract: a comprehensive review with a focus on genetic alterations . Arch Pathol Lab Med 2014, 138 (6):731-744. Solomon LW, Magliocca KR, Cohen C, Muller S: Retrospective analysis of nuclear protein in testis (NUT) midline carcinoma in the upper aerodigestive tract and mediastinum . Oral Surg Oral Med Oral Pathol Oral Radiol 2015, 119 (2):213-220. Hellquist H, French CA, Bishop JA, Coca-Pelaz A, Propst EJ, Paiva Correia A, Ngan BY, Grant R, Cipriani NA, Vokes D et al : NUT midline carcinoma of the larynx: an international series and review of the literature . Histopathology 2017, 70 (6):861-868. 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Tables Table − 1: The characteristic of patient Patient characteristic No.(%)or median (range) Age at initial cancer diagnosis, y 33.3(2-69y), n = 33 Sex Male 18 of 33(55) Female 15 of 33(45) Primary tumor site Nasal cavity 6 of 33(18) Maxillary sinus 5 of 33(15) Tonsil 1 of 33(3) Thyroid 1 of 33(3) Lung 16 of 33(48) Mediastinum 1 of 33(3) Submandibular 1 of 33(3) Vulva 1 of 33(3) External auditory canal 1 of 33(3) Gene fusion BRD4-NUTM1 4 of 33(12) BRD3-NUTM1 - MIER1-NUTM1 1 of 33(3) CIC-NUTM1 1 of 33(3) Unknown NUTM1(fusion partner was tested, but not identified) 27 of 33(81) Tumor diameter at diagnosis, cm ༜6cm 12 of 33(36) ≥6cm 8 of 33(24) Unknown 13 of 33(39) Lymph node and/or organ metastasis Yes 19 of 33(56) No 3 of 33(1) Unknown 11 of 33(43) PD-L1 expression Positive ≥ 1% 12 of 33(36) Negative 5 of 33(15) Unknown 16 of 33(49) Treatment Chemotherapy 5 of 33(12) Chemotherapy combined with Surgery 3 of 33(9) Chemotherapy combined with surgery and radiotherapy 4 of 33(12) Chemotherapy combined with radiotherapy and immunotherapy 2 of 33(6) Chemotherapy combined with Surgery and immunotherapy 2 of 33(6) Chemotherapy combined with immunotherapy 3 of 33(9) Surgery combined with radiotherapy and immunotherapy 1 of 33(3) Chemotherapy combined with Surgery and immunotherapy and radiotherapy 3 of 33(9) Chemotherapy combined with radiotherapy 1 of 33(3) Unknown 5 of 33(18) Oral BET-inhibitors 4 of 33(12) Initial response Complete or partial response 21 of 33(54) Stable or progression disease 6 of 33(18) Unknown 6 of 33(18) Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.xlsx Table-2：Detailed case data and treatment history of patient Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3230156","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":230984899,"identity":"980ec44b-7700-4678-8070-1676eb0a0f11","order_by":0,"name":"Xiaoxiao Wu","email":"","orcid":"","institution":"National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoxiao","middleName":"","lastName":"Wu","suffix":""},{"id":230984901,"identity":"9dd817d6-51bc-408c-9ab8-6879bdb3510e","order_by":1,"name":"Na Shen","email":"","orcid":"","institution":"Affiliated Hospital of Hebei Engineering University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Shen","suffix":""},{"id":230984904,"identity":"4b0a702b-dabb-4f6c-a2f1-74bd27d49ad2","order_by":2,"name":"Liyan Xue","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liyan","middleName":"","lastName":"Xue","suffix":""},{"id":230984905,"identity":"ba5b86f2-71d2-4a9d-ac4f-396961dd5140","order_by":3,"name":"Zhimin Bian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYBACNv7mgw8SKmyYGRsOJAIZNYS18EkcSzZ4cCaNnbnxwGMg4xhhLXIMOWqSD9sO87M3H3wm+bCFmQiHMZxhNkhgY5bmbTucVpHYwMbA396dgF8Lcy/QLzxsxpI9x9JuJO6QYZA4c3YDAVvOJRskSPAkG844A9Ryho3BQCKXkJYcM4kEA4n6/ffffytIbGMmVkuCASiQ0xiI0wIK5IQDCSAtyRIJZ47xEPSLfH/zwYc///0HR+XHHxU1cvztvfi1YAAe0pSPglEwCkbBKMAKAJXWUGQj37wwAAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Zhimin","middleName":"","lastName":"Bian","suffix":""}],"badges":[],"createdAt":"2023-08-03 06:59:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3230156/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3230156/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":44593438,"identity":"17a3a715-22b8-45bd-9c28-abd68a439937","added_by":"auto","created_at":"2023-10-13 18:37:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":725175,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3230156/v1/66fd7213-882a-4f9e-9832-1121b17482e2.pdf"},{"id":42930765,"identity":"764e8c1c-30d6-41dc-baf4-a3bc5b6187c6","added_by":"auto","created_at":"2023-09-11 11:54:00","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12815,"visible":true,"origin":"","legend":"\u003cp\u003eTable-2：Detailed case data and treatment history of patient\u003c/p\u003e","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3230156/v1/027114f5156fe5f404dce68c.