Miyagi Prefectural Hospital Organization

Accurate clinical staging of upper tract urothelial carcinoma (UTUC) remains challenging, and discrepancies between clinical and pathological T stages may result in missed opportunities for appropriate treatment. This study aimed to elucidate real-world discrepancies between clinical and pathological T staging in UTUC, emphasizing the diagnostic uncertainty associated with clinical T2 (cT2) disease. A retrospective analysis was conducted involving 739 patients with cTa–4N0M0 UTUC who underwent radical nephroureterectomy (RNU) at multiple institutions. Patients who received neoadjuvant therapy or had missing pathological T stage data were excluded. Discrepancies between clinical and pathological staging, treatment patterns, and survival outcomes were evaluated. Among 739 patients, substantial discrepancies between clinical and pathological T stages were observed, with an overall diagnostic concordance rate of 44.7%. Only 16% of cT2 cases were pathologically confirmed as pathological T2 (pT2), whereas most were either down-staged to ≤pT1 or up-staged to ≥pT3, indicating marked diagnostic uncertainty. Clinical heterogeneity within the cT2 group resulted in marked survival differences based on pathological stage, as pT3 patients had significantly worse outcomes than pT2 patients. Within the pT3 subgroup, lymphovascular invasion independently correlated with poor prognosis, whereas adjuvant therapy improved survival. However, only approximately one-third of patients with pT3 disease received adjuvant therapy, indicating a treatment gap in this high-risk population. This multicenter study identified real-world discrepancies between clinical and pathological staging in UTUC. cT2 disease represents a heterogeneous and diagnostically uncertain category, requiring careful interpretation for appropriate treatment planning.

This study aimed to examine the effects of concomitant use of proton-pump inhibitors (PPIs) on the survival outcomes in patients with endocrine-sensitive chemotherapy-naïve advanced breast cancer (BC) treated with palbociclib or abemaciclib. This multicenter, retrospective study was conducted at five hospitals in Japan. Data were collected from consecutive patients treated with palbociclib or abemaciclib in combination with endocrine therapy as first-line treatment for endocrine-sensitive chemotherapy-naïve advanced BC between December 2017 and August 2022. Associations between concomitant PPI use and survival outcomes were analyzed. Among 202 patients, 38 (19%) were concomitant PPI users. In the palbociclib population (n = 123), concomitant PPI use was associated with a trend toward decreased progression-free survival (PFS) and a significant reduction in overall survival (OS; crude hazard ratio [HR], 1.67; 95% confidence interval [CI], 0.86–3.00 and crude HR, 3.51; 95% CI, 1.53–7.64, respectively). In multivariable analyses, consistent results were obtained (adjusted HR, 1.29; 95% CI, 0.66–2.53 and adjusted HR, 3.23; 95% CI, 1.28–7.67, respectively). In contrast, concomitant PPI use did not significantly affect either PFS or OS in the abemaciclib group (n = 79). Concomitant PPI use decreased the efficacy of palbociclib regardless of the formulation, with no such impact observed with abemaciclib.

Intraoperative use of urokinase is a recognized method for salvaging compromised free flaps. However, protocols for dosage and administration vary, and no consensus exists regarding the optimal technique. Herein, we report a case of postoperative venous thrombosis in a free fibular flap. Despite the unsuccessful intra-arterial administration of urokinase owing to an extensive venous thrombus, we attempted to dissolve the thrombus through direct intravenous infusion using a 27 G needle at multiple sites in the vein where the thrombus had formed. Ten minutes after direct injection into the venous thrombus, venous blood flowed out and successful thrombolysis was achieved. Re-anastomosis was performed, leading to full use of the skin flap without partial necrosis. No hemorrhagic complications were observed. Intra-arterial injection of urokinase is an effective method of thrombolytic therapy for flap salvage. However, when the vein is completely occluded by thrombus, intraflap circulation of the agent via arterial infusion becomes difficult. Direct injection of urokinase into the occluded vein may serve as a potential method for resolving venous obstruction within the limited ischemic time of the flap.

Autistic symptoms have been shown to influence functional outcomes and prognosis not only in schizophrenia but also in individuals at clinical high-risk of psychosis (CHR-P) and those experiencing their first-episode psychosis (FEP). However, it remains unclear whether these symptoms reflect enduring traits that persist over time or whether they are states that can improve with treatment in CHR-P and FEP. This study aimed to investigate the one-year trajectory of autistic symptoms in individuals at CHR-P and with FEP. A total of 59 participants who completed a one-year follow-up [CHR-P, n=34; FEP, n=25] were categorized into high and low autistic symptom groups based on baseline symptom severity, as assessed by the Positive and Negative Syndrome Scale Autism Severity Score. We then examined changes in psychiatric symptoms, including autistic symptoms, as well as global and cognitive function, between the two groups over one year. After one year of follow-up, psychiatric symptoms other than autistic symptoms, as well as global and cognitive function, improved in both groups. The significant differences in these symptoms and functions at baseline disappeared after one year. However, while autism symptoms demonstrated some improvement from baseline, the significant differences between the high and low autistic symptom groups persisted. These findings suggest that autistic symptoms may exhibit both transient state and enduring traits in individuals at CHR-P and with FEP. Further studies with larger sample sizes and follow-up periods exceeding one year are needed to validate the long-term stability of these symptoms.

