University of Yamanashi Hospital

Tissue clearing has been widely used for fluorescence imaging of fixed tissues, but its application to live tissues has been limited by toxicity. Here we develop minimally invasive optical clearing media for fluorescence imaging of live mammalian tissues. Light scattering is minimized by adding spherical polymers with low osmolarity to the extracellular medium. A clearing medium containing bovine serum albumin (SeeDB-Live) is compatible with live cells, enabling structural and functional imaging of live tissues, such as spheroids, organoids, acute brain slices and the mouse brains in vivo. SeeDB-Live minimally affects neuronal electrophysiological properties and sensory responses in vivo, and facilitates fluorescence imaging of deep cortical layers in live animals without detectable toxicity to neurons or behavior. We further demonstrate its utility to epifluorescence voltage imaging in acute brain slices and in vivo preparations. Thus, SeeDB-Live expands both the depth and modality range of fluorescence imaging in live mammalian tissues.

Glucocorticoids (GC) comprise a cornerstone in the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV); however, prolonged GC exposure leads to substantial toxicity and immune system-related complications. Hence, identifying treatment strategies that enable early GC withdrawal while maintaining disease control is of clinical importance. To investigate the proportion and characteristics of patients achieving GC-free clinical remission (GFCR) 48 weeks after treatment initiation in patients with newly diagnosed microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) and examine their long-term clinical outcomes (up to week 96). We conducted a retrospective cohort study using clinical data from a multicenter, nationwide registry in Japan comprising patients with newly diagnosed MPA or GPA and at least 48 weeks of follow-up. GFCR was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 with complete GC withdrawal. Univariable and multivariable logistic regression analyses were used to identify independent predictors of GFCR at week 48, and a sensitivity analysis using a matched cohort was performed to validate robustness. A total of 728 patients were enrolled in the registry, of whom 544 were followed for ≥ 48 weeks; among them, 29 (5.3%) achieved GFCR at week 48. Use of rituximab (RTX) for induction therapy and avacopan within 48 weeks were independently associated with achieving GFCR (multivariable analysis, model 1: RTX: odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.5–10.0; avacopan: OR: 24.3, 95% CI: 5.8–101.9; both p < 0.01). Conversely, methylprednisolone pulse therapy was associated with a lower likelihood of achieving GFCR (multivariable analysis, model 1: OR: 0.08, 95% CI: 0.02–0.44; p < 0.01). Patient’s demographic and baseline disease characteristics were not predictive of GFCR. In the long-term (weeks 48 through 96), the rates of death, relapse, and serious infection were similar regardless of GFCR status at week 48. The use of RTX for induction therapy and avacopan within 48 weeks is independently associated with achieving GFCR at week 48 in patients with MPA and GPA, supporting their potential as key components of GC-sparing strategies in AAV. Prospective studies are needed to confirm these results and optimize treatment algorithms to ensure disease control and minimize GC-related toxicity.

The combination of bleomycin, etoposide, and cisplatin is the standard regimen for good-risk metastatic nonseminomatous germ cell tumors, with etoposide and cisplatin used when pulmonary risk is present. Etoposide and cisplatin therapy is generally well tolerated, and severe toxicities are particularly rare after the first standard-dose cycle. We report a case of early-onset, simultaneous multiorgan failure after a single cycle of etoposide and cisplatin therapy, successfully managed with etoposide-carboplatin. A 54-year-old Japanese man with stage IIa nonseminomatous germ cell tumor received a standard-dose first cycle of etoposide and cisplatin therapy (etoposide 100 mg/m2, cisplatin 20 mg/m2, days 1-5). Despite appropriate hydration, he developed hepatic dysfunction, severe diarrhea, ototoxicity, acute kidney injury requiring hemodialysis, pancytopenia, and visual impairment. Supportive therapy, including dialysis, corticosteroids, broad-spectrum antibiotics, and granulocyte colony-stimulating factor, was provided. Although renal function partially improved, the patient had persistent severe renal dysfunction consistent with Kidney Disease: Improving Global Outcomes stage 3 acute kidney injury, rendering further cisplatin therapy unsafe. He subsequently received three cycles of etoposide-carboplatin (etoposide 100 mg/m2, days 1-5; carboplatin area under the curve 5), which were well tolerated. Tumor markers normalized, and imaging confirmed complete remission. At 12-month follow-up, he remained disease-free with stable renal function and improved general condition. This case demonstrates that even a standard-dose, first-cycle etoposide and cisplatin regimen can trigger abrupt, life-threatening multiorgan toxicities affecting renal, hepatic, auditory, hematologic, and visual systems. Such early, simultaneous onset has rarely been described in scientific literature. When cisplatin continuation is unsafe, etoposide-carboplatin may serve as a feasible alternative to achieve remission while minimizing systemic toxicity. Careful evaluation of patient-specific risk factors, including hypertension, renal reserve, and renin-angiotensin system inhibitor use, is essential before initiating cisplatin-based therapy. This case highlights the importance of individualized treatment planning and prompt recognition of severe chemotherapy-induced toxicities.

