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Abstract Background Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment.

This review is based on the literature published between 2000 and 2023 and presents an up-to-date evidence-based discussion of anatomical considerations relevant to the management of pelvic trauma. In addition, it discusses the significance of the pelvic ligaments in stabilizing the pelvic ring and of bone mineral density (BMD) in fragility fracture of the pelvis (FFP), which is becoming increasingly common in today’s aging societies. Following an overview of the anatomy and function of the sacroiliac joint (SIJ), the pubic symphysis, and the surrounding ligaments, the suitability of the widely-used Young-Burgess classification (YB) of high-energy impact pelvic ring fractures, which emphasizes the role of the ligaments in pelvic ring injuries, is discussed. Based on the current body of knowledge, using 2.5 cm of pubic symphysis diastasis as the determinant for surgical intervention in anterior-posterior compression fracture is questioned, and evaluation under anesthesia and lateral stress radiography for accurate diagnosis and treatment planning is proposed instead. The review underscores the need for further research on how the pelvic ligaments can provide optimal stability in the treatment of various types of pelvic fracture. On the other hand, for fragility fracture of pelvis (FFP) in older adults caused by low-energy trauma, the emphasis is on the fragility of the bones. To better manage FFP, the importance of understanding the distribution of BMD in the pelvis is highlighted. Dual-energy X-ray absorptiometry is a common method for measuring BMD, but it has drawbacks. The advantages of measuring BMD using Hounsfield units on computed tomography scans as an alternative method are discussed. An understanding of these issues may lead to better management of the increasing number of FFP cases in older people with reduced BMD.

Introduction: Osimertinib is used as the first-line treatment for EGFR mutation-positive NSCLC. Nevertheless, its efficacy and safety in clinical practice remain to be fully elucidated and the pattern of progression and the optimal subsequent treatment after osimertinib remains unclear. Methods: This was a multicenter prospective observational study. EGFR mutation-positive patients with NSCLC who started first-line osimertinib from September 2018 to August 2020 were enrolled and followed up until August 2022. Results: A total of 583 patients received osimertinib. The median progression-free and overall survival were 20.0 (95% confidence interval [CI]: 17.6–21.7) months and 41.0 (95% CI: 37.1–44.1) months, respectively. Grade 3 or worse adverse events were observed in 136 patients (23.3%). Progression patterns were categorized as central nervous system only, oligo-progression, and multiple organs on the basis of the Response Evaluation Criteria in Solid Tumors—progressive disease and occurred in 37 (10.8%), 156 (45.4%), and 151 patients (43.9%). The patient’s condition on progression was asymptomatic in 195 patients (56.7%). Osimertinib was continued in 163 patients (47.4%) after confirming progression. In clinically stable population with progressive disease (n = 247), survival after progression was 13.3 (95% CI: 10.9–16.4) months for those who continued osimertinib beyond progressive disease (n = 124), and 24.1 (95% CI: 17.7–34.0) months for those who discontinued osimertinib (n = 123) (hazard ratio = 2.01, 95% CI: 1.38–2.91, p = 0.0002). Platinum plus pemetrexed had the best overall survival benefits after osimertinib. Conclusions: First-line osimertinib was found to have good effectiveness comparable to that reported in pivotal studies. Nevertheless, osimertinib should be discontinued among those who develop progression. Trial registration number: UMIN000038683

