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The human endometrium is an essential component in human reproduction that has the unique characteristic of undergoing cyclic regeneration during each menstrual cycle. Vigorous regeneration after shedding may be sustained by stem/progenitor cells, for which molecular markers have not been fully identified. Although clonality analysis using X chromosome inactivation patterns has shown that normal human endometrial glands are composed of a monoclonal cell population, whether clonal expansion is derived from stem/progenitor cells remains unclear. Remarkable advances in next‐generation sequencing technology over the past decade have enabled somatic mutations to be detected in not only cancers, but also normal solid tissues. Unexpectedly frequent cancer‐associated mutations have been detected in a variety of normal tissues, and recent studies have clarified the mutational landscape of normal human endometrium. In epithelial glandular cells, representative cancer‐associated mutations are frequently observed in an age‐dependent manner, presumably leading to growth advantage. However, the extremely high mutation loads attributed to DNA mismatch repair deficiency and POLE mutations, as well as structural and copy number alterations, are specific to endometrial cancer, not to normal epithelial cells. The malignant conversion of normal epithelial cells requires these additional genetic hits, which are presumably accumulated during aging, and may therefore be a rare life event. These discoveries could be expected to shed light on the physiology and pathogenesis of the human endometrium and urge caution against the application of genetic screening for the early detection of endometrial cancer. Human endometrial gland exhibits clonal growth in each menstrual cycle possibly via stem/progenitor cells, with harboring frequent somatic gene mutations in cancer‐associated genes. These mutations may plays role in endometrial regeneration and pathogenesis of endometriosis or endometrial cancer.

Approximately 70% of women with epithelial ovarian cancer (EOC) are diagnosed with advanced stage disease, which is associated with high morbidity and mortality. The standard approach to treating patients with advanced EOC remains primary debulking surgery (PDS) followed by chemotherapy. EOC is one of the most sensitive of all solid tumors to cytotoxic drugs, with over 80% of women showing a response to standard chemotherapy combined with taxane and platinum. Furthermore, residual disease is a major prognostic factor for survival. On the basis of the clinical features, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is considered to be an alternative treatment option to standard treatment in patients unable to undergo complete resection during PDS. Noninferiority of NACT-IDS to PDS has been demonstrated in some randomized controlled trials and meta-analyses. NACT would also lead to improved quality of life (QOL) of patients, however there are still problems to be solved in the treatment strategy. The uncertainty of perioperative visual assessment of tumor dissemination after NACT has been reported. In addition, several papers have shown the possibility that NACT induces platinum resistance. Furthermore, a notable risk associated with NACT is that patients with significant side effects and refractory disease will lose the opportunity for debulking surgery. Appropriate selection of the patient cohort for NACT is an important issue. Bevacizumab (Bev) is active in patients with advanced EOC. However, the use of Bev is not recommended in the neoadjuvant setting. Bev has a specific adverse event profile that needs to be considered, especially for surgical management, such as gastrointestinal perforation, hemorrhage, and thromboembolic events. NACT could be an alternative treatment option in patients with stage III or IV EOC. However, further studies are needed to clarify the precise role of NACT in the management of advanced EOC.

Background Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC. Methods A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen. Results Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD. Conclusions Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.

In endoscopic full‐thickness resection (EFTR), luminal collapse can occur due to communication between the gastrointestinal lumen and peritoneal cavity, making visualization and procedural continuity difficult. We propose the underwater pressure lumen expansion (UPLE) method, in which hydraulic pressure is applied in a fluid‐filled environment to re‐expand the collapsed lumen, thereby restoring visualization and allowing continued endoscopic manipulation. The UPLE method was applied during peroral endoscopic tumor resection in a clinical case and in an animal model of EFTR, and its utility was successfully demonstrated.