In proton beam therapy (PBT), the analytical pencil beam (PB) algorithm involves dose uncertainties in inhomogeneous regions, making accurate Monte Carlo (MC) dose calculation desirable but time-consuming. Deep learning, converting the dose calculated by the PB algorithm into an MC-equivalent dose distribution, can resolve the trade-off between calculation accuracy and speed. Training a DL-based dose conversion model that can be applied to any tumor site would be ideal; however, the appropriate training regions and its generalizability remain unclear. We developed a DL-based dose conversion model trained on four representative tumor sites (i.e., head and neck, lung, liver, and prostate), and evaluated its generalizability. Data from 339 patients (a total of 1147 beams) were used. PB doses were obtained from the treatment planning system, and MC doses were calculated using an in-house MC platform. Our developed DL-based dose conversion model was designed to input a treatment planning computed tomography image and PB dose in a single field and output an MC-equivalent dose. The model's generalizability was evaluated on untrained tumor sites, including the esophagus, pancreas, colorectum, brain, breast, cervix, and limb bone and soft tissue. The conversion performance was assessed using 3D γ-analysis and the Dice similarity coefficient (DSC) for isodose volumes. For most untrained tumor sites, the model achieved average γ-passing rates of ≥90% with a criterion of 3%/2mm. The esophagus, breast, which are close to the lung, and limb bone and soft tissue showed slightly lower passing rates of 91.3%, 85.9%, and 89.1%, respectively. The average DSC values exceeded 0.8 for most untrained tumor sites. The proposed DL-based dose conversion model demonstrated high accuracy and generalizability, even for untrained tumor sites. These findings suggest that the model can be adapted to biases in collecting disease data at each PBT center and for rare diseases.

Chemotherapy-induced nausea and vomiting (CINV) remain major challenges during concurrent chemoradiotherapy (CCRT) for cervical cancer. Mannitol and furosemide are agents widely used to prevent cisplatin-induced nephrotoxicity; however, the differences in their effect on CINV have not been characterized. This study aimed to evaluate the impact of concomitant diuretic administration (mannitol versus furosemide) on the incidence and timing of vomiting in patients with cervical cancer undergoing CCRT. This multicenter, retrospective study evaluated the impact of concomitant diuretic administration on CINV in 485 patients receiving weekly, cisplatin-based CCRT between 2016 and 2024, including 206 who received mannitol and 279 who received furosemide. Vomiting occurred more frequently in the mannitol group than in the furosemide group (18.4% vs. 10.4%). Time-to-event analysis found that vomiting occurred earlier with mannitol during the entire CCRT course. These findings may reflect mannitol's osmotic properties and the increased, intestinal permeability associated with CCRT-related mucosal injury. To the best of our knowledge, this study is the largest investigation to date comparing diuretic agents in this setting. The results suggested that furosemide may be a more appropriate option for patients with a high risk of CINV.

Endophthalmitis continues to represent a vision-threatening complication of intravitreal injection. Herein, we present a rare case of endophthalmitis caused by α-streptococcal following intravitreal ranibizumab biosimilar administration using a prefilled syringe. A 72-year-old woman was referred to our clinic and diagnosed with acute endophthalmitis in the left eye, following intravitreal administration of a ranibizumab biosimilar delivered via a prefilled syringe. A hypopyon was noted at a height of 3 mm, and the fundus examination of the left eye was obscured by corneal edema. The best-corrected visual acuity (BCVA) in the left eye was limited to hand motion. Urgent vitrectomy was performed with intraoperative irrigation using ceftazidime sodium (20 mg/500 mL) and vancomycin (10 mg) in the left eye. α-Streptococcal was isolated from both the aqueous humor and vitreous culture specimens. At 19 days postoperatively, the fundus was clearly visible, and the BCVA had recovered to 0.4 in the left eye, which corresponded to the pretreatment level. Urgent vitrectomy with irrigation using ceftazidime sodium and vancomycin may facilitate visual recovery in the affected eye.

