Expression of B7-H3 and B7-H4 in Gastric Gastrointestinal Stromal Tumors.

Gastric gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first-line treatment for metastatic GIST. However, despite a clinical benefit rate of 80%, the majority of patients with GIST experience disease progression after 2 to 3 years of imatinib therapy. This shows the need for novel treatment approaches for imatinib refractory GISTs. The checkpoint proteins B7-H3 and B7-H4 inhibit the activation and function of T cells by potently suppressing the proliferation, cytokine production, and cytotoxicity of activated T cells, which is a mechanism for immune escape. This study aims to clarify B7-H3 and B7-H4 expression in gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). We confirmed B7-H3 expression (H-score ≥50 points) in 92% and B7-H4 expression in 0% of GIST samples. We examined B7-H3 mRNA expression in 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. B7-H3 is expressed at a particularly high rate in GISTs. This suggests that B7-H3 might operate as part of an immune checkpoint in GISTs.

Virtual multi-staining in a single-section view for renal pathology using generative adversarial networks.

Sections stained in periodic acid-Schiff (PAS), periodic acid-methenamine silver (PAM), hematoxylin and eosin (H&E), and Masson's trichrome (MT) stain with minimal morphological discordance are helpful for pathological diagnosis in renal biopsy. Here, we propose an artificial intelligence-based re-stainer called PPHM-GAN (PAS, PAM, H&E, and MT-generative adversarial networks) with multi-stain to multi-stain transformation capability. We trained three GAN models on 512 × 512-pixel patches from 26 training cases. The model with the best transformation quality was selected for each pair of stain transformations by human evaluation. Frechet inception distances, peak signal-to-noise ratio, structural similarity index measure, contrast structural similarity, and newly introduced domain shift inception score were calculated as auxiliary quality metrics. We validated the diagnostic utility using 5120 × 5120 patches of ten validation cases for major glomerular and interstitial abnormalities. Transformed stains were sometimes superior to original stains for the recognition of crescent formation, mesangial hypercellularity, glomerular sclerosis, interstitial lesions, or arteriosclerosis. 23 of 24 glomeruli (95.83 %) from 9 additional validation cases transformed to PAM, PAS, or MT facilitated recognition of crescent formation. Stain transformations to PAM (p = 4.0E-11) and transformations from H&E (p = 4.8E-9) most improved crescent formation recognition. PPHM-GAN maximizes information from a given section by providing several stains in a virtual single-section view, and may change the staining and diagnostic strategy.

Epstein-Barr virus-positive plasmacytoma in an immunocompetent female: A case report.

Plasmacytoma is defined as a plasma cell neoplasm forming a solitary osseous or extramedullary tumor without evidence of myeloma or organ damage related to a plasma cell neoplasm. Epstein-Barr virus (EBV) is associated with various B-cell neoplasms, particularly in patients with immune dysregulation; however, plasmacytoma is typically negative for EBV. Here, a case of EBV-positive sternal plasmacytoma in an immunocompetent female is presented. A 76-year-old female with no immunodeficiency presented with a tumor on the anterior thoracic wall. Imaging analysis revealed a 6.3 cm-sized tumor at the manubrium, and a needle biopsy was performed. The tumor in the bone was composed of a diffuse proliferation of plasmacytes with eccentric nuclei and a perinuclear halo. By immunohistochemistry and in situ hybridization, tumor cells were CD20-, CD3-, CD138+, κ+, λ-, EBER+, and the Ki67-labeling index was approximately 20%. Subsequent studies identified IgG κ monoclonal protein in serum but no evidence of plasma cell neoplasm-related organ damage, such as hypercalcemia, anemia, or renal dysfunction. No plasma cell neoplasm was detected in the bone marrow in the morphological and flowcytometric studies. Accordingly, the diagnosis was EBV-positive plasmacytoma. The patient was treated with local radiation therapy and achieved complete remission. EBV-positive plasmacytoma is rare in immunocompetent patients and should be carefully distinguished from plasmablastic lymphoma, another EBV-positive neoplasm with a plasma cell phenotype and an aggressive clinical course. This case also raises an important question: "when to perform EBER in situ hybridization in diagnosing plasma cell neoplasm?", which prompts further large case-series studies.

Detailed characterization of auditory neuropathy in Perrault syndrome with TWNK variants.