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features, Therapy and Long-Term Outcomes of NUT Carcioma in China","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNut carcinoma is a rare but aggressive and poorly differentiated carcinoma characterized by chromosomal rearrangement of the NUT gene ,also known as t(15;19)(q15;p13)[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This rearrangement lead to NUT in-frame with BRD4, a ubiquitously-expressed transcriptional co-activator, or with BRD3 and other unknown genes, which possess as yet unresolved molecular biology[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Histologically, NUT carcinoma displays undifferentiated carcinoma or poorly differentiated squamous cell carcinoma[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], which leads to misdiagnosed. Detection of NUT gene translocation by immunohistochemistry, fluorescence in situ hybridization (FISH) or gene sequencing has become the only way to diagnose NUT carcinoma.\u003c/p\u003e \u003cp\u003eLarge series studies described that NC occurs in the midline, affecting the mediastinum/thymus, upper digestive tract, nasal cavity and sinuses were the most common[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003csup\u003e-\u003c/sup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], however, cases that occur in non-midline structures break traditional cognition[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e],which causing different clinical symptoms. NUT carcinoma is locally aggressive, with early disease progression, extremely poor treatment effect. Recurrence and mortality are high, with a median overall survival in NUT carcinoma is 6.5\u0026ndash;6.7 months[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eTreatment approaches have been heterogeneous. There is no standard treatment for NUT carcioma. Chemotherapy and radiotherapy seems to be ineffective[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] ,the clinical outcomes were variable among patients. Complete resection of tumor may prolong the survival of patient[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], which is not always possible because of surgical inaccessibility or metastatic disease[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].Since its recognition as NUT translocation, and leading to dysregulation of normal differentiation, which promoted many researchers focused on targeted drugs, for example bromodomain and extraterminal (BET) inhibitor. BET inhibitor has been shown in vitro and in vivo to eliminate growth disorders and translate into clinical activity[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough NUT carcinoma is aggressive, we have noted that response to treatment can be quite variable depend on the patient\u0026rsquo;s situation[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The underdiagnosed and rarity have thus far precluded treatment timely, even led to misdiagnosis. In this study, we accessed progression-free survival and overall survival of 33 patients diagnosed with NUT carcinoma, as well as treatment variables including extent of surgical resection, provision of radiotherapy and selected chemotherapeutic agents.\u003c/p\u003e"},{"header":"Methods and Materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eA total of 33 patients with NUT carcinoma who were defined as NUT rearrangement demonstrated by fluorescent in situ hybridization(FISH), immunohistochemistry showed abnormal NUT expression, or characteristic t(15;19), or next-generation sequencing(NGS). For 33 cases, a questionnaire was sent to patients, including clinical, demographic, treatment, and outcome variables. Retrospective clinical data were obtained for 33 patients.\u003c/p\u003e \u003cp\u003eCollect and summarize patient data, clinical staging was depended on the site of primary tumor, lymph node involvement, and location of metastasis. Initial therapy and relapse or progression were included, and treatment includes surgery and chemotherapy, with either a total or partial excision, chemotherapy with platinum containing or anthracycline containing agents, or immunological drugs. And many people have received combination therapy.\u003c/p\u003e \u003cp\u003eFor progression-free survival (PFS), time-events are the time between the first diagnosis of cancer at the treating hospital and the first recurrence, progression, or death of the disease, or if these events do not occur, until the last exposure. For overall survival (OS), the time from diagnosis to death or to last follow-up if censored. Clinical responses to initial treatment are classified as complete or partial response, stable disease, or progressive disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarized the demographic and clinical characteristic of patients. Calculation of OS from initial cancer diagnosis to death or to last follow-up. All analyses were performed in SPSS version 24.0, P values less than or equal to .05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eClinical Features and Tumor Characteristics\u003c/h2\u003e \u003cp\u003eThe clinical features and tumor characteristics of the 33 patients with NUT carcinoma are summarized in Table\u0026nbsp;1. The media age at diagnosis was 33.3 years(range\u0026thinsp;=\u0026thinsp;2-69years), and 51% were male, 48% (16 of 33)of