Folate receptor (FR) α expression in normal tissues is restricted to a subpopulation of epithelial cells. In contrast, FRα is overexpressed in epithelial ovarian cancer (EOC) and non-small-cell lung carcinoma. Therefore, FRα is considered a promising therapeutic target for EOC and non-small-cell lung carcinoma. Farletuzumab (MORAb-003) is a humanized monoclonal antibody of immunoglobulin G subtype 1 kappa, targeting human FRα. To date, Phase I/II clinical trials have clearly demonstrated the feasibility and safety of farletuzumab as a treatment option against solid tumors. However, in Phase III clinical trial that was conducted to verify the combined effect of paclitaxel-carboplatin combination therapy and farletuzumab for patients with recurrent EOC, improvement in progression-free survival was not statistically significant. This result might be owing to the fact that the eligibility criteria for these studies did not include FRα expression. The significance of FRα as a predictive/prognostic biomarker remains unclear. In addition, there is currently no established biomarker to predict the response and toxicities among patients receiving farletuzumab therapy. Furthermore, the primary mechanism of action of farletuzumab has not yet been identified. Therefore, further research to identify the mechanism of farletuzumab in tumor suppression is necessary to clarify the full potential of this chemotherapeutic agent.

Endoscopic antireflux therapy is a novel endoscopic treatment for refractory gastroesophageal reflux disease. We developed antireflux myoplasty (AR‐MP), a modified version of antireflux mucoplasty (ARM‐P), in which exposed bilateral sling fibers are sutured directly via endoscopic hand‐suturing. AR‐MP was performed on a 60‐year‐old man, resulting in symptomatic improvement and allowing discontinuation of acid‐suppressive medication 3 months after the procedure. One month postoperatively, endoscopy showed an improvement in the Hill classification from grade 3 to grade 1. Before AR‐MP, endoscopic pressure study integrated system findings showed a maximum intragastric pressure value of 13.7 mmHg, indicating a flat pattern. After AR‐MP, maximum intragastric pressure exceeded 20 mmHg, and the pattern shifted to uphill. AR‐MP is an innovative endoscopic technique that reconstructs the native antireflux mechanism by suturing the sling fibers and reforming the gastroesophageal flap valve. This innovative endoscopic procedure, like ARM‐P, provides immediate symptom relief and represents a breakthrough in the endoscopic treatment of gastroesophageal reflux disease.

Background: The effect of claudin 18.2 (CLDN18.2) expression on the outcomes of a first-line immune checkpoint inhibitor (ICI)-containing chemotherapy (ICI-chemo) in patients with human epidermal growth factor receptor 2 (HER2)-negative, proficient mismatch repair (pMMR), and programmed death-ligand 1 (PD-L1)-expressing metastatic or recurrent gastric or gastroesophageal junction cancers (mGC/GEJC) remains unclear. Objectives: We assessed the effects of CLDN18.2 expression on the outcomes of first-line ICI-containing chemotherapy in patients with HER2-negative, pMMR, and PD-L1-expressing mGC/GEJC. Patients and methods: Medical records of patients with HER2-negative, pMMR, and PD-L1 combined positive score (CPS) ⩾1 unresectable/metastatic or recurrent GC/GEJC who received first-line ICI-chemo or chemotherapy alone (chemo-alone) between January 2016 and August 2024 were retrospectively analyzed. The impact of CLDN18.2 status on the clinical outcomes was evaluated in patients receiving ICI-chemo and chemo-alone to assess the prognostic significance of CLDN18.2 in the absence of ICI. Results: A total of 150 patients were treated with ICI-chemo, whereas 313 patients received chemo-alone. CLDN18.2 positivity (⩾2+ in ⩾75% tumor cells) was identified in 42 patients (28.0%) in the ICI-chemo group and 94 patients (30.0%) in the chemo-alone group. There were no significant differences in the objective response rate (ORR; 68.3% vs 70.3%, p = 0.842), disease control rate (DCR; 92.7% vs 94.1%, p = 0.718), progression-free survival (PFS; hazard ratio (HR) 1.01, p = 0.955), or overall survival (OS; HR 1.12, p = 0.615) between CLDN18.2-positive and CLDN18.2-negative patients in the ICI-chemo group. Similarly, the DCR, ORR, PFS, and OS outcomes were comparable between the CLDN18.2-positive and -negative patients in the chemo-alone group. Conclusion: CLDN18.2 expression exerted no impact on outcomes of first-line ICI-chemo and chemo-alone in patients with HER2-negative, pMMR, and PD-L1 CPS ⩾1 mGC/GEJC.

