Citrus-type crude drugs (CCDs) are commonly used to formulate decoctions in Kampo formula (traditional Japanese medicine). Our previous study reported metabolomic analyses for differentiation of the ...methanol extracts of Citrus-type crude drugs (CCDs) using ultra-HPLC (UHPLC)/MS, and 13C- and 1H-NMR. The present study expanded the scope of its application by analyzing four CCD water extracts (Kijitsu, Tohi, Chimpi, and Kippi); these CCDs are usually used as decoction ingredients in the Kampo formula. A principal component analysis score plot of processed UPLC/MS and NMR analysis data indicated that the CCD water extracts could be classified into three groups. The loading plots showed that naringin and neohesperidin were the distinguishing components. Three primary metabolites, α-glucose, β-glucose, and sucrose were identified as distinguishing compounds by NMR spectroscopy. During the preparation of CCD dry extracts, some compounds volatilized or decomposed. Consequently, fewer compounds were detected than in our previous studies using methanol extract. However, these results suggested that the combined NMR- and LC/MS-based metabolomics can discriminate crude drugs in dried water extracts of CCDs.
PIK3CA is an oncogene that encodes the p110α component of phosphatidylinositol 3‐kinase (PI3K); it is the second most frequently mutated gene following the TP53 gene. In the clinical setting, PIK3CA ...mutations may have favorable prognostic value for hormone receptor‐positive breast cancer patients and, during the past few years, PIK3CA mutations of cell‐free DNA (cfDNA) have attracted attention as a potential noninvasive biomarker of cancer. However, there are few reports on the clinical implications of PIK3CA mutations for TNBC patients. We investigated the PIK3CA major mutation status of cfDNA as a noninvasive biomarker of cancer using droplet digital polymerase chain reaction (ddPCR), which has high level sensitivity and specificity for cancer mutation, in early‐stage 49 triple negative breast cancer (TNBC) patients. A total of 12 (24.4%) of 49 patients had PIK3CA mutations of cfDNA. In a median follow up of 54.4 months, the presence of PIK3CA mutations of cfDNA had significant impacts on relapse‐free survival (RFS; P = 0.0072) and breast cancer‐specific survival (BCSS; P = 0.016), according to the log‐lank test. In a Cox proportional hazards model, the presence of PIK3CA mutations of cfDNA had significant prognostic value in the univariate and multivariate analysis. Additionally, the presence of PIK3CA mutations of cfDNA was significantly correlated with positive androgen receptor phosphorylated form depending on PI3K signaling pathway (pAR) which is independent favorable prognostic factors of TNBC. We demonstrated that the presence of PIK3CA major mutations of cfDNA could be a discriminatory predictor of RFS and BCSS in early‐stage TNBC patients and it was associated with PI3K pathway‐dependent AR phosphorylation.
We demonstrated the presence of PIK3CA major mutations of cfDNA could be discriminatory predictor of RFS and BCSS in early‐stage TNBC patients which may be associated with PI3K pathway dependent AR phosphorylation.
Recent studies have indicated the clinical significance of tumor‐associated macrophages (TAM) in several malignant tumors including breast cancer. Although recent studies have focused on ...CD68‐positive or CD163‐positive TAM in breast cancer, no study has investigated the significance of CD204‐positive TAM in breast cancer. We found that CD204 expression on macrophages was evaluated following stimulation with the conditioned medium (CM) of breast cancer cell lines. Paraffin sections of 149 breast cancer samples which were diagnosed as invasive ductal carcinoma were immunohistochemically analyzed for CD68, CD163 and CD204 expression. The results of analyses indicated that a high number of CD204‐positive TAM was associated with worse clinical prognoses, including relapse‐free survival, distant relapse‐free survival and breast cancer‐specific survival; however, neither the numbers of CD68‐positive or CD163‐positive TAM were associated with clinical courses. Of the clinicopathological factors investigated, estrogen receptor, Ki‐67 index, hormone subtype, and histological grade were significantly related to the increased number of CD163‐positive and CD204‐positive TAM. These data indicate the clinical significance of CD204‐positive TAM in breast cancer progression and CD204 is a marker for predicting clinical prognosis in breast cancer.
CD204 is a independent prognostic factor in breast cancer patients.
