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Background: Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient's immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets., Methods: We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed., Results: We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1 + and CTLA4 + myeloid subsets within tumors at baseline, PDL1 + , B7H3 + and CD115 + myeloid subsets in peripheral blood at baseline, and LAG3 + , CD155 + and CD115 + myeloid subsets in peripheral blood at post-treatment., Conclusions: This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC., Competing Interests: Competing interests: HS received research grants from Ono Pharmaceutical and Takeda Pharmaceutical, and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. CK-S received a grant from Chiome Bioscience, and honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. KN received honoraria from Pfizer, Fujimoto Pharmaceutical, Senju Pharmaceutical, and Toray. HI received honoraria from Ono Pharmaceutical. NT received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, and Taiho Pharmaceutical. TK received honoraria from Ono Pharmaceutical and Bristol-Myers Squibb. NO received honoraria from Taiho Pharmaceutical, Eli Lilly Japan, Eisai, Bayer, Chugai Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, and GlaxoSmithKline. YN received honoraria from Eli Lilly, Daiichi Sankyo, Taiho, Ono Pharmaceutical, and Bristol-Myers Squibb. YY received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, Taiho, Sanofi, Yakult, Nihon Servier, Lilly, Asahi Kasei Parma. KA received grants from Ono Pharmaceutical, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, and Chiome Bioscience. KM received honoraria from Amgen, AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Daiichi Sankyo, Taiho, and Bristol-Myers Squibb. NB received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Eli Lilly, and Daiichi Sankyo. Other authors have no competing financial interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib., Methods: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/μL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression., Results: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019)., Conclusion: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer., (© 2024. The Author(s).)

Purpose: Taxanes are widely used chemotherapeutic agents that frequently cause nail changes and have a significant impact on patients' quality of life. Despite the prevalence of taxane-induced nail toxicity, limited data are available regarding evidence-based management strategies for the prevention or treatment of taxane-induced nail changes. Therefore, we aimed to gain insights into the prevention, treatment, and evaluation of nail changes in patients with cancer in Japan by conducting a questionnaire survey of physicians, pharmacists, and nurses involved in oncology treatment., Methods: The questions addressed prophylactic methods, evaluation practices, and treatment approaches for various nail disorders. The questionnaires were distributed on March 1, 2022, with a response deadline of December 1, 2022., Results: Of the 120 questionnaires distributed, 88 (73.3%) were returned, and all of them were analyzed. The respondents included 69 physicians (32 oncologists, 26 breast surgeons, 6 dermatologists, 3 obstetricians/gynecologists, 1 gastroenterological surgeon, and 1 urologist), 9 pharmacists, and 10 nurses. Prophylactic measures included moisturizing (58.0%), protection (42.0%), cooling therapy (37.5%), and cleanliness (33.0%). Approximately 70% of the respondents used the Common Criteria for Adverse Events (CTCAE), while approximately 30% did not use a specific evaluation method. Opinions regarding treatment with antimicrobial or corticosteroid ointments varied; however, all severe cases were referred by dermatologists., Conclusion: Our survey revealed that the management of chemotherapy-induced nail changes varies in clinical practice in Japan. These findings emphasize the need for standardized management strategies and further research., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute lung injury (ALI) is characterized by respiratory failure resulting from the disruption of the epithelial and endothelial barriers as well as immune system. In this study, we evaluated the therapeutic potential of airway epithelial cell-derived extracellular vesicles (EVs) in maintaining lung homeostasis. We isolated human bronchial epithelial cell-derived EVs (HBEC-EVs), which endogenously express various immune-related surface markers and investigated their immunomodulatory potential in ALI. In ALI cellular models, HBEC-EVs demonstrated immunosuppressive effects by reducing the secretion of proinflammatory cytokines in both THP-1 macrophages and HBECs. Mechanistically, these effects were partially ascribed to nine of the top 10 miRNAs enriched in HBEC-EVs, governing toll-like receptor-NF-κB signaling pathways. Proteomic analysis revealed the presence of proteins in HBEC-EVs involved in WNT and NF-κB signaling pathways, pivotal in inflammation regulation. ANXA1, a constituent of HBEC-EVs, interacts with formyl peptide receptor (FPR)2, eliciting anti-inflammatory responses by suppressing NF-κB signaling in inflamed epithelium, including type II alveolar epithelial cells. In a mouse model of ALI, intratracheal administration of HBEC-EVs reduced lung injury, inflammatory cell infiltration, and cytokine levels. Collectively, these findings suggest the therapeutic potential of HBEC-EVs, through their miRNAs and ANXA1 cargo, in mitigating lung injury and inflammation in ALI patients., (© 2024. The Author(s).)