tumors arose from the lung,15% (5 of 33) from nasal cavity,15% (5 of 33) from maxillary sinus, tonsil, thyroid, mediastinum, submandibular, vulva and external auditory canal were one case each. The mean (SD) primary tumor diameter at diagnosis was 5.8cm, lymph node involvement or distant metastasis were found in 56% (19 of 33), and the most common site of metastasis is bone. PD-L1 positivity accounts for approximately 36%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eTreatment Outcomes\u003c/h2\u003e \u003cp\u003eThe prognosis of NUT patients is generally poor, and the response to initial treatment was only 21 (54%) of patient having a complete or partial response, most people received multimodality therapy. Three (9%) patients with primary site in the lung underwent initial chemotherapy combined with immunotherapy, among whom two had partial responses and one had stable disease at first but finally died no matter the expression of PD-L1,the first two patients were treated with paclitaxel liposome, cisplatin combined with sintilimab and etoposide, carboplatin combined with nivolumab respectively, and the efficacy evaluation was PR every two cycles. However, the last patient achieved SD with one cycle of paclitaxel liposome, nedaplatin combined with tislelizumab, followed six cycles of bevacizumab combined with paclitaxel and cisplatin, which reduced the primary tumor from 9cm to 3.4cm, and continued with lung radiation therapy only, but also developed abdominal metastasis, so instead of radiation, and the adjustment plan was gemcitabine hydrochloride, nedaplatin and anlotinib with durvalumab, but the patient died after two cycles due to the inability to effectively control the tumor, and the overall survival time was nine months. This seems to prove that early chemotherapy combination of immunotherapy can effectively control tumor progression and even prolong PFS.\u003c/p\u003e \u003cp\u003ewhereas the other five patients received chemotherapy only, and the response was stable, but it was progressing rapidly. Two patients with primary lung disease received paclitarel with cisplatin only or etoposide with cisplatin, one of which was combined with bevacizumab, but had an overall survival of 4\u0026ndash;5 months. The other two patients were 8 and 20 years old and the primary site was tonsil and mediastinum. In patients with mediastinal tumor, the tumor reached stability after 6 cycles of alternating application of doxorubicina, cyclophosphamide combined with vindesil sulfate and ifosfamide combined with etoposide, but the tumor progressed after 3 cycles of irinotecan combined with anlotinib. In patients with primary tonsil disease, the tumor remained under control after alternating 12 cycles of cyclophosphamide, cisplatin combined with pirarubicin and ifosfamide combined with etoposide. The last patient initially diagnosed as lung squamous cell carcinoma, two cycles of paclitaxel combinend with paraplatin were administered, followed by surgery, and the postoperative pathology indicated NUT. After 4 cycles of gemcitabine combined with cisplatin, the tumor progressed. Chemotherapy alone is less effective, but patients can benefit from alternating chemotherapy regiments, and the most impotent is that the incidence of nut was low, pathology in most hospitals were not used as a routine examination item, resulting in misdiagnosis and further delay in treatment.\u003c/p\u003e \u003cp\u003eHowever, only one male patient with primary lung tumor, the assessed efficacy was PR after 4 cycles of chemotherapy with paclitaxel combined with cisplatin, followed by 28 times of radiotherapy, and radiotherapy was performed on the lung and metastatic site: left gastric lymph node, followed by 2 cycles of chemotherapy with the original regimen. To our surprised, the tumor recurred 10 months after oral anlotinib monotherapy, which suggests that radiotherapy for primary and metastatic tumors may be beneficial for survival.\u003c/p\u003e \u003cp\u003eRadical chemotherapy combined with surgery was shown to be beneficial in delaying tumor recurrence in three patients. The ages of three patients were 27, 27, and 19 years old, respectively. The primary tumors were located in the lungs, sinuses, and vulva. The first patient had tumor recurrence after 17 cycles of alternating vindesine sulfate, epirubicin hydrochloride combined with cyclophosphamide and ifosfamide combined with etoposide regimens after surgery. The second patient was evaluated as PR after 2 cycles of albumin paclitaxel combined with cisplatin, and then underwent surgery. Currently, the tumor is still in a stable state 8 months after surgery. After the third patient underwent surgery, alternating application of cisplatin, vincristine sulfate combined with pirarubicin hydrochloride and cisplatin, cyclophosphamide, vincristine sulfate combined with pirarubicin hydrochloride for 10 cycles resulted in a stable reduction in the size of the inguinal lymph node metastasis from 17mm to 6mm. The above suggests that NUT patients still need early surgical treatment.