Accumulating evidence indicates the importance of natural killer (NK) cells in controlling tumor growth and metastasis. NK cell subsets display diversities in their function and tissue distribution ...and Mac‐1hi CD27lo NK cells are the predominant population of lung‐resident NK cells. Although the lung is a major organ where primary tumor develops and cancer cells metastasize, there is no clear evidence whether circulating NK cells and/or tissue‐resident NK cells control tumor growth in the lung. In the present study, we examined an antitumor function of lung‐resident NK cells to control pulmonary tumor growth. In an orthotopic lung tumor model, NK cells controlled pulmonary tumor growth, and mature circulating NK cell subsets were increased in tumor‐bearing lungs through a C‐X‐C motif chemokine receptor 3 (CXCR3)‐dependent mechanism. Although such increase in migratory NK cell subsets can be blocked by anti‐CXCR3 treatment, there was no difference in pulmonary tumor growth in anti‐CXCR3‐treated mice compared with control mice. In addition to pulmonary tumor growth, lung‐resident NK cells, but not migratory NK cells, play a dominant role in controlling metastatic growth of cancer cells in lung. These results strongly indicate an importance of lung‐resident NK cells for controlling pulmonary tumor growth.
Although lung is a major organ where primary tumor develops and cancer cells metastasize, there is no clear evidence whether circulating NK cells and/or tissue‐resident NK cells control tumor growth in lung. Presented results indicate the importance of lung‐resident NK cells for controlling pulmonary tumor growth.
Purpose
In most stapes surgeries, the posterior ear canal is enlarged and a piston is inserted posterior to the chorda tympani nerve (post-chorda tympani approach; Post C). Although reports vary, ...some indicate that more than 60% of the patients experience lingual symptoms following surgery. Endoscopic surgery may permit an anterior approach to the nerve (pre-chorda tympani approach; Pre C). Herein, we propose a suitable approach for endoscopic stapes surgery based on the classification of the chorda tympani nerve.
Methods
We retrospectively reviewed the medical records of 23 patients who underwent endoscopic stapes surgery at our institution between 2019 and 2021. The nerve classification previously reported, the modified nerve classification (attached long type is divided into Category 1: lenticular process is visible with 0° endoscope and Category 2: not visible), selected approach (Pre C or Post C), use of a 30° endoscope, and manipulation of the nerve (number of contacts and traction, with or without suction, with or without malposition or extension and amputation, and damage score) were evaluated.
Results
The damage score was significantly lower in the Pre C group (
p
< 0.05); however, using this approach for all cases is not desirable owing to the high risk of damage to the nerve during posterior malpositioning.
Conclusion
The Post C should be used for the detached and attached long 1 types, while the Pre C with a 30° endoscope should be used for the attached long 2, attached short, ultrashort, and external auditory canal types.
Tumor‐associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and ...resistance to anticancer therapy. Numerous studies using human breast cancer samples, cell lines, and murine breast cancer models have revealed details of the mechanisms by which the protumor functions of TAMs are activated. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy. Tumor‐associated macrophages express a number of immunosuppressive genes, and single‐cell sequence analyses of human and murine cancer samples have helped elucidate the mechanism of TAM‐induced immunosuppression. As TAMs are considered suitable targets for anticancer therapies, we summarized the protumor functions of TAMs and the potential of anticancer therapies targeting TAMs, with a focus on breast cancer research.
Tumor‐associated macrophages (TAMs) are the most prominent immune cells in the breast cancer microenvironment, and the protumor functions of TAMs are thought to affect cancer progression and resistance to anti‐cancer therapy. Recent advances have highlighted the significant involvement of TAMs in the resistance of breast cancer cells to immunotherapy.