The clinical significance of serum lysozyme in sarcoidosis remains unclear. This study aimed to evaluate the clinical characteristics and kidney function of sarcoidosis patients with elevated serum lysozyme. We retrospectively analyzed 28 patients with sarcoidosis and measured levels of serum lysozyme. Clinical characteristics, laboratory data, and estimated glomerular filtration rate (eGFR) were evaluated. Median age was 57 years (interquartile range, 43–70 years), and 21% were men. High serum lysozyme levels were associated with a greater number of organ involvements (median 4 vs. 2, p = 0.022) and more frequent renal involvement (50 vs. 7%, p = 0.033). Serum lysozyme levels correlated inversely with eGFR (r = −0.814). Median serum lysozyme level was significantly higher in patients with renal sarcoidosis (RS) (30.2 μg/mL) than in non-RS patients (9.5 μg/mL, p = 0.003). Prominent intracytoplasmic lysozyme staining in proximal tubular epithelial cells was observed in the kidney of RS patients. Multiple regression analysis identified serum lysozyme as an independent risk factor for eGFR decline. Elevated serum lysozyme in sarcoidosis was associated with multiorgan involvements and renal impairment. Lysozyme may contribute to tubulointerstitial injury in RS, potentially through tubular reabsorption and cytotoxic effects. Further studies are warranted to clarify the role of lysozyme in the pathogenesis of RS.

Haematological manifestations of immunoglobulin (Ig)G4-related disease (IgG4-RD) are atypical, and few studies have addressed cytopenia in this condition. We present here a case of IgG4-RD with marked pancytopenia and splenomegaly in the absence of bone marrow abnormalities. A 67-year-old woman developed diplopia, dyspnoea, pancytopenia, and hypocomplementemia. Contrast-enhanced computed tomography showed bilateral lacrimal and submandibular gland swelling, enlargement of the cervical, mediastinal, inguinal, and para-aortic lymph nodes, splenomegaly, and granular shadows in both lungs. She had been referred to our hospital on suspicion of malignant lymphoma, but a lymph node biopsy indicated the possibility of IgG4-RD. A lacrimal gland biopsy showed infiltration of numerous lymphocytes and IgG4-positive plasma cells along with mild fibrosis. A bone marrow biopsy showed normocellular marrow with no increase in plasma cells. The IgG4-positive plasma cell count was 4 per high-power field, with an IgG4/IgG ratio of 10%. After excluding potential mimics, the diagnosis was IgG4-RD presenting with pancytopenia and splenomegaly. Prednisolone was initiated at 40mg/day, leading to the rapid normalisation of pancytopenia, recovery of complement levels, and resolution of other organ involvement such as splenomegaly. Physicians should keep in mind that IgG4-RD can present with pancytopenia and splenomegaly.

The authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

The circular stapling technique (CST) is reported to be a simple and time-efficient method; however, it is associated with a high incidence of anastomotic stenosis for McKeown esophagectomy. Meanwhile, the impact of circular stapler size remains controversial. We aimed to investigate the impact of circular stapler size on both short-term outcomes and long-term quality of life (QOL) after McKeown esophagectomy. In total, 63 consecutive patients who underwent McKeown esophagectomy for esophageal cancer between 2019 and 2022 were eligible. We examined the association between circular stapler size and short-term outcomes and long-term QOL using the PGSAS-37. 35 (55.6%) patients underwent anastomosis with a 21 mm stapler, whereas 28 (44.4%) patients used a 23 mm stapler. No significant differences were observed between the groups. The incidence of anastomotic leakage did not differ significantly between the groups (5.7% vs. 7.1%, p = 1.00) Also, the incidence of anastomotic stenosis did not differ between the groups (25.7% vs. 21.4%, p = 0.77). However, in QOL assessment, the meal-related subscale (SS) score in the 21 mm group was significantly worse than in the 23 mm group (p = 0.02). Regarding the details the meal-related SS score, the feeling of dysphagia was significantly worse in the 21 mm group (p < 0.01). Short-term outcomes did not differ between patients who underwent anastomosis with a 21 mm stapler and those with a 23 mm stapler, however QOL, particularly the feeling of dysphagia, was worse in patients who used a 21 mm stapler compared to those who used a 23 mm stapler.