\u003c/p\u003e \u003cp\u003eTo our surprised, two patients (6%) received chemotherapy combined with surgery and sintilimab maintenance therapy, however the outcome was quite different. A 34-year-old patient with a primary submandibular tumor of about 2.4*1.6cm before surgery, accompanied by lymph node metastasis in the upper neck, had a tumor recurrence of about 2.4*1.4cm in a half month after surgery. The tumor remained uncontrolled after 4 cycles of alternating cyclophosphamide, doxorubicin hydrochloride liposome combined with vindesine sulfate and ifosfamide combined with etoposide, and was re-operated after 6 cycles of paclitaxel, cisplatin, sintilimab combined with anlotinib. During the postoperative maintenance treatment with sintilimab, the tumor has reached a stable state. However, another 53-year-old male patient with primary lung tumor was treated with paclitaxel combined with cisplatin for two cycles, the tumor increased, forced surgery, and given nedaplatin, gemcitabine hydrochloride combined with sintilimab for one cycle, regrettably the patient died, with an overall survival of about 5 months.\u003c/p\u003e \u003cp\u003eSurgery in combination with chemotherapy and radiotherapy seems to benefit patients' survival. The 4 patients with NUT were 47,39,67 and 38, and the primary sites were nasal cavity, nasal cavity, maxillary sinus and frontal sinus, respectively. One of the patients had a recurrence soon after surgery, and was treated with concurrent chemotherapy and oral chidamide maintenance treatment, and now the tumor was in a stable state. Similar to the other patient, the tumor remained stable after surgery by oral administration of chidamide combined with chemoradiotherapy. Another female patient was diagnosed with NUT only when she recurred 2 years after chemoradiotherapy after the malignant transformation of nasal papilloma. She was treated with carboplatin combined with paclitaxel for 2 cycles. So far, the tumor has been stable. Unfortunately, a 38-year-old female patient underwent chemotherapy for 3 cycles after surgery, followed by radiotherapy. Later, the tumor recurred and received radiotherapy again, but she suddenly died of unconsciousness\u003c/p\u003e \u003cp\u003ePatients with primary tumors located in the lung were treated with paclitaxel combined with carboplatin for 6 cycles and then treated with 25 radiotherapy for significant tumor shrinkage. The tumors recurred 7 months later and were treated again with paclitaxel, nedaplatin, tislelizumab combined with anlotinib for 4 cycles, and the tumor remained stable now. Another patient at the same site received simultaneous chemoradiotherapy, specifically radiotherapy 25 times, and one cycle of paclitaxel, carboplatin, tislelizumab combined with bevacizumab resulted in tumor shrinkage, unfortunately, the patient died of myelosuppression. Chemotherapy combined with radiotherapy and immunotherapy may be beneficial for the treatment of tumor.\u003c/p\u003e \u003cp\u003eSurprisingly, the prognosis for patients after surgery combined with chemotherapy, radiotherapy, and immunotherapy is not ideal. A patient with primary thyroid disease was treated with palliative surgery, postoperative radiotherapy, and chemotherapy with nivolumab, paclitaxel combined with anlotinib after 2 cycles, but the tumor shrank after 3 cycles. The treatment effect of this case was not ideal, and we considered that palliative surgery could not benefit the survival of the patient. The second patient was 9 years old, and the primary tumor site was the right maxillary sinus. Radical radiotherapy was followed by 2 cycles of lobaplatin chemotherapy, the evaluated efficacy was PR. After 2 cycles of chemotherapy with paclitaxel, lobaplatin combined with nimtotuzumab, surgery was performed, and the tumor recurred after surgery, unfortunately, we did not track the time from surgery to recurrence. The last 5-year-old patient, whose primary site was the maxillary sinus, was treated with 6 cycles of paclitaxel, etoposide combined with cisplatin after surgery, followed by radiotherapy, and concurrent immunotherapy. The patient died due to infection, and the overall survival was 9 months. The patient was MIER1-NUTM1 fusion, which was the reason for the poor treatment effect of the patient.\u003c/p\u003e \u003cp\u003eA 13-year-old patient with primary nasal cavity tumor was treated with 30 radiotherapy after surgery, followed by maintenance therapy with toripalizumab, and is now in a stable state. Maintenance of immunotherapy can improve the survival of patients\u003c/p\u003e \u003cp\u003eIn addition, there were 4 patients who received oral BET inhibitors, which quickly controlled the tumor, but had high blood toxicity, such as thrombocytopenia that caused the patient to be intolerant.