BackgroundDigital peer support, defined as peer support delivered through technology such as smartphone apps, may be promising to promote activity in the form of step counts. Interactions among users have a positive impact on retention rates, and apps with social elements show significant improvements in daily step count. However, the feasibility of digital peer support in promoting physical activity (PA) is unknown; therefore, its effectiveness on step count and the clinical implications remain unconfirmed. ObjectiveThis study aimed to assess the feasibility of digital peer support over a 3-month intervention period using the retention rate as the outcome. Moreover, changes in daily step count and physical measurements were compared between pre- and postintervention. MethodsThe study design was a 3-month 1-arm intervention with participants from local government offices in Kanagawa, Japan. We used an available smartphone app, Minchalle, as the tool for the group intervention. Participants were required to report their daily step count to a maximum of 5 members composed exclusively of study participants. The primary outcome was the retention rate. Secondary outcomes included daily step count, the rate of achieving daily step goals, physical measurements, and lifestyle characteristics. Descriptive statistics and the Pearson coefficient were used to examine the relationship between goal achievement and step count, as well as changes in step count and various variables including physical measurements. ResultsOf the 63 participants, 62 completed the intervention. The retention rate was 98% (62/63). The average daily step count during the intervention was 6993 (SD 2328) steps, an 1182-step increase compared with the count observed 1 week before the intervention began. The rate of achieving the daily step count during the intervention was 53.5% (SD 26.2%). There was a significant correlation (r=0.27, P=.05) between achieving daily step goals and increasing daily step count. Comparative analyses showed that changes in weight (68.56, SD 16.97 kg vs 67.30, SD 16.86 kg; P

Abstract We explore the quantum algebraic formalism of the gauge origami system in ℂ 4, where D2/D4/D6/D8-branes are present. We demonstrate that the contour integral formulas have free field interpretations, leading to the operator formalism of qq-characters associated with each D-brane. The qq-characters of D2 and D4-branes correspond to screening charges and generators of the affine quiver W-algebra, respectively. On the other hand, the qq-characters of D6 and D8-branes represent novel types of qq-characters, where monomial terms are characterized by plane partitions and solid partitions. The composition of these qq-characters yields the instanton partition functions of the gauge origami system, eventually establishing the BPS/CFT correspondence. Additionally, we demonstrate that the fusion of qq-characters of D-branes in lower dimensions results in higher-dimensional D-brane qq-characters. We also investigate quadratic relations among these qq-characters. Furthermore, we explore the relationship with the representations, q-characters, and the Bethe ansatz equations of the quantum toroidal gl 1 $$ {\mathfrak{gl}}_1 $$ . This connection provides insights into the Bethe/Gauge correspondence of the gauge origami system from both gauge-theoretic and quantum-algebraic perspectives. We finally present conjectures regarding generalizations to general toric Calabi-Yau four-folds. These generalizations imply the existence of an extensive class of qq-characters, which we call BPS qq-characters. These BPS qq-characters offer a new systematic approach to derive a broader range of BPS/CFT correspondence and Bethe/Gauge correspondence.

Ovarian mature teratomas are benign, but malignant transformation can occur infrequently, especially in women of advanced age. The tissue that undergoes malignant change is mostly squamous cell carcinoma, although adenocarcinoma has been reported in a small number of cases. The immunostaining results of adenocarcinoma usually show a cytokeratin (CK)7−/CK20+ expression profile, corresponding to lower gastrointestinal tract origin. In this report, we describe a case of mucinous carcinoma arising from an ovarian mature teratoma showing a CK7+/CK20+ profile and discuss its imaging features. A 40-year-old woman presented to her primary care physician with abdominal distension and poor oral intake, and she was referred to our hospital. She had been diagnosed with an ovarian mature teratoma at our institution 3 years earlier. At the current presentation, pelvic magnetic resonance imaging showed a large multilocular cystic mass with adipose tissue extending into the upper abdomen. Densely packed cysts were observed inside the mass, which showed weak contrast enhancement on contrast-enhanced imaging and a mildly high signal on diffusion-weighted imaging. A portion of the cysts also showed abnormal 18F-fluorodeoxyglucose uptake (maximum standardized uptake value, 13.2) on positron emission tomography/computed tomography. The patient was subsequently diagnosed with mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma by pathologic examination. This mucinous carcinoma arising from a mature teratoma showed a CK7+/CK20+ profile and took the form of densely packed multilocular cysts. In this respect, it was similar to primary ovarian epithelial mucinous carcinoma on both magnetic resonance imaging and pathologic examination despite showing a much higher maximum standardized uptake value than that of primary ovarian mucinous carcinoma. When a large ovarian teratoma contains a large multilocular cyst, the presence of densely packed multilocular cysts should not be missed even in a mass without solid components. Clinicians should consider the possibility of mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma in such cases.