The immune status of patients can impact on the clinical course of cancer. Lymph node (LN) macrophages play critical roles in anti-cancer immunity via the activation of cytotoxic T-lymphocytes ...(CTLs). In this study, the prognostic significance of CD169+ LN macrophages was examined in patients with breast cancer. For this purpose the number of CD169+ cells and their ratio relative to total macrophages (CD68+) in regional LNs (RLNs), as well as the number of CD8+ CTLs in tumor tissues, were investigated using immunohistochemistry of paraffin-embedded tissue samples from 146 patients with breast cancer. The association of these data with clinicopathological factors was then analyzed. The number of cells positive for the pan-macrophage marker CD68 remained relatively uniform, while the number of CD169+ cells varied across all cases. Moreover, a high density of CD169+ cells correlated with early clinical stage and no LN metastasis, while a higher CD169+ to CD68+ ratio was significantly associated with small tumor size and a low Ki-67+ rate. There was also a significant correlation between the number of CD8+ CTLs and that of CD169+ macrophages in high grade breast cancer cases with a Ki-67 index greater than 40%. However, neither the density nor the ratio of CD169+ cells, nor the density of CD8+ CTLs, were associated with relapse-free survival, distant relapse-free survival, or breast cancer-specific survival. These findings suggest that CD169+ macrophages in RLNs might be a useful marker for assessing clinical stage, including LN states, in patients with breast cancer.
The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor ...disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.
Cholesteatoma is a progressive middle ear disease that can only be treated surgically but with a high recurrence rate. Depending on the extent of the disease, a surgical approach, such as ...microsurgery with a retroarticular incision or transcanal endoscopic surgery, is performed. However, the current examination cannot sufficiently predict the progression before surgery, and changes in approach may be made during the surgery. Large amounts of data are typically required to train deep neural network models; however, the prevalence of cholesteatomas is low (1-in-25, 000). Developing analysis methods that improve the accuracy with such a small number of samples is an important issue for medical artificial intelligence (AI) research. This paper presents an AI-based system to automatically detect mastoid extensions using CT. This retrospective study included 164 patients (80 with mastoid extension and 84 without mastoid extension) who underwent surgery. This study adopted a relatively lightweight neural network model called MobileNetV2 to learn and predict the CT images of 164 patients. The training was performed with eight divided groups for cross-validation and was performed 24 times with each of the eight groups to verify accuracy fluctuations caused by randomly augmented learning. An evaluation was performed by each of the 24 single-trained models, and 24 sets of ensemble predictions with 23 models for 100% original size images and 400% zoomed images. Fifteen otolaryngologists diagnosed the images and compared the results. The average accuracy of predicting 400% zoomed images using ensemble prediction model was 81.14% (sensitivity = 84.95%, specificity = 77.33%). The average accuracy of the otolaryngologists was 73.41% (sensitivity, 83.17%; specificity, 64.13%), which was not affected by their clinical experiences. Noteworthily, despite the small number of cases, we were able to create a highly accurate AI. These findings represent an important first step in the automatic diagnosis of the cholesteatoma extension.
Background
Tympanoplasty using the interlay technique has rarely been reported in transcanal endoscopic ear surgery, unlike the underlay technique. This is because many surgeons find it challenging ...to detach the epithelial layer of the tympanic membrane using only one hand. However, the epithelial layer can be easily detached from the inferior part of the tympanic membrane. Another key point is to actively improve anteroinferior visibility even if the overhang is slight because most perforations and postoperative reperforations are found in the anteroinferior quadrant of the tympanic membrane. We report the application of the interlay technique in endoscopic tympanoplasty type I for tympanic perforations.
Methods
We retrospectively reviewed the medical records of 51 patients who had undergone tympanoplasty using the interlay technique without ossiculoplasty between 2017 and 2020. We then compared the data with those of patients who underwent microscopic surgery (MS) using the underlay technique between 1998 and 2009 (n = 104). No other technique was used in each group during this period. Repair of tympanic membrane perforation and hearing outcomes were assessed for > 1 year postoperatively.
Results
The perforation sites were limited to the anterior, posterior, and anterior–posterior quadrants in 23, 1, and 27 ears, respectively. Perforations were closed in 50 of the 51 ears (98.0%), and the postoperative hearing was good (average air-bone A-B gap was 6.8 ± 5.8 dB). The surgical success rate for the repair of tympanic membrane perforation was not significantly different from the MS group (93.3%, P = 0.15). The average postoperative average A-B gap in the group that underwent the interlay technique was significantly different from that in the MS group (10.1 ± 6.6 dB, P < 0.01).
Conclusion
The interlay technique should be considered as one of the treatment methods in endoscopic surgery for tympanic perforations. Further study of the postoperative outcomes of this procedure should be conducted to establish the optimal surgical procedure for tympanic perforations. Trial registration: This study was retrospectively approved by the Institutional Review Board of the Jikei University, Tokyo, Japan (approval number: 32-205 10286).
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