<div>Abstract<p>Isocitrate dehydrogenase-mutant low-grade gliomas (IDHmut-LGG) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDH<sup>mut</sup>/1p19q<sup>codel</sup> and IDH<sup>mut</sup>/1p19q<sup>noncodel</sup>) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole-exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8 to 2.8 times compared with before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs (≤ 50 cm<sup>3</sup>). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm<sup>3</sup>); adjuvant therapies delayed malignant transformation in IDH<sup>mut</sup>/1p19q<sup>noncodel</sup> but often accelerated it in IDH<sup>mut</sup>/1p19q<sup>codel</sup>. Notably, PI3K mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDH<sup>mut</sup>/1p19q<sup>codel</sup>. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.</p>Significance:<p>A mathematical model successfully estimates malignant transformation-free survival and reveals a link between genetic alterations and progression, identifying precision medicine approaches for optimal treatment of IDH-mutant low-grade gliomas.</p></div>
Extracellular vesicles (EVs) contain a subset of proteins, lipids, and nucleic acids that maintain the characteristics of the parent cell. Immunotherapy using EVs has become a focus of research due to their unique features and bioinspired applications in cancer treatment. Unlike conventional immunotherapy using tumor fragments, EVs can be easily obtained from bodily fluids without invasive actions. We previously fabricated nanowire devices that were specialized for EV collection, but they were not suitable for cell culturing. In this study, we fabricated a ZnO/Al2O3 core–shell nanowire platform that could collect more than 60% of the EVs from the cell supernatant. Additionally, we could continue to culture dendritic cells (DCs) on the platform as an artificial lymph node to investigate cell maturation into antigen-presenting cells. Finally, using this platform, we reproduced a series of on-site immune processes that are among the pivotal immune functions of DCs and include such processes as antigen uptake, antigen presentation, and endocytosis of cancer-derived EVs. This platform provides a new ex vivo tool for EV-DC-mediated immunotherapies.
Abstract Recent clinical studies improved prognosis of primary central nervous system lymphoma (PCNSL) using multiple treatment reagents combined with radiation therapy. However, for recurrent and refractory cases after treatment with regimen consisting of multiple reagents, potent effective treatment has not been established yet. Tirabrutinib, Bruton's tyrosine kinase inhibitor was introduced for treatment of recurrent and refractory PCNSL in Japan. However, case series study investigating the clinical outcome of PCNSL cases treated with tirabrutinib have not been reported yet excepting for phase I/II study of tirabrutinib. We treated nine recurrent and two refractory cases. In all of these cases, except for one case exhibiting severe skin rash in spite of cessation of administration of tirabrutinib, we obtained favorable overall response rate (CR or Cru=5 and PR=5) together with favorable progression free survival (median; 339 days). Five cases exhibited skin rash (CTCAE grade 3; n=2 and grade 2; n=3). Grade 3 or 2 skin rash were found on day 9 or 75 of tirabrutinib treatment, respectively. In one case, MYD88 mutations in ctDNA derived from blood plasma were turned to be negative after one week administration of tirabrutinib. Although adverse effects such as skin rash was frequently found, tirabrutinib is effective for recurrent or refractory PCNSL cases. Our data suggested that treatment response of tirabrutinib could be evaluated via evaluation of copy number analysis of MYD88 mutations in ctDNA of blood plasma.