In the few articles describing MRI findings of myxoid leiomyosarcoma (MLMS), high signal intensity (SI) on T2-weighted images (T2WI) due to myxoid change was believed to be one of the common features. However, we encountered an MLMS with low SI similar to uterine myometrium on T2WI that subsequently grew with extremely edematous change even after 3 cycles of gonadotropin-releasing hormone agonist (GnRHa) treatment. Here we present this atypical MLMS case with radiologic-pathologic correlation. The patient was a 46-year-old woman with a chief complaint of low abdominal pain. The tumor was a pedunculated mass arising from the right anterior wall of the uterus that included a low-SI tumor-like component that partially transitioned into a peripheral high-SI component on T2WI and was diagnosed as hydropic leiomyoma. After 3 cycles of GnRHa therapy, the tumor size increased along with the size of the peripheral high-SI component on T2WI, while the size of the low-SI tumor-like component decreased. A small markedly low-SI area on both T1 and T2WI and a subtle high-SI area on fat-saturated T1WI indicating hemorrhage were present within the tumor. Pathologically, not only the peripheral high-SI component but also the low-SI tumor-like component on T2WI corresponded to MLMS, and the high-SI component was associated mainly with edematous change rather than myxoid change. MLMS may initially show low SI on T2WI and change to high SI mainly due to edematous change with rapid growth. Intratumoral hemorrhage might be the only key feature to differentiates MLMS from hydropic leiomyoma.

Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms. Through quantitative 13C metabolic flux analysis of glucose metabolism using high-sensitivity glucose tracing and mathematical modeling, we found that HSCs activate the glycolytic rate-limiting enzyme phosphofructokinase (PFK) during proliferation and oxidative phosphorylation (OXPHOS) inhibition. Real-time measurement of ATP levels in single HSCs demonstrated that proliferative stress or OXPHOS inhibition led to accelerated glycolysis via increased activity of PFKFB3, the enzyme regulating an allosteric PFK activator, within seconds to meet ATP requirements. Furthermore, varying stresses differentially activated PFKFB3 via PRMT1-dependent methylation during proliferative stress and via AMPK-dependent phosphorylation during OXPHOS inhibition. Overexpression of Pfkfb3 induced HSC proliferation and promoted differentiated cell production, whereas inhibition or loss of Pfkfb3 suppressed them. This study reveals the flexible and multilayered regulation of HSC glycolytic metabolism to sustain hematopoiesis under stress and provides techniques to better understand the physiological metabolism of rare hematopoietic cells.

Abstract Background Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy. Methods This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC. Results The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3–4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3–4 hematologic toxicities were vitamin B12 level T). Risk factors for Grades 2–4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A]. Conclusion The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed. Trial registration This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

Although imaging studies are not typically performed for clinical diagnosis of cervicitis, in this case magnetic resonance imaging (MRI) was performed because a lesion with a tumor-like gross appearance was found in the uterine cervix. We present a case of cervicitis in which clinical, imaging and pathological features overlapped with those of gastric-type mucinous adenocarcinoma (GAS). The patient, a 30-year-old woman, was referred to a gynecologist with a complaint of watery vaginal discharge. On visual examination, the uterine cervix was irregularly enlarged and bled easily, suggesting cervical cancer. The next day, the patient had a fever of 39°C and blisters appeared on her vulva due to herpes simplex virus type II infection. MRI showed a diffusely enlarged cervix with poorly marginated high signal intensity on T2-weighted imaging (WI) and apparent diffusion coefficient map as well as strong enhancement on contrast-enhanced T1WI, which are findings consistent with GAS. Although a punch biopsy showed only mild atypia of the cervical glands, this was not enough to completely rule out GAS. Consequently, laser conization of the lesion was performed for definitive diagnosis, and the diagnosis of cervicitis was made. Acute cervicitis can be difficult to differentiate from GAS based on symptoms, results of cervical biopsy and MR imaging because of their overlapping features. Even when a patient presents with a lesion with tumor-like gross appearance, acute cervicitis should be included in the differential diagnosis if the result of cervical biopsy is negative, especially when accompanied by infection-like fever.

