A 59-year-old woman developed sudden but constant rhinorrhea with yellow mucus or occasional blood in January 2020. She denied any family history or mental illness. A month later, she developed hyposmia in addition to the symptoms above. She was evaluated at a local hospital and the brain magnetic resonance imaging (MRI) showed a mass located in the nose and protruded into the skull. This result was confirmed by a rhinoscopy. A grayish-white, infiltrative neoplasm, centered in the inferior meatus and common nasal meatus, was found.
To further diagnose the disease, the patient underwent endoscopic nasal tumor resection, open sinus surgery, skull base repair following endoscopy, and radiofrequency ablation at the local hospital in April 2020. The surgical procedure was successful, and the postoperative pathology confirmed ONB with 90% Ki-67 ( Figure 1 ). The patient received radiotherapy with a total dose of 59.36Gy/28F from April to June 2020. She was also treated with 1 cycle of etoposide (200mg, day1-3) and cisplatin (40mg, day1-2) in April 2020. Unfortunately, the treatment was unsuccessful, and the patient's symptoms remained unimproved.
In July 2020, two weeks before she was admitted to our hospital, her symptoms progressed with a developed and worsening weakness in both lower legs.
When the patient was transferred to our hospital in July 2020, she complained that her rhinorrhea was not getting any better compared to 6 months ago, and the weakness in both legs was worsening. On admission, physical examination revealed reduced mental clarity and a lack of speech fluency. She also had impaired orientation, comprehension, calculation, and memory. Cranial nerve testing showed that the pupillary light reflex was dull and that the shoulder shrug was bilaterally eliminated. The grading of power was 2-3 in the right lower limb, 2 in the left lower limb, and 5 in both upper limbs. She also had hypotonia and hyperesthesia, but no abnormalities in proprioceptive sensation.
To better evaluate her condition, we performed a series of baseline tests. The MRI revealed abnormal signals in the front lobe, nasal cavity, cervical spinal cord, upper thoracic spinal cord, and lumbar spinal cord ( Figure 2B ). CSF, which nourishes the brain tissue and carries away the metabolites, can relatively reflect the tumor condition in the brain. Correspondingly, the CSF test showing the presence of tumor cells (7%) confirmed the progression of the LM ( Figure 3A ). Based on the patient's symptoms, physical examination, MRI, and pathology, we concluded that the patient had ONB with Kadish stage D. Kadish D is the most advanced grade, according to the Kadish classification.
As previous chemotherapy had been unsatisfactory, we sought to apply a more individualized treatment. We performed a next-generation sequencing (NGS) and the result showed a nonsense mutation in the APC gene, a tumor suppressor gene involved in the regulation of cell proliferation, migration, adhesion, and chromosomal stability ( Table 1 ). APC mutation can accelerate the cell cycle, and further promote tumorigenesis and metastasis. Considering that there were no obvious immunotherapeutic target genes detected, we chose to use the broad-spectrum chemotherapeutic agent, MTX, with a novelty way of intrathecal injection.
Based on these findings, the patient received two cycles of intrathecal MTX injection (10mg, day1, 4, 6) and the intravenous ICE regimen (isocyclophosphamide 1.5g day1-3, etoposide 100mg day1-3, cisplatin 30mg day1-3) since July 2020 ( Figure 2A ). After the first cycle and to reduce the damage and discomfort of each intrathecal injection through a lumbar puncture, we performed Ommaya reservoir implantation in her right frontal brain. The intrathecal injection was performed through the Ommaya reservoir thereafter. The patient was regularly followed up with monthly complete blood count, T and B natural killer cells (TBNK) panel, comprehensive metabolic panel (CMP), and advanced MRI scan.
Due to the severe side effects of isocyclophosphamide, we changed the treatment to intrathecal MTX injection (10mg, day1, 4, 7) and intravenous EC regimen (etoposide 100 mg, day1-4, and carboplatin 100 mg, day1-4) for a total of 3 cycles during October to December 2020. Strikingly, we had a thrilling result of achieving a partial response (PR) and there was an improvement in her physical examination. She became capable of conversing fluently with her healthcare team. She had normal orientation, comprehension, and calculation, with a mildly decreased memory. The grading of power in both upper limbs remained 5. The grading of power was 4 in the right lower limb and 3-4 in the left lower limb. In October 2020, her brain and spine lesions shrunk by >= 30% ( Figure 2C ), and in December 2020, her CSF test showed no tumor cells ( Figure 3B ). The proportion of T cells and T helper cells with killing functions increased. The proportion of the Ts cells, which suppress T cells, decreased, further indicating that the treatment had a good regulatory effect on the T cell population( Figure 3C ).
However, after the third cycle of intrathecal MTX injection and intravenous EC chemotherapy, the patient relapsed on February 2021. She rapidly developed drowsiness and a lack of conversation fluency. Her orientation and comprehension remained normal. However, her calculating capacity and memory were impaired. Her grading of power in the lower limbs decreased, with 2-3 in right lower limb and 3 in the left lower limb. The grading of power of both upper limbs was 5. The MRI showed that the intracranial lesion increased by over 20%, along with cerebral edema ( Figure 2D ). There was also an increase in the percentage of tumor cells in the CSF ( Figure 3B ). When combining the above results with the patient's symptoms and physical examination, we concluded that she had progressive disease (PD). Although craniospinal irradiation was recommended by our hospital department of radiotherapy, the patient and her family were concerned about the risk of organ damage and bone marrow suppression, and therefore, decided to pursue chemotherapy as a treatment option.
To eliminate the brain edema and better prolong the patient's survival, bevacizumab was added for four cycles from February to May 2021. During this period, there was no significant difference in her physical examination. Thus, based on these results and the MRI findings ( Figure 2E ), we determined that she reached stable disease (SD). Bevacizumab was stopped in June 2021.
Unfortunately, these approaches failed to further prolong her lifespan. After adjusting to intrathecal MTX injection and intravenous IC regimen with bevacizumab for one cycle, and intrathecal injection of cytarabine (Ara-C) and intravenous IC regimen for another cycle, she passed away in November 2021.