Hiroshima Prefectural Hospital

Abstract Background: Tumor-infiltrating lymphocytes (TILs) reflect host immune response and are associated with prognosis and treatment response in HER2-positive and triple-negative breast cancer (TNBC). While the International Immuno-Oncology Biomarker Working Group recommends evaluating stromal TILs in tumor areas, intratumoral heterogeneity and small sample size in core needle biopsy (CNB) specimens limit consistent assessment. It remains unclear whether central tumor (CT) or invasive margin (IM) regions should be prioritized and what cut-off values are clinically relevant. Ultrasonographic (US) features may also reflect the immune microenvironment. We previously proposed a TILs-US score based on three US features that predicts lymphocyte-predominant breast cancer (LPBC). This study evaluated the clinical utility of TILs assessment from CT and IM regions, appropriate cut-off values for predicting response in HER2-positive and TNBC using CNB, and explored optimal biopsy targeting through pathologic and US comparisons. Methods: In this multicenter retrospective study, we analyzed 239 patients (124 HER2-positive, 115 TNBC) with cT1-3/cN0-2 breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). TILs were evaluated using CNB specimens obtained before NAC and assessed separately in the central tumor (CT) and invasive margin (IM) regions. The IM was defined as a 1-mm-wide area centered on the interface between the tumor and surrounding stroma, while the CT was defined as the remaining intratumoral area within the IM boundary. TILs were analyzed using binary cut-offs of 30% and 50%, as well as a three-tier classification: low (0-10%), intermediate (11-49%), and high (≥50%). Pre-treatment ultrasound (US) findings included tumor shape (scored 0-2), internal echo (0-2), and posterior echo (0-3), which were used to calculate a composite TILs-US score ranging from 0 to 7. Associations between TIL levels, US features, and pathological complete response (pCR) were analyzed. Results: Overall, 104 patients achieved pCR (HER2-positive: 39; TNBC: 65). Using a 30% cut-off, TILs were evenly distributed both CT and IM, while ≥50% cases were relatively rare especially CT (CT: 10%; IM: 20%). CT TILs ≥30% was significantly associated with pCR (p=0.001), whereas the ≥50% cut-off was not (p=0.128). In contrast, both 30% and 50% cut-offs in the IM region were predictive of pCR (p<0.001 and p=0.009, respectively). Subtype analysis revealed that in TNBC, TILs ≥30% in both CT and IM regions were significantly correlated with pCR. In HER2-positive cases, however, only IM TILs ≥30% was predictive of pCR. Similar trends were observed with the three-tier classification. Among US features, a small lobulated shape was associated with high TILs levels in both CT and IM regions, while an enhanced posterior echo was correlated with high TILs in the IM region. Conclusion: Our findings suggest that TILs assessment should include the IM in addition to the CT, especially in CNB specimens as provide valuable information. Given the limited tissue area available in CNB specimen, using a 30% cut-off for TILs may offer a clinically meaningful threshold to predict treatment response. In cases where US findings suggest central fibrosis, targeting only the tumor center may result in sampling fibrotic areas with sparse immune and tumor cells, potentially hindering proper evaluation. Therefore, selecting the biopsy target based on US imaging is essential. Especially in HER2-positive breast cancer, as well as TNBC, it is important for operators to consider the optimal needle insertion angle and sampling site to ensure appropriate sampling of viable tumor tissue and immune microenvironment for accurate pathological and immunological evaluation. Citation Format: Y. Kimura, R. Yamaguchi, K. Fukui, A. Kanou, M. Noma, S. Akashi-Tanaka, K. Arihiro, N. Iwamoto, Y. Ohta, T. Okuno, S. Kashiwagi, Y. Kamei, Y. Tanada, S. Nakano, A. Nagata, A. Murakami, Y. Mochitomi, A. Yamakawa, M. Yamaguchi, H. Shima, A. Emi. Ultrasound-guided biopsy-based tils assessment at tumor margins as a predictive biomarker of neoadjuvant treatment response in early her2-positive and triple-negative breast cancer: a multicenter study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-18.

