PMC9197190_01
Clinical course and management of the patient using multimodal treatment strategy until temozolomide and capecitabine (CAPTEM). Serum levels of growth hormone (GH; blue lines) and insulin-like growth factor-1 (IGF-1; orange lines) before CAPTEM (A). Gadolinium-enhanced MR T1 images show that the tumor initially extending laterally to the right and posteriorly, and finally localized right-dorsal part of the brainstem. The upper row is coronal images and the lower row is axial images (B).
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She was initially treated with octreotide long-acting release (LAR), but it was ineffective even with increasing doses ( Figure 1A ) and was replaced with increasing doses of pasireotide LAR along with cabergoline (dose was up to 2 mg weekly) ( Figure 1A . MRI revealed a large sellar mass invading the right CS with complete internal carotid artery (ICA) encasement, which was equivalent to Knosp grade 4; in addition, the tumor extended posteriorly, compressing the brainstem ( Figure 1B ). However, even with the subsequent medical therapy, the tumor continued growing and serum GH levels continued to rise ( Figure 1 ). These intensive treatments worked and tumor volume and serum levels of GH and IGF-1 drastically decreased ( Figure 1A ). However, the tumor reappeared in the dorsal part of the right midbrain and serum IGF-1 levels increased one year after ( Figure 1A ). Serial MRI in this period revealed that the tumor volume became 30 times larger in 5 months ( Figure 1B ). The fifth surgery was performed for the tumor, but only small part was removed because it was deep and adhered to the brainstem ( Figure 1B ). Figure 1A ). Following this result,
Hematoxylin and eosin (HE) staining and immunohistochemical studies of the specimen from the 5th surgery (A) using the following antibodies: growth hormone (GH), CAM5.2, O
6-methylguanine-DNA-methyltransferase (MGMT), Ki-67, p53, MutS Homolog 6 (MSH6), somatostatin receptor (SSTR) 2A, SSTR5. Scale bar represents 20 mm and applies to all the pictures (A). Patient-derived ex vivo three-dimensional (3D) spheroid culture assay (B). Cell Viability Assay is shown in the bar graph. X-axis represents the time after drug treatment (hours) while the y-axis represents the value of luminescence (RLU). The luminescence readout is directly proportional to the number of viable cells in culture. Temozolomide (TMZ) combined with 5-fluorouracil (5-FU) (red line) had significantly more effect than TMZ alone (orange line). TMZ alone (orange line) showed no effect compared to the vehicle treatment (black line). 50% inhibition concentration (IC50) was used as a reference for setting drug concentration conditions. The p-value of the two-sided test less than 0.05 was considered to represent statistical significance. RLU: relative light unit. *p < 0.05.
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Pathological examination of the resected fragments confirmed the pleomorphic nature of the majority of the tumor cells; only scattered cells were immunopositive for GH antibody (<1%) ( Figure 2A ); CAM5.2 was almost negative, and Ki-67 LI was further increased up to 22%. Although SSTR5 was previously 3+, it was almost negative this time, while SSTR2 remained positive (3+) ( Figure 2A ). The results showed that TMZ in combination with 5-FU reduced cell viability by 50% compared to vehicle treatment (p<0.05), while no reduction was seen with TMZ alone, indicating that CAPTEM treatment would be more effective than TMZ monotherapy for the present case ( Figure 2B ).
Temozolomide and capecitabine (CAPTEM) had a significant effect on reduction of the tumor volume and serum levels of growth hormone (GH) and insulin-like growth factor (IGF-1). Thin-slices of plain T2 images were used to show the dramatic changes of the tumor volume by CAPTEM treatment (A). The upper row shows coronal images and the lower row shows axial images (A). Two orthogonal diameters of the tumor were measured in the coronal and axial T2-weighted images. The average of the 4 diameters was assumed as the diameter of an approximated sphere. Then, the formula of a sphere volume; 4/3pir3 was used to calculate the approximate tumor volume (A). MRI just before TMZ administration did not show the volume reduction (dotted lines) but MRI just after TMZ showed considerable shrinkage (solid lines) (A). CAPTEM had a significant effect on reduction of morning serum GH (B) and IGF-1 (C) levels. IGF-1 normal range for the patient's age and sex is 78-213 ng/ml.
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MR T2 images obtained after capecitabine administration (prior to TMZ administration) (day 10) showed no tumor shrinkage, but remarkable reduction of the tumor volume was visible on MRI obtained just after TMZ administration (day 15) ( Figure 3A ), suggesting that the tumor shrinkage was not caused by capecitabine itself, but by the use of TMZ after capecitabine. CAPTEM treatment ( Figures 3B, C ). CAPTEM was highly tolerable for the patient with no noteworthy side effects.