\u003c/p\u003e \u003cp\u003eTo sum up, we concluded that the alternative application of different chemotherapy regimen or combination of immunotherapy on the basis of chemotherapy can effectively control the tumor, and combination of radiotherapy on the basis of chemotherapy can benefit the survival of patients, which is the icing on the cake. Radical surgery can help keep the tumor in a stable state and even delay the recurrence of the tumor. Radical surgery combined with chemotherapy, radiotherapy and immunotherapy can benefit the survival of patients. However, palliative surgery does not benefit patients, either in tumor control or in survival, and immune drugs may be used to maintain treatment. MIER1-NUTM1 gene fusion leads to more malignant tumors. BET inhibitors can be very effective in tumor control and can even change the status quo of NUT treatment. We call on hospital pathology departments to establish routine NUT testing programs to reduce the rate of misdiagnosis. Detailed patient data are shown in Table\u0026nbsp;2.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn order to better describe the clinical outcomes of NUT cancer patients, we conducted a retrospective analysis of the results of all known cases, which representing the most comprehensive collection of reports to date. Although we have included all known cases, the sample size is still very small, and the results should be interpreted with caution.\u003c/p\u003e \u003cp\u003eWe found that the incidence of NUT diagnosis and the age of diagnosis seem to be increasing, however we recognize that this may reflect reporting bias in this still rare and potentially underappreciated disease. So we recommend using immunohistochemistry to detect NUT expression in all poorly differentiated carcinomas with or without squamous cell differentiation, as the number of patients may continue to increase.\u003c/p\u003e \u003cp\u003eNUT is a rare tumor characterized by the presence of a fusion gene between NUT (testicular nucleus) and BRD4 (encoding the dual bromodomain and the ET-containing protein) and its variants[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] ,and usually has a poor prognosis. Because they lack specific clinicopathological features, NUT cancer is often misdiagnosed as squamous cell carcinoma, Ewing\u0026rsquo;s sarcoma, and lymphomas[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], leading to delayed treatment, which requires IHC and FISH, because NUT is pathologically characterized by translocation of NUT gene (also known as NUTM1 or chr15orf55) on chromosome 15q14, and in about two-thirds of cases, NUT is balanced translocation with the BET family gene BRD4 on chromosome 19p13.1 [t(15;19)(q14; p13.1)], forming an in-frame BRD4-NUT fusion oncogene whose product is driven by the BRD4 promoter [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and the partner gene is either BRD3 on chromosome 9 (25%) [t(9;15) (q34.2; q14)], either another BRD-free gene, such as histone methyltransferase NSD3 on chromosome 8 [t(8;15) (p11.23;q14)], or ZNF532 t(15; 18)(q14; q23) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Only specific FISH and immune structure tests can support the correct diagnosis of this rare tumor and FISH detects potential NUT variants. Previous statistics have shown that the survival time of BRD4-NUT fusion is about 28 weeks[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], while in the other variants, the overall survival appears to be longer, about 96 weeks[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], both are equally lethal, but there are also conflicting reports. NUT rearrangement is a key driver of tumor initiation, and BRD3-NUT is a catastrophic event in cell tumor transformation[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].NUT is most common in the mediastinum (56%) and head and neck (21%), while sinonasal (57%) account for more than half of head and neck cases, followed by nasopharynx, oropharynx, hypopharynx, larynx and salivary glands [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, rare cases occur below the diaphragm (e.g., bladder) or in the parotic gland, iliac bone, adrenal gland, and pancreas[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The malignant degree of NUT is very high, and two-thirds of patients have already developed distant metastasis when diagnosed. The most common metastatic sites are lymph nodes, bone, lung and pleura, while metastasis to the liver and brain is rare[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The head and neck are often accompanied by distant lymph node metastasis (26%), while distant metastasis is uncommon (6%). The main reason is that head and neck symptoms occur early.