Recent studies have demonstrated that breast pathological complete response (pCR) can be accurately diagnosed preoperatively using image-guided needle biopsy after neoadjuvant chemotherapy (NAC), underscoring the value of incorporating ypT stage into prediction models for axillary response (ypN0). Based on this evidence, we developed and externally validated a nomogram to predict ypN0 in patients with clinically node-positive (cN+) breast cancer treated with NAC. This retrospective, multicenter study included 609 patients with cN + breast cancer who underwent NAC followed by surgery. A nomogram was developed using a training cohort (n = 330) and validated in an independent cohort (n = 279). Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, decision curve analysis (DCA), and positive predictive value (PPV). The nomogram incorporated five predictors: ypT stage, cN stage, hormone receptor status, HER2 status, and post-NAC cN stage. It showed strong discriminative ability, with bias-corrected AUCs of 0.858 in the training cohort and 0.855 in the validation cohort. Calibration and DCA confirmed good model performance. PPV exceeded 0.90 when the nomogram-predicted probability was ≥ 0.7 in both cohorts. This nomogram demonstrated high diagnostic accuracy for predicting ypN0 and may support the selection of candidates for axillary surgery de-escalation based on post-NAC biopsy findings. Prospective validation using biopsy-confirmed pCR is warranted.

Medication-related osteonecrosis of the jaw is currently classified only by clinical staging, with no imaging-based qualitative classification available. To establish foundational data for a new classification method that could help guide treatment decisions and predict prognosis, this study investigated the computed tomography findings commonly observed in patients with medication-related osteonecrosis of the jaw and their frequencies. Computed tomography scans from 784 patients across 19 medical institutions were analyzed for the presence of osteolysis, sequestrum separation, periosteal reactions, mixed-type osteosclerosis, and the bone-within-bone appearance. Clinical factors associated with each finding were also examined. Osteolysis appeared as localized in 55.1% of cases, extended in 27.7%, and advanced in 13.8%. In contrast, 3.4% of patients showed no osteolysis. This non-osteolytic pattern was more common among patients treated with denosumab. Sequestrum separation was seen in 34.7% of patients, most frequently among those with osteoporosis. Periosteal reactions were observed in 5.9% of cases as the attached type, 12.4% as the gap type, and 5.6% as the irregular type. Mixed-type osteosclerosis occurred in 31.9% of cases, most often in the mandibles of patients with malignant tumors. The bone-within-bone appearance was observed in 3.1% of cases. Patients with sequestrum separation had more favorable treatment outcomes. In contrast, those without osteolysis and those with periosteal reactions, mixed-type osteosclerosis, or bone-in-bone appearance were more likely to have poorer outcomes. This multicenter study clarified the prevalence of several key computed tomography features in medication-related osteonecrosis of the jaw, highlighting their potential relevance to clinical outcomes. These findings lay the groundwork for future research into their prognostic and therapeutic implications to support the development of a new imaging-based classification system.

To summarize descriptively health-related quality of life (HRQOL) and physical activity (PA) evaluated with a mobile application and wearable device among patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer (ABC) treated with first- or second-line palbociclib plus endocrine therapy (ET) or ET alone. HRQOL was assessed with the EORTC QLQ-C30 at baseline and Day 15 of 6 treatment cycles (~ 24weeks). PA metrics were averaged on a weekly basis for 24weeks. Co-primary endpoints were mean change from baseline in Global Health Status (GHS) and sedentary time. Ninety-nine patients were enrolled; 78 received palbociclib plus ET (mean age: 57.2years; 75.6% initiated first-line treatment) and 21 received ET alone (mean age: 56.3years; 90.5% initiated first-line treatment). Baseline mean GHS score was 60.9 in the palbociclib plus ET group and 64.3 in the ET alone group; mean changes from baseline to Day 15 of Cycle 6 were +4.8 and +2.9, respectively, and not deteriorated beyond the 10-point clinically significant threshold in either treatment group. Baseline mean sedentary time was 581min/day in the palbociclib plus ET group and 513min/day in the ET alone group; mean changes from baseline to Week 24 were -22 and -102min/day, respectively. In this real-world study of women with HR+/HER2- ABC in Japan, neither palbociclib plus ET nor ET alone had any substantial detrimental impacts on HRQOL, according to patients' assessments recorded in a smartphone-based mobile application, and PA, as measured by a wearable device. ClinicalTrials.gov NCT04736576; registered, February 3, 2021.