Abstract We discuss the 5d AGT correspondence of supergroup gauge theories with A-type supergroups. We introduce two intertwiners called positive and negative intertwiners to compute the instanton partition function. The positive intertwiner is the ordinary Awata-Feigin-Shiraishi intertwiner while the negative intertwiner is an intertwiner obtained by using central charges with negative levels. We show that composition of them gives the basic Nekrasov factors appearing in supergroup partition functions. We explicitly derive the instanton partition functions of supergroup gauge theories with A and D-type quiver structures. Using the intertwiners, we briefly study the Gaiotto state, qq-characters and the relation with quiver W-algebra. Furthermore, we show that the negative intertwiner corresponds to the anti-refined topological vertex recently defined by Kimura and Sugimoto. We also discuss how superquiver theories should appear in our formalism if they exist. The existence of the AGT correspondence of the theories we study in this paper implies that there is a broader 2d/4d (5d/q-algebra) correspondence, or more generally the BPS/CFT correspondence, where new non-unitary theories play important roles.

Pulmonary hamartomas are common benign lung tumors; however, endobronchial hamartomas are relatively rare. We report a case of asymptomatic endobronchial hamartoma in a 51-year-old man. Chest computed tomography revealed a 10-mm protrusion in the right main bronchus. Preoperative virtual bronchoscopy (VBS) was performed; subsequently, minimally invasive bronchoscopic resection was safely performed under local anesthesia. The use of VBS is a useful treatment strategy and follow-up modality.

Summary: Background: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. Methods: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. Findings: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. Interpretation: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. Funding: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

To maintain homeostasis, many tissues contain stem cells that can self-renew and differentiate. Based on these functions, stem cells can reconstitute the tissue even after injury. In reproductive organs, testes have spermatogonial stem cells that generate sperm in men throughout their lifetime. However, in the ovary, oocytes enter meiosis at the embryonic stage and maintain sustainable oogenesis in the absence of stem cells. After birth, oocytes are maintained in a dormant state in the primordial follicle, which is the most premature follicle in the ovary, and some are activated to form mature oocytes. Thus, regulation of dormancy and activation of primordial follicles is critical for a sustainable ovulatory cycle and is directly related to the female reproductive cycle. However, oocyte storage is insufficient to maintain a lifelong ovulation cycle. Therefore, the ovary is one of the earliest organs to be involved in aging. Although stem cells are capable of proliferation, they typically exhibit slow cycling or dormancy. Therefore, there are some supposed similarities with oocytes in primordial follicles, not only in their steady state but also during aging. This review aims to summarise the sustainability of oogenesis and aging phenotypes compared to tissue stem cells. Finally, it focuses on the recent breakthroughs in vitro culture and discusses future prospects.

Abstract Recently, Li and Yamazaki proposed a new class of infinite-dimensional algebras, quiver Yangian, which generalizes the affine Yangian gl $$ \mathfrak{gl} $$ 1. The characteristic feature of the algebra is the action on BPS states for non-compact toric Calabi-Yau threefolds, which are in one-to-one correspondence with the crystal melting models. These algebras can be bootstrapped from the action on the crystals and have various truncations. In this paper, we propose a q-deformed version of the quiver Yangian, referred to as the quiver quantum toroidal algebra (QQTA). We examine some of the consistency conditions of the algebra. In particular, we show that QQTA is a Hopf superalgebra with a formal super coproduct, like known quantum toroidal algebras. QQTA contains an extra central charge C. When it is trivial (C = 1), QQTA has a representation acting on the three-dimensional crystals, like Li-Yamazaki’s quiver Yangian. While we focus on the toric Calabi-Yau threefolds without compact 4-cycles, our analysis can likely be generalized to all toric Calabi-Yau threefolds.