\u003c/p\u003e \u003cp\u003eDespite multiple treatment modalities, the outcome of patient with NUT is poor, the median overall survival was 6.7 months, and the overall survival rate of 19% at 2 years, and more than 80% of patients died within 1 year of their diagnosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Surprisingly, the overall survival of patients with head and neck tumors is better than that of lung tumors. This suggests that early diagnosis can help improve survival [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the largest series so far reported which enrolled 63 NMC patients, which suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS, and no chemotherapeutic regimen was associated with improved outcome[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A similar retrospective study in 40 NUT patients found that surgery with or without chemoradiation or radiation (P\u0026thinsp;=\u0026thinsp;0.04), as well as resection of negative margins (P\u0026thinsp;=\u0026thinsp;0.01) improved the progression free survival(PFS) and overall survival(OS) of patients significantly[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile these are only for patients diagnosed early, most patients are already at an advanced stage by the time they are diagnosed. Studies so far have shown that chemotherapy or radiotherapy alone has no effect on survival. Moreover, studies have shown that no specific chemotherapy regimen is superior, and the combination of platinum-based regimen with Ewing's sarcoma regimen (vincristine, doxorubicin and cyclophosphamide, alternating with ifosfamide and etoposide) is the most commonly used treatment combination when necessary[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Paclitaxel has also been used as an alternative [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Most patients respond to chemotherapy, but soon the tumor progresses and no remedial chemotherapy has been shown to be effective. Given no better treatment options to date, and new treatment strategies are urgently needed to challenge NUT tumors. Conventional chemotherapy is difficult to achieve good therapeutic effects, leading to the emergence of molecular targeted drugs. BET inhibitors are acetyl-histone mimetics compounds that target BRD4-NUT by competitively inhibiting its binding to chromatin. Recently, regarding the use of BET inhibitors OTX015/MK-8628 in 4 patients with advanced NUT, 2 patients achieved partial response and 4 had stable disease, more interestingly, the two patients achieved an OS of 18 and 19 months which is the longest so far described in the literature. CDK inhibitors are selected from a large number of kinase inhibitors, LDC67 mediates impaired cell viability by inducing apoptosis and DNA damage, and CDK9 is a promising drug target.\u003c/p\u003e \u003cp\u003eNUT is an epigenetic-driven tumor due to an ectopic NUT gene, insensitivity to conventional chemotherapy, radiation and rapid tumor progression leading to a very poor survival. Recently, the nut fusion protein has been a small analytical inhibition target to identify this rare patient population and has broader prospects in the clinic. Future clinical treatment is to study targeted drugs combined with multimodal treatment strategies. Correct and timely diagnosis of NUT is the key to improve patients\u0026rsquo; outcome. Clinical and molecular analysis of 33 NUT patients confirms the generally poor outcomes in this disease, which provides the most comprehensive understanding of the natural history of NUT and highlights the desperate need for effective therapies.\u003c/p\u003e \u003cp\u003eThe prognosis of NUT is very poor, traditional chemotherapy is not enough, targeted therapy is imminent, and local treatment, such as surgery may improve the survival rate of patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Youth Program, grant No.81172252). We thank everyone who participated in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaoxiao Wu and Na Shen collected clinical data; Liyan Xue and Zhimin Bian designed research, and Xiaoxiao Wu wrote the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data is obtained from the clinical diagnosis and treatment data of each patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by Institutional Ethics Committee of the National Clinical Research Center for Cancer/Cancer Hospital. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all individuals or individuals\u0026rsquo; guardians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1\u0026nbsp;\u003c/em\u003eDepartment of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2\u0026nbsp;\u003c/em\u003eDepartment of\u003cem\u003e\u0026nbsp;\u003c/em\u003ePathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3 Department of Hematology, Affiliated Hospital of Hebei Engineering University, Hebei, China.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e*Corresponding author:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLiyan Xue\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDepartment of\u003cem\u003e\u0026nbsp;\u003c/em\u003ePathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.