Abstract Pituitary neuroendocrine tumors (PitNETs) are tumors that originate from the anterior pituitary gland. While they are mostly benign, they can cause various clinical symptoms due to hormonal secretion abnormalities. PitNET can be broadly categorized into three lineages, each of which has its differentiation controlled by specific transcription factors. Treatment options for PitNET include surgical resection and pharmacotherapy, but available drugs are limited, and their efficacy markers remain unclear. To develop novel drugs for PitNET and identify their efficacy markers, it is necessary to develop new research models. In recent years, organoid models have garnered attention as novel research models for various cancer types. In this study, we established novel organoid models derived from PitNET patients and analyzed their histological and endocrinological characteristics. Surgical specimens from 4 cases of somatotroph adenoma, 1 case of double adenoma, 1 case of gonadotroph adenoma, and 1 case of corticotroph adenoma were minced in dissection medium and embedded in Matrigel basement membrane matrix respectively. The organoids were cultured under 5% CO2 at 37°C using media supplemented with various growth factors. After 28 days of culture, formalin-fixed paraffin-embedded sections were prepared to examine histological homology with patient tumors. Hematoxylin and eosin staining results showed that all organoids maintained cell morphology and tissue structure similar to the original tumors. Immunohistochemical staining for markers specific to each PitNET revealed similar staining patterns between the organoids and the original tumors. Furthermore, analysis of hormone levels in the culture medium showed that hormone production capabilities, such as growth hormone and follicle stimulating hormone, were maintained even after long-term culture. In this study, we successfully established PitNET organoid models that retain histological and endocrinological characteristics. These models are expected to serve as useful research tools for elucidating the molecular mechanisms of PitNET and developing novel therapies targeting critical molecular abnormalities.
Abstract Background Eccrine spiradenocarcinoma (SC), also known as malignant eccrine spiradenoma, is a rare malignant cutaneous adnexal neoplasm arising from long-standing benign eccrine spiradenoma. Malignant skin tumors rarely show direct intracranial invasion. However, once the intracranial structure is infiltrated, curative excision with sufficient margins can become extremely difficult, particularly when the venous sinuses are involved. No effective adjuvant therapies have yet been established. Here, we report an extremely rare case of scalp eccrine SC with direct intracranial invasion, which does not appear to have been reported previously. Case presentation An 81-year-old woman presented with a large swelling on the parietal scalp 12 years after resection of spiradenoma from the same site. The tumor showed intracranial invasion with involvement of the superior sagittal sinus and repeated recurrences after four surgeries with preservation of the sinus. The histopathological diagnosis was eccrine SC. Adjuvant high-precision external beam radiotherapy (EBRT) proved effective after the third surgery, achieving remission of the residual tumor. The patient died 7 years after the first surgery for SC. Conclusions Scalp SC with direct intracranial invasion is extremely rare. Radical resection with tumor-free margins is the mainstay of treatment, but the involvement of venous sinuses makes this unfeasible. High-precision EBRT in combination with maximal resection preserving the venous sinuses could be a treatment option for local tumor control.
Abstract In recent years, R-MPV therapy has been widely used for treatment of primary central nervous system lymphoma (PCNSL). Although a high response rate and favorable prognosis have been reported with R-MPV therapy using multiple drugs, the treatment strategy for cases refractory to induction therapy has not been established. High-dose radiotherapy is currently recommended for refractory cases, however, the efficacy and frequency of adverse events such as leukoencephalopathy are not yet clear. Tirabrutinib has been available for recurrent or refractory PCNSL cases since 2020. However, there have been few reports on the results of tilabrutinib in these refractory cases. We have been using tirabrutinib for these refractory cases since its introduction. Here, we compared the results of tirabrutinib with those before the introduction of tirabrutinib. We investigated 30 cases with PCNSL treated with R-MPV at our hospital since 2013. 5 (16.7%) of the 30 cases revealed refractory to R-MPV. Two cases were promptly treated with irradiation (total 40-45 Gy) and both remitted, but one (a 70's male) had extensive white matter changes. One case (40's female) also had white matter changes but maintained CR for 4 years and 8 months. All three patients treated with tirabrutinib achieved CR or PR immediately, and two patients (a 60's woman and a 70's man) received whole brain irradiation of 23.4 Gy at 26 and 28 days after tirabrutinib introduction and remained in remission for 2 years 3 months and 2 years 4 months respectively with no significant white matter changes. The results suggest that tirabrutinib may be useful for cases refractory to R-MPV therapy. Because the long-term results of tirabrutinib are not yet clear, careful consideration should be given to the necessity of radiotherapy for cases who have achieved remission with tirabrutinib.