Recent studies reported the presence of oncogenic mutations in normal endometrial glands, but the biological significance remains unclear. The present study investigated the status of KRAS/PIK3CA driver mutations in normal endometrial glands as well as spheroids derived from single glands. The normal endometria of surgically removed uteri (n = 3) were divided into nine regions, and 40 endometrial single glands were isolated from each region. The DNAs of 10 glands in each region were extracted and subjected to Sanger sequencing for KRAS or PIK3CA driver mutations, while the remaining 30 glands were conferred to a long‐term spheroid culture, followed by Sanger sequencing. Immunohistochemical analyses of stem cell (Axin2, ALDH1A1, SOX9) markers were undertaken for spheroids. Sanger sequencing successfully detected oncogenic mutations of KRAS or PIK3CA in a single gland. Twenty‐five of the 270 glands (9.3%) had mutations in either KRAS or PIK3CA, and the mutation frequency in each endometrial region varied from 0% to 50%. The droplet digital PCR showed high mutation allele frequency (MAF) of PIK3CA mutation, suggestive of clonal expansion of mutated cells within a gland. Over 60% of the collected spheroids had PIK3CA mutations, but no KRAS mutations were detected. Immunohistochemically, spheroids were mainly composed of cells with stem cell marker expressions. High MAF of PIK3CA mutation in a single gland as well as frequent PIK3CA mutation in stem cell‐rich spheroids that originated from a single gland suggest the role of PIK3CA mutation in stem cell propagation. This information could improve our understanding of endometrial physiology as well as stem cell‐oriented endometrial regeneration and carcinogenesis. The present study investigated the status of KRAS/PIK3CA driver mutations in normal endometrial glands as well as spheroids derived from single glands. High mutation allele frequency of PIK3CA mutation in a single gland as well as frequent PIK3CA mutation in stem cell‐rich spheroids that originated from a single gland suggest the role of PIK3CA mutation in stem cell propagation.

The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.

PurposeThis study aimed to assess the image characteristics of deep-learning-based image processing software (DLIP; FCT PixelShine, FUJIFILM, Tokyo, Japan) and compare it with filtered back projection (FBP), model-based iterative reconstruction (MBIR), and deep-learning-based reconstruction (DLR).MethodsThis phantom study assessed the object-specific spatial resolution (task-based transfer function [TTF]), noise characteristics (noise power spectrum [NPS]), and low-contrast detectability (low-contrast object-specific contrast-to-noise ratio [CNRLO]) at three different output doses (standard: 10 mGy; low: 3.9 mGy; ultralow: 2.0 mGy). The processing strength of DLIPFBP with A1, A4, and A9 was compared with those of FBP, MBIR, and DLR.ResultThe standard dose with high-contrast TTFs of DLIPFBP exceeded that of FBP. Low-contrast TTFs were comparable to or lower than that of FBP. The NPS peak frequency (fP) of DLIPFBP shifts to low spatial frequencies of up to 8.6% at ultralow doses compared to the standard FBP dose. MBIR shifted the most fP compared to FBP—a marked shift of up to 49%. DLIPFBP showed a CNRLO equal to or greater than that of DLR in standard or low doses. In contrast, the CNRLO of the DLIPFBP was equal to or lower than that of the DLR in ultralow doses.ConclusionDLIPFBP reduced image noise while maintaining a resolution similar to commercially available MBIR and DLR. The slight spatial frequency shift of fP in DLIPFBP contributed to the noise texture degradation suppression. The NPS suppression in the low spatial frequency range effectively improved the low-contrast detectability.