\u003c/p\u003e\n\u003cp\u003eEmail:[email protected] \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*Corresponding author:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZhimin Bian\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDepartment of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.\u003c/p\u003e\n\u003cp\u003eEmail: [email protected]\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShah AA, Jeffus SK, Stelow EB: \u003cstrong\u003eSquamous cell carcinoma variants of the upper aerodigestive tract: a comprehensive review with a focus on genetic alterations\u003c/strong\u003e. \u003cem\u003eArch Pathol Lab Med \u003c/em\u003e2014, \u003cstrong\u003e138\u003c/strong\u003e(6):731-744.\u003c/li\u003e\n\u003cli\u003eSolomon LW, Magliocca KR, Cohen C, Muller S: \u003cstrong\u003eRetrospective analysis of nuclear protein in testis (NUT) midline carcinoma in the upper 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Cancer \u003c/em\u003e2006, \u003cstrong\u003e6\u003c/strong\u003e:69.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv id=\"Par60\" class=\"Para\"\u003eTable \u0026minus;\u0026thinsp;1: The characteristic of patient\u003c/div\u003e\n\u003cdiv id=\"Par62\" class=\"Para\"\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatient characteristic\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNo.(%)or median (range)\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eAge at initial cancer diagnosis, y\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e33.3(2-69y), n\u0026thinsp;=\u0026thinsp;33\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSex\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMale\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e18 of 33(55)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eFemale\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e15 of 33(45)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePrimary tumor site\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNasal cavity\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6 of 33(18)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMaxillary sinus\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5 of 33(15)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTonsil\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eThyroid\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLung\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e16 of 33(48)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMediastinum\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSubmandibular\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eVulva\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eExternal auditory canal\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eGene fusion\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBRD4-NUTM1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4 of 33(12)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eBRD3-NUTM1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eMIER1-NUTM1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eCIC-NUTM1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown NUTM1(fusion partner was tested, but not identified)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e27 of 33(81)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTumor diameter at diagnosis, cm\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e༜6cm\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e12 of 33(36)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u0026ge;6cm\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e8 of 33(24)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e13 of 33(39)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eLymph node and/or organ metastasis\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eYes\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e19 of 33(56)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNo\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3 of 33(1)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e11 of 33(43)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePD-L1 expression\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePositive\u0026thinsp;\u0026ge;\u0026thinsp;1%\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e12 of 33(36)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNegative\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5 of 33(15)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e16 of 33(49)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eTreatment\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5 of 33(12)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with Surgery\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3 of 33(9)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with surgery and radiotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4 of 33(12)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with radiotherapy and immunotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2 