Abstract Recently, new classes of infinite-dimensional algebras, quiver Yangian (QY) and shifted QY, were introduced, and they act on BPS states for non-compact toric Calabi-Yau threefolds. In particular, shifted QY acts on general subcrystals of the original BPS crystal. A trigonometric deformation called quiver quantum toroidal algebra (QQTA) was also proposed and shown to act on the same BPS crystal. Unlike QY, QQTA has a formal Hopf superalgebra structure which is useful in deriving representations. In this paper, we define the shifted QQTA and study a class of their representations. We define 1d and 2d subcrystals of the original 3d crystal by removing a few arrows from the original quiver diagram and show how the shifted QQTA acts on them. We construct the 2d crystal representations from the 1d crystal representations by utilizing a generalized coproduct acting on different shifted QQTAs. We provide a detailed derivation of subcrystal representations of ℂ3, ℂ3 /ℤ n (n ≥ 2), conifold, suspended pinch point, and ℂ3 /(ℤ2 × ℤ2).

Abstract Background Adenosarcoma is classified as a mixed epithelial and mesenchymal tumor composed of a benign epithelial component and a malignant stromal component. The stromal component in adenosarcoma is usually low grade, and consequently the prognosis is relatively favorable. While, adenosarcoma with sarcomatous overgrowth (SO) is defined as an adenosarcoma in which the sarcomatous component constitutes more than 25% of the tumor. The stromal component is also high-grade sarcoma showing greater nuclear pleomorphism and mitotic activity, thus, it is associated with worse prognosis. MRI findings of adenosarcoma without SO have been described in previous literatures but the imaging findings in adenosarcoma with SO may be poorly defined. Therefore we present two cases of uterine adenosarcoma with SO. Case presentation Patient 1 was a 76-year-old woman referred to our hospital with complaint of abdominal distension and postmenopausal bleeding. Patient 2 was a 57-year-old woman with complaint of lower abdominal pain and abnormal uterine bleeding. On magnetic resonance imaging (MRI), T2 weighted imaging showed a large, heterogeneous high-intensity mass with hyperintense tiny cysts that expanded the uterine cavity and extended into the cervical canal for both patients. On diffusion-weighted imaging (DWI), both masses appeared as high signal intensity. Patient 2 also had a right ovarian adult granulosa cell tumor that may have contributed to development of the adenosarcoma. Patient 1 recurred with peritoneal sarcomatosis 6 months after surgery and died of the disease. Patient 2 also recurred with a left upper lung metastasis 3 months after surgery. Conclusions DWI may depict pathological changes produced by SO of adenosarcoma as high signal intensity, even though SO does not seem to change MRI findings of adenosarcoma on other sequences. Therefore, DWI could potentially predict SO in presumptive adenosarcoma on MRI and the patient’s prognosis. It is also important for pathologists to know if SO can arise in adenosarcoma because they need to examine the tumor thoroughly to determine the percentage of SO component in the tumor volume when SO is present.

Abstract Docetaxel is a cytotoxic taxane frequently used to treat patients with various cancers, including non‐small cell lung cancer (NSCLC). Docetaxel is known to cause acute myalgias, arthralgias, and neuropathy, but there have been few published case reports of myositis. Here, we describe a rare case of docetaxel‐induced myositis diagnosed based on laboratory data, thigh magnetic resonance imaging (MRI), and electromyography (EEG). A 66‐year‐old male was admitted for thigh pain and fatigue that onset 1 week prior. He had been diagnosed with stage IVA (cT4N0M1a) NSCLC 3 years ago and had been started on docetaxel (60 mg/m2 intravenously every 3 weeks; fourth‐line chemotherapy) 1 month earlier. After the second cycle, he developed both thigh pain and fatigue. On admission, his creatinine phosphokinase (CPK) level was elevated, thigh MRI revealed diffuse muscle edema, and EEG showed myogenic changes. We found no plausible cause for myositis except docetaxel. He was diagnosed with myositis and treated with oral prednisolone. His symptoms were relieved and the CPK level declined. Although rare, this case indicates that clinicians should consider the possibility of myositis as a complication in patients on docetaxel.