ABSTRACTExosomal microRNAs (miRNAs) are candidates for liquid biopsies. Organoid culture systems enable long‐term expansion of the colon epithelium. This study evaluated exosomal miRNAs from colorectal cancer organoids for liquid biopsy. Organoids were established from normal colon and colorectal cancer tissues. Exosomes were isolated from conditioned media. miRNAs were extracted from exosomes and compared using microarray analysis. Exosomal miRNAs expression levels in the sera of healthy patients and patients with colorectal cancer were compared at a single institution. The multicenter study was validated using miRNAs upregulated in the serum of colorectal cancer patients, along with exosomal miRNAs reported to be upregulated in colorectal adenoma organoids and sera. A total of 44 exosomal miRNAs were commonly expressed in both normal colorectal epithelial cells and colorectal cancer organoids, whereas 59 were exclusively expressed in colorectal cancer organoids. In a single‐center cohort study, two exosomal miRNAs (miR‐4284 and miR‐5100) were upregulated in the serum of colorectal cancer patients. In a multicenter study, four exosomal miRNAs (miR‐4284, miR‐5100, miR‐1246, and miR‐1290) were upregulated in the serum of patients with colorectal cancer. The combination of these four exosomal miRNAs had comparable diagnostic performance to carcinoembryonic antigen, with an area under the curve of 0.75 (95% confidence interval: 0.65–0.83) versus 0.79 (95% confidence interval: 0.70–0.87). Combining the four miRNAs with carcinoembryonic antigen improved diagnostic accuracy, with an area under the curve of 0.82 (95% confidence interval: 0.74–0.89). Exosomal miRNAs derived from colorectal cancer organoids can serve as diagnostic biomarkers for colorectal cancer.

8596 Background: Osimertinib is commonly used as a first-line treatment for EGFR-mutated advanced NSCLC. However, the optimal treatment following osimertinib failure remains unclear. This study evaluated afatinib plus chemotherapy for EGFR-mutated NSCLC resistant to osimertinib. Initial findings were presented at ASCO2023, and this report provides final data, including blood NGS analysis. Methods: Patients (pts) with EGFR mutations (Del19 or L858R) after osimertinib failure were treated with afatinib (20 mg daily) combined with carboplatin (AUC5 mg/mL/min) and pemetrexed (500 mg/m² every 3 weeks), followed by maintenance therapy with afatinib plus pemetrexed until progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (6M-PFSR). Secondary endpoints included PFS, OS, ORR, DOR, and safety. Blood samples were collected before and during treatment, and at progression, to evaluate biomarkers using CAPP-SEQ. Results: Between June 7, 2020, and January 19, 2022, 36 pts were enrolled. One pt met exclusion criteria, leaving 35 pts for efficacy analysis. The mean age was 70 years; 60% were women, and 54.3% were nonsmokers. The median observation period was 29.1 months (cutoff date: January 18, 2024). The primary endpoint, 6M-PFSR, was 57.1% (95% CI, 39.3–71.5), exceeding the threshold of 35%. Notably, 28.6% of pts achieved long-term PFS of ≥1 year. ORR was 51.4%, DCR was 88.6%, median PFS was 8.2 months, median DOR was 5.6 months, and median OS was 22.5 months. By mutation type, ORRs were similar for Del19 and L858R (46.7% and 55.0%, respectively), but median PFS was longer for Del19 than for L858R (9.6 vs. 5.2 months). Pts who had responded to prior osimertinib (CR/PR, n=29) had longer median PFS than non-responders (SD/PD/NE, n=6) (8.5 vs. 5.8 months). Adverse events (AEs) from TKI and chemotherapy were common but manageable. The most frequent AEs were diarrhea (52.8%), anorexia (47.2%), fatigue (36.1%), and paronychia (36.1%). Interstitial pneumonia occurred in 3 pts (8.3%), with one treatment-related death. In plasma NGS analysis, clearance of EGFR mutations during treatment was a key predictive factor. Pts without EGFR mutation clearance had shorter PFS and OS compared to those with clearance (PFS: 5.7 vs. 12.0 months; OS: 15.7 vs. 34.4 months). Efficacy was observed even in pts with p53 mutations, a known resistance factor. MET gene amplification was detected in 4 pts upon resistance. Conclusions: Afatinib combined with platinum-based chemotherapy demonstrated satisfactory efficacy and manageable toxicity in pts with tumors refractory to osimertinib. EGFR mutation clearance during treatment was predictive of therapeutic outcomes. This regimen may be a promising second-line option after osimertinib failure. Clinical trial information: 021200005 .

BackgroundPlatinum and anti-PD-1 antibodies are the front-line systemic therapy for recurrent or metastatic head and neck squamous cell carcinoma (RM-HNSCC). However, limited data are available on clinical outcomes and appropriate regimens for patients with RM-HNSCC following treatment failure with these agents.Patients and methodsWe retrospectively analyzed the clinical data of patients with RM-HNSCC from 10 Japanese institutions in whom platinum and nivolumab treatment failed.ResultsOf the 480 patients included in the study, 236 were treated with the best supportive care and had a median overall survival of 3.1 months. The remaining 244 patients received salvage-line chemotherapy, which was paclitaxel + cetuximab in 72 (30%), paclitaxel or docetaxel in 89 (36%), and tegafur/gimeracil/oteracil in 48 (20%); the respective objective response rates were 54.9%, 27.9%, and 25.5%, with median progression-free survival of 5.4 months and median overall survival of 13.0 months. Multivariable analysis identified disease stabilization or response on prior nivolumab and paclitaxel + cetuximab as salvage-line chemotherapy to be associated with encouraging progression-free and overall survival.ConclusionThis study sheds light on clinical outcomes and prognostic factors in patients with RM-HNSCC after failure of platinum and anti-PD-1 antibody therapy. The findings provide essential baseline data for future therapeutic development in salvage-line settings.