of 33(6)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with Surgery and immunotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2 of 33(6)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with immunotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3 of 33(9)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eSurgery combined with radiotherapy and immunotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with Surgery and immunotherapy and radiotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3 of 33(9)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eChemotherapy combined with radiotherapy\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1 of 33(3)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e5 of 33(18)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eOral BET-inhibitors\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4 of 33(12)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eInitial response\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eComplete or partial response\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e21 of 33(54)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eStable or progression disease\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6 of 33(18)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eUnknown\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e6 of 33(18)\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 is available in the Supplementary Files section.\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"NUT carcinoma, treatment, outcomes","lastPublishedDoi":"10.21203/rs.3.rs-3230156/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3230156/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNUT carcinoma is a rare, poorly differentiated tumor typically driven by a t(15;19) rearrangement leading to a NUT gene rearrangement event. This uniformly fatal tumor has promoted targeted therapy, yet the clinical characteristics of Chinese patients with NUT carcinoma and the efficacy of all treatment have not been systematically summarized. In order to better understanding the disease characteristic and treatments, correlate them with outcome, we have here compiled findings pertaining to a large population of such patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA clinical database from all know cases of NUT carcinoma was established. Pathologic, demographic, and survival data of 33 patients were analyzed by questionnaires, the largest cohort studied of NMC patients to data in China.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePrimary tumors sites included nasal cavity (n\u0026thinsp;=\u0026thinsp;6), maxillary sinus (n\u0026thinsp;=\u0026thinsp;5),tonsil (n\u0026thinsp;=\u0026thinsp;1), thyroid (n\u0026thinsp;=\u0026thinsp;1), lung (n\u0026thinsp;=\u0026thinsp;16), mediastinum (n\u0026thinsp;=\u0026thinsp;1), submandibular(n\u0026thinsp;=\u0026thinsp;1), vulva(n\u0026thinsp;=\u0026thinsp;1), external auditory canal༈n\u0026thinsp;=\u0026thinsp;1༉. The patient age ranged from 2 to 69 years with the male/female ratio of 1.3/1,11 of them died, the media overall survival for those patients was 5.5 months. Multivariate analysis proved that the primary site NUT carcinoma was not related to the prognosis, alternative application of different chemotherapy regimen or combination of immunotherapy on the basis of chemotherapy can effectively control the tumor, and combination of radiotherapy on the basis of chemotherapy can benefit the survival of patients, which is the icing on the cake. Radical surgery can help keep the tumor in a stable state and even delay the recurrence of the tumor. Radical surgery combined with chemotherapy, radiotherapy and immunotherapy can benefit the survival of patients. Notably, NUT progresses quickly when therapy is terminated. Unfortunately, radiotherapy alone does not significantly improve outcome in China.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBreaking the traditional understanding that NUT carcinoma tends to occur in the midline, and not all originate from squamous cell carcinoma. The finding that conventional chemotherapy and radiotherapy have been not sensitively. Chemotherapy combined with immunotherapy or early surgical might improve overall survival.\u003c/p\u003e","manuscriptTitle":"Clinical Features, Therapy and Long-Term Outcomes of NUT Carcioma in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-11 11:53:55","doi":"10.21203/rs.3.rs-3230156/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9741a6fe-be6e-4aaf-ad05-cd345c092e07","owner":[],"postedDate":"September 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-10-13T18:29:19+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-11 11:53:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3230156","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3230156","identity":"rs-3230156","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}