Abstract Background Surgeons sometimes have difficulty determining which result to favor when preoperative results (MRI + preoperative endometrial biopsy [pre-op EB]) differ from intraoperative frozen section histology (FS) results. Investigation of how FS can complement ordinary preoperative examinations like MRI and pre-op EB in identification of patients at high risk of lymph node metastasis (high-risk patients) could provide clarity on this issue. Therefore, the aim of this study is to assess the utility of pre-op EB, MRI and FS results and determine how to combine these results in identification of high-risk patients. Methods The subjects were 172 patients with endometrial cancer. Patients with a histological high-grade tumor (HGT), namely, grade 3 endometrioid cancer, clear cell carcinoma or serous cell carcinoma, or with any type of cancer invading at least half of the uterine myometrium were considered high-risk. Tumors invading at least half of the uterine myometrium were classified as high-stage tumors (HST). We compared (a) detection of HGT using pre-op EB versus FS, (b) detection of HST using MRI versus FS, and (c) identification of high-risk patients using MRI + pre-op EB versus FS. Lastly, we determined to what degree addition of FS results improves identification of high-risk patients by routine MRI + pre-op EB. Results (a) Sensitivity, specificity, and accuracy for detecting HGT were 59.6, 98.4 and 87.8% for pre-op EB versus 55.3, 99.2 and 87.2% for FS (P = 0.44). (b) These figures for detecting HST were 74.4, 83.0 and 80.8% for MRI versus 46.5, 99.2 and 86.0% for FS (P < 0.001). (c) These figures for identifying high-risk patients were 78.3, 85.4 and 82.6% for MRI + pre-op EB versus 55.1, 99.0 and 81.2% for FS (P < 0.001). The high specificity of FS improved the sensitivity of MRI + pre-op EB from 78.3 to 81.2%, but this difference was not statistically significant (P < 0.16). Conclusion Frozen section enables identification of high-risk patients with nearly 100% specificity. This advantage can be used to improve sensitivity for identification of high-risk patients by routine MRI + pre-op EB, although this improvement is not statistically significant.

Pro-opiomelanocortin (POMC)-expressing neurons in the hypothalamic arcuate nucleus (ARC) play key roles in feeding and energy homoeostasis, hence their development is of great research interest. As the process of neurogenesis is accompanied by changes in adhesion, polarity, and migration that resemble aspects of epithelial-to-mesenchymal transitions (EMTs), we have characterised the expression and regulation within the prospective ARC of transcription factors with context-dependent abilities to regulate aspects of EMT. Informed by pseudotime meta-analysis of recent scRNA-seq data, we use immunohistochemistry and multiplex in situ hybridisation to show that SOX2, SRY-Box transcription factor 9 (SOX9), PROX1, Islet1 (ISL1), and SOX11 are sequentially expressed over the course of POMC neurogenesis in the embryonic chick. Through pharmacological studies ex vivo, we demonstrate that while inhibiting either sonic hedgehog (SHH) or Notch signalling reduces the number of SOX9+ neural progenitor cells, these treatments lead, respectively, to lesser and greater numbers of differentiating ISL1+/POMC+ neurons. These results are consistent with a model in which SHH promotes the formation of SOX9+ progenitors, and Notch acts to limit their differentiation. Both pathways are also required to maintain normal levels of proliferation and to suppress apoptosis. Together our findings demonstrate that hypothalamic neurogenesis is accompanied by dynamic expression of transcription factors (TFs) that mediate EMTs, and that SHH and Notch signalling converge to regulate hypothalamic cellular homoeostasis.

Summary: Our understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

Abstract A 62‐year‐old woman with rheumatoid arthritis and a history of receiving immunosuppressant therapy had a recurrence of lung adenocarcinoma with EGFR L858R mutation. Following 14 months of treatment with erlotinib, computed tomography (CT) findings revealed the presence of small diffuse nodules. Bronchoscopy was performed as metastasis was suspected; however, this was not detected on lung biopsy with forceps. Transbronchial lung cryobiopsy (TBLC) succeeded in detecting metastatic adenocarcinoma, and T790M and L858R gene mutations. Pathological examination revealed a cluster of tumor cells in the intralobular interstitial areas, which was consistent with the CT findings. This report provides important information regarding the role of TBLC in diagnosing metastatic cancer, such as diffuse small miliary nodules, and its genetic mutations.