Elevated serum IgG4 is a key diagnostic marker for type 1 autoimmune pancreatitis (AIP), but some patients lack IgG4 elevation, complicating diagnosis. This study investigated the clinicopathological features of AIP without elevated serum IgG4 levels. A total of 323 patients diagnosed with AIP at Hiroshima University Hospital and affiliated institutions were analyzed. Patients were categorized into IgG4-positive (≥ 135 mg/dL), IgG4-negative (< 135 mg/dL with “definite” or “probable” diagnosis), and possible (with “possible” diagnosis) groups. Comparative analysis was performed between the IgG4-positive (n = 281) and IgG4-negative (n = 20) groups. Segmental or focal narrowing of the main pancreatic duct (MPD) and retroperitoneal fibrosis were significantly more common in the IgG4-negative group (90.0% vs. 58.7%, P = 0.011; and 35.0% vs. 12.5%, P = 0.012, respectively). Although the number of pathological findings was comparable, the rate of surgical intervention was significantly higher in the IgG4-negative group (P < 0.001). No significant differences were observed in relapse rates or relapse sites between the two groups. These findings suggest that MPD narrowing and retroperitoneal fibrosis may be characteristic of AIP without elevated IgG4. Vigilant monitoring for relapse is warranted, regardless of serum IgG4 levels.

Bronchopleural fistula (BPF) is a postoperative complication with a poor prognosis, and its treatment remains challenging. This study aimed to accumulate cases through a multi-institutional registry and gain insights to improve the treatment outcomes. This retrospective multi-institutional study included patients who developed BPF after undergoing thoracic surgery between January 2000 and July 2023. The primary end-point was the BPF cure rate. Secondary end-points included overall survival and factors associated with non-cure. This study included 81 patients. Endoscopic interventions were performed in 29.6% of patients, and BPF cure with endoscopic treatment alone was achieved in 20.8% of them. Surgery for BPF was performed in 85.2% of the patients, with open-window thoracostomy being the most frequent procedure. Among open-window thoracotomies, the cure rates with muscle flaps and omentum for closing windows were 82.4% and 100%, respectively. Overall, BPF was cured in 53.1% of the patients, while 46.9% were not cured. The mortality rate during the observation period was 58.0%, with BPF-related deaths accounting for 48.9%. A multivariate analysis identified low albumin levels (<3.0 g/l) and low haemoglobin levels (<11.0 g/l) at BPF onset as significant non-cure factors (odds ratio: 4.12, 95% CI 1.43-11.80; odds ratio: 3.53, 95% CI 1.28-9.75, respectively). BPF remains a postoperative complication with both high non-cure and mortality rates. The nutritional status, particularly the albumin and haemoglobin levels at onset, significantly influences the outcomes, thus highlighting the importance of enhanced perioperative nutritional management to improve the BPF outcomes.

Background:EGFR L858R mutation is associated with poorer efficacy of EGFR-tyrosine kinase inhibitors (TKIs) than EGFR Ex19del in patients with non-small cell lung cancer (NSCLC). However, ramucirumab (RAM) + erlotinib (ERL) therapy exhibited comparable efficacy between patients with L858R mutation and Ex19del mutation (median progression-free survival (PFS): 19.6 vs 19.4 months) in the RELAY study, with favorable PFS for both gene mutations at 19.4 months in the Japanese subset. Meanwhile, the FLAURA study revealed shorter PFS with osimertinib (OSI) for L858R mutation than Ex19del mutation, with poorer PFS in the Japanese subset than in the overall population. The treatment discontinuation rates of RAM + ERL and OSI in Japanese patients were 18% and 29%, respectively. Consequently, RAM + ERL may exhibit superior efficacy and safety in Japanese patients with the L858R mutation.Objectives:To evaluate the therapeutic efficacy and safety of RAM + ERL as a first-line treatment for advanced or recurrent NSCLC harboring the L858R mutation in Japanese patients.Design:A multicenter, noninterventional, retrospective cohort study.Methods and analysis:This study will involve patients with advanced or recurrent NSCLC (ECOG PS score 0–2) with L858R mutation who received RAM + ERL between November 1, 2020 and August 31, 2023, with the planned sample size of 200 patients. The primary endpoint is time to treatment failure, and the secondary endpoints are overall survival, PFS, PFS2, time to discontinuation of any EGFR-TKI, time to failure of strategy, objective response rate, disease control rate, and safety. Exploratory endpoints are effects of ERL and RAM on PD-L1 expression and neutrophil-to-lymphocyte ratio.Discussion:To the best of our knowledge, this is the first retrospective study focusing on L858R mutations associated with the RELAY regimen, providing the corresponding real-world data.Trial registration:UMIN Clinical Trials Registry identifier: UMIN000052047.