Perrault syndrome is an autosomal recessive condition characterized by hearing loss and ovarian failure. Hearing loss in Perrault syndrome has been reported as sensorineural; however, only two cases in a single report have comprehensively investigated hearing in Perrault syndrome with TWNK variant, and the association between this variant and auditory neuropathy has not been established. The proband presented with hearing difficulties and primary amenorrhea. Hearing tests revealed mild hearing loss. Maximum speech intelligibility score was 95 % with normal otoacoustic emission. However, no auditory brainstem responses were observed, leading to the diagnosis of auditory neuropathy. Genetic tests identified compound heterozygous variants of TWNK (p.Ile253Met and p.Arg391His), which lead to the genetic diagnosis of Perrault syndrome. Electrocochleography suggests a decreased cochlear nerve function. The patient's sister was also subsequently genetically diagnosed with Perrault syndrome upon identification of the same TWNK variant and had auditory neuropathy with low-tone hearing loss on pure-tone audiometry. These cases highlight the importance of detailed hearing tests, including auditory brainstem response and genetic tests in patients with Perrault syndrome, even in cases of mild hearing loss, for accurate diagnosis and appropriate management.

Long-term hearing prognosis after vestibular schwannoma surgery with retrolabyrinthine approach.

PURPOSE: The retrolabyrinthine approach is a surgical method designed to preserve hearing after surgery. When paired with intraoperative monitoring and an endoscope, this approach has demonstrated high rates of postoperative hearing preservation. However, the long-term prognosis of hearing preservation after utilizing this approach for vestibular schwannomas remains unexplored. This study aimed to examine the long-term outcomes of preserved hearing, providing insights into the suitability of the retrolabyrinthine approach for hearing preservation surgery. METHODS: This study included 34 patients with preserved hearing after vestibular schwannoma surgery using the retrolabyrinthine approach at a single center. Long-term hearing prognosis and requirement for additional interventions were retrospectively examined. RESULTS: Immediate after post-operative hearing preservation rate was 71.7%. Among the 34 patients with preserved hearing post-vestibular schwannoma surgery, four (11.8%) required additional interventions. Other patients experienced a gradual deterioration in their hearing status, with an approximate 10 dB decline during the 5-year follow-up; however, a serviceable hearing level persisted long after the surgery in these individuals. CONCLUSIONS: This study indicated the rationale for the retrolabyrinthine approach as a hearing preservation surgery for vestibular schwannomas, emphasizing its long-term hearing prognosis.

Binaural hearing aid intervention for a patient with nonserviceable hearing loss after surgery for vestibular schwannoma: A case report.

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner-Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable.

Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.

PURPOSE: The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). MATERIALS AND METHODS: VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. RESULTS: Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. CONCLUSION: This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.

Expression of TGF-ß1 in Gastrointestinal Stromal Tumor (GIST) and the Occurrence of Frequent Desmoplasia.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. Frequently, GISTs have fibrous stroma within tumor cell proliferation areas, which is unlike other types of malignant tumors. If this desmoplasia is active, there is a possibility that some sort of transmitter exists between GIST cells and cells related to fibrosis in the tumor cell proliferation areas. Transforming growth factor (TGF)-ß isoforms, particularly TGF-ß1, are critical for fibrosis pathogenesis. TGF-ß1 regulation of myofibroblasts and fibroblasts during fibrosis is well described. The induced fibroblast activation resulting in myofibroblast differentiation has been reported as an important source of collagen, glycoproteins, proteoglycans, and matrix metallopeptidases in wound healing and fibrosis. However, there are a few reports on the relationship between TGF-ß1 and GISTs. This study aims to clarify TGF-ß1 expression in 30 gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we also enrolled 30 samples of gastric tubular adenocarcinoma (GTAC). We confirmed TGF-ß1 expression (H-score ≥50 points) in 57% of GIST and 13% of GTAC samples, a significant difference between the 2 tumor types ( P =0.001). We examined the TGF-ß1 mRNA expression of 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. Finding TGF-ß1 expression may indicate that this cytokine plays a part in the formation of desmoplasia within GIST cell proliferative areas.

Natural history of hearing and tumor growth in vestibular schwannoma in neurofibromatosis type 2-related schwannomatosis.

OBJECTIVES: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. METHODS: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. RESULTS: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). CONCLUSIONS: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014).