In female reproduction, the oocyte number is limited after birth. To achieve a continuous ovulatory cycle, oocytes are stored in primordial follicles. Therefore, the regulation of primordial follicle dormancy and activation is important for reproductive sustainability, and its collapse leads to premature ovarian insufficiency. In this review, we summarize primordial follicle development and the molecular mechanisms underlying primordial follicle maintenance and activation in mice. We also overview the mechanisms discovered through in vitro culture of functional oocytes, including the establishment of primordial follicle induction by environmental factors, which revealed the importance of hypoxia and compression by the extra cellular matrix (ECM) for primordial follicle maintenance in vivo.

Abstract Recently, Gaiotto and Rapcak proposed a generalization of W N algebra by considering the symmetry at the corner of the brane intersection (corner vertex operator algebra). The algebra, denoted as Y L,M,N , is characterized by three non-negative integers L, M, N. It has a manifest triality automorphism which interchanges L, M, N, and can be obtained as a reduction of W 1+∞ algebra with a “pit” in the plane partition representation. Later, Prochazka and Rapcak proposed a representation of Y L,M,N in terms of L + M + N free bosons by a generalization of Miura transformation, where they use the fractional power differential operators. In this paper, we derive a q-deformation of the Miura transformation. It gives a free field representation for q-deformed Y L,M,N , which is obtained as a reduction of the quantum toroidal algebra. We find that the q-deformed version has a “simpler” structure than the original one because of the Miki duality in the quantum toroidal algebra. For instance, one can find a direct correspondence between the operators obtained by the Miura transformation and those of the quantum toroidal algebra. Furthermore, we can show that the both algebras share the same screening operators.

Abstract Background Many animals switch between asexual and sexual reproduction in nature. We previously established a system for the sexual induction of planarian Dugesia ryukyuensis by feeding asexual planarians with minced sexual planarians. We identified dl-tryptophan (Trp) as one of the sex-inducing substances. dl-Trp can induce ovarian development, the first and essential step of sexual induction. d-Trp must act as a principal bioactive compound in terms of ovarian development, because the ovary-inducing activity of d-Trp was 500 times more potent than that of l-Trp. However, how Trp controls sexual induction is still unknown. Results In this study, qRT-PCR analyses suggested that the putative amino acid transporter gene Dr-SLC38A9 is highly expressed in sexual worms, especially in the yolk glands. In situ hybridization analyses showed that Dr-SLC38A9 is expressed in the ovarian primordia of asexual worms and in the mature ovaries, testes, and yolk glands of sexual worms. In addition, Dr-SLC38A9 RNA interference during sexual induction resulted in the suppression of the development of reproductive organs. These results suggest that Dr-SLC38A9 is involved in the development of these organs. Moreover, we demonstrated that the reproductive organ-specific expression of Dr-SLC38A9 is enhanced by the addition of d-Trp. Conclusion We propose that d-Trp activates the expression of Dr-SLC38A9 to promote sexual induction in the planarian D. ryukyuensis.

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. Conclusion Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

Abstract Immune checkpoint inhibitors (ICIs) are reportedly effective against many kinds of neoplasm, but may be responsible for several kinds of immune‐related adverse events (irAEs). Among these irAEs, the incidence of myelosuppression due to ICIs is relatively low. Corticosteroids are needed to control most cases of myelosuppression. Here, we report an 88‐year‐old woman with squamous cell lung cancer who was administered pembrolizumab. After five cycles of pembrolizumab, she developed severe pancytopenia. The pancytopenia improved under observation without steroid administration after cessation of pembrolizumab. During recovery from this irAE, the patient also maintained long‐term antitumor efficacy. Key points Significant findings of the study There are several kinds of immune‐related adverse events. We encountered a case of pembrolizumab‐induced pancytopenia with squamous cell lung cancer. What this study adds Corticosteroids are needed to control most cases of myelosuppression induced by ICIs, but pancytopenia induced by pembrolizumab in our case improved without steroids.