Background: The Chemotherapy-induced Alopecia Distress Scale (CADS) is a patient-reported outcome measure for assessing distress associated with Chemotherapy-induced alopecia (CIA). This study aimed to confirm the psychometric validity of the Japanese version of the CADS (CADS-J)., Methods: A total of 132 patients with breast cancer who developed CIA were asked to complete the CADS-J twice at 2 week intervals to confirm test-retest reliability. The body image domain of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) breast cancer-specific module, the self-esteem scale from the Rosenberg Self-Esteem Scale, and the emotional domain of the EORTC QLQ Core 30 were used to confirm the convergent validity of the CADS-J. The overall quality of life and physical domains of the EORTC QLQ Core 30 were used to confirm the discriminant validity of the CADS-J., Results: In total, 125 participants provided valid responses. The mean age was 52.2 years. The overall Cronbach's alpha for the CADS-J was 0.903. The intraclass correlation coefficients of the first and second responses were r = 0.874, r = 0.952, r = 0.911, and r = 0.959 for the physical domain, emotional domain, activity domain, and relationship domain, respectively. In terms of convergent validity, the total CADS-J score was moderately correlated with body image (r = - 0.63), self-esteem (r = - 0.48), and the emotional domain (r = - 0.61). Regarding discriminant validity, the total CADS-J score was weakly correlated with the overall quality of life (r = - 0.34) and physical domain (r = - 0.24)., Conclusions: The CADS-J is psychometrically reliable and valid for evaluating the distress caused by CIA. It is expected to be used in daily practice and as an endpoint in various studies., (© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Aortitis is a rare adverse event associated with granulocyte colony-stimulating factor (G-CSF). Contrast-enhanced computed tomography (CECT) is widely used to diagnose G-CSF-associated aortitis. However, the usefulness of gallium scintigraphy for the diagnosis of G-CSF-associated aortitis is unknown. We herein report a set of pre- and post-treatment gallium scintigrams of a patient with G-CSF-associated aortitis. During the diagnosis, gallium scintigraphy revealed hot spots on the arterial walls that appeared inflamed on CECT. Both the CECT and gallium scintigraphy findings disappeared. Gallium scintigraphy can be a supportive diagnostic tool for G-CSF-associated aortitis, especially in patients with an impaired renal function or allergy to iodine contrast.

Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease with a poor prognosis. Despite extensive research, the cause of IPF remains largely unknown and treatment strategies are limited. Proposed mechanisms of the pathogenesis of IPF are a combination of excessive accumulation of the extracellular matrix and dysfunctional lung tissue regeneration. Epithelial cell dysfunction, in addition to fibroblast activation, is considered a key process in the progression of IPF. Epithelial cells normally maintain homeostasis of the lung tissue through regulated proliferation, differentiation, cell death, and cellular senescence. However, various stresses can cause repetitive damage to lung epithelial cells, leading to dysfunctional regeneration and acquisition of profibrotic functions. The Hippo pathway is a central signaling pathway that maintains tissue homeostasis and plays an essential role in fundamental biological processes. Dysregulation of the Hippo pathway has been implicated in various diseases, including IPF. However, the role of the Hippo pathway in the pathogenesis of IPF remains unclear, particularly given the pathway's opposing effects on the 2 key pathogenic mechanisms of IPF: epithelial cell dysfunction and fibroblast activation. A deeper understanding of the relationship between the Hippo pathway and the pathogenesis of IPF will pave the way for novel Hippo-targeted therapies., (© 2023. Japanese Society of Inflammation and Regeneration.)

Background/aim: Synchronous colorectal cancer, which occurs in approximately 4.8-8.4% of all colorectal cancers, has a genetic profile with a higher rate of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and microsatellite instability-high than solitary colorectal cancer. However, little information is available on heterogeneity among tumor lesions because of difficulty in performing genetic tests in all lesions in clinical practice., Case Report: A 44-year-old man presented with multiple recurrent lung metastases 42 months after the endoscopic resection of early stage synchronous ascending and sigmoid colon cancers. The genetic testing of sigmoid colon cancer tissue samples, their state being more advanced than that of ascending colon cancer, revealed a v-Ki-ras 2 Kirsten rat sarcoma viral oncogene homolog mutation (G13C) and BRAF wild type. However, the tumor was refractory to initial chemotherapy and rapidly progressed to new liver metastases. Therefore, we suspected that there may be biological heterogeneity between the primary sigmoid colon lesion and liver metastases. Next, we performed next-generation sequencing on circulating tumor DNA from the patient's plasma (Foundation One Liquid CDx ® ), which revealed the V600E mutation of BRAF, suggesting that there was genetic heterogeneity among the synchronized primary lesions, one of which was responsible for the chemo-refractory rapid-growing liver metastases., Conclusion: Genetic profiling with liquid biopsy at the time of recurrence and metastasis may be useful in patients with multiple synchronous cancers because there is less heterogeneity between primary and metastatic sites., Competing Interests: All Authors have no competing financial interests to declare, except for Y. Miura, who reports receiving honoraria from ONO Pharmaceutical, Bristol-Myers Squibb, MSD, Eisai, and Takeda separate from the submitted work., (Copyright 2023, International Institute of Anticancer Research.)

Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargo-mediated fibroblast-tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.

Purpose: This systematic review aimed to investigate the efficacy of telemedicine (TM) using videoconferencing systems in outpatient care for patients with cancer., Methods: We searched six electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, ICTRP, and ClinicalTrials.gov) through June 2021 to identify randomized controlled trials that evaluated the use of TM using videoconferencing systems compared with usual face-to-face care in outpatient care for patients with cancer. We assessed the certainty of evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation., Results: From the 2,400 articles screened, six randomized controlled trials were eligible for this study. Two studies evaluated the use of TM in cancer follow-up and four investigated psychotherapy for cancer. TM using videoconferencing systems may result in no differences in primary outcomes such as patient satisfaction (standardized mean difference, 0.11; 95% CI, -0.18 to 0.40) and outpatient attendance complete proportion (risk difference, 0.02%; 95% CI, -0.04 to 0.09), and secondary outcomes such as medical professional satisfaction, time devoted to outpatient care, and depression score. The certainty of evidence for these outcomes was low. Although the average money spent on outpatient visit was a primary outcome, the level of evidence was uncertain., Conclusion: Our results suggest that TM using videoconferencing systems in outpatient care for patients with cancer may be as effective as usual face-to-face care. Use of TM more frequently may be considered for patients with cancer who are expected to obtain benefit from TM using videoconference systems.

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR-expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C-terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ-EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ-targeting therapy for liver cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Competing Interests: Declaration of interests YM has received honoraria from Bristol-Myers Squibb, MSD, and Takeda for lectures; has been on advisory boards for Takeda and Chugai Pharmaceutical; and has received research grants from MSD and Ono Pharmaceutical. All other authors declare no competing interests.

A 60-year-old man developed aphasia and transient right upper limb paresis in the presence of chronic subdural hematoma and was transferred to our hospital at an early stage. Cranial MRI within an hour after onset showed diffusion-weighted image (DWI) hyperintensity in the left parietal, temporal, and insular cortex and the pulvinar, and decreased apparent diffusion coefficient (ADC) in the left parietal cortex and pulvinar, suggesting a differential diagnosis of hyper-acute ischemic stroke. However, the distribution and timing of the MRI abnormalities were considered to be atypical for hyper-acute ischemic stroke. The area with both DWI hyperintensity and decreased ADC included the cerebral cortex adjacent to the hematoma and the ipsilateral pulvinar, and fluid-attenuated inversion recovery (FLAIR) hyperintensity co-existed with DWI hyperintensity within only an hour from onset. Furthermore, FLAIR images showed infiltration of the hematoma content into the subarachnoid space, which might have triggered the attack. These findings collectively led us to diagnose an epileptic seizure. The present case suggests that the distribution and timing of MRI abnormalities are essential to differentiate epileptic seizures from hyper-acute ischemic stroke.

Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. PKCδ is known to be a multifunctional PKC family member and has been rigorously studied as an intracellular signaling molecule. Here we show that PKCδ is a secretory protein that regulates cell growth of liver cancer. Full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKCδ secretion was executed in an endoplasmic reticulum (ER)-Golgi-independent manner, and the inactivation status of cytosolic PKCδ was required for its secretion. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody attenuated activation of both IGF1R and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKCδ at the extracellular space and the function of PKCδ as a growth factor and provides a rationale for the extracellular PKCδ-targeting therapy of liver cancer. SIGNIFICANCE: PKCδ secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets., (©2020 American Association for Cancer Research.)

Malignant spinal cord compression(MSCC)is defined as a compression of the spinal cord or cauda equina with neuropathy caused by tumor spreading to the vertebral body. The common symptoms of MSCC are back pain, neck pain, muscle weakness, sensory reduction, bladder and rectal disturbance. The risk of MSCC is relatively high in patients with lung cancer, breast cancer, and prostate cancer. MSCC is one of the oncologic emergencies that requires prompt diagnosis and treatment to preserve and improve neurological function. Evaluation by magnetic resonance imaging(MRI)and computed tomography( CT)are useful for the diagnosis. The prognosis of these patients is often poor at the time of diagnosis of MSCC, thus it is important for deciding the treatment strategy to consider the prognosis and background of the patient in addition to the objective findings including the degree of MSCC and spinal instability. Treatment options consist of medical, surgical, and radiation therapy. We need a multidisciplinary approach because the pathology of MSCC involves multiple departments, such as medical oncology, orthopedics, and radiology. Supportive care including rehabilitation and preventing skeletal related events are also important. The cancer board, in which each physician and multidisciplinary health care professionals regularly have a discussion and review the cases, is required.

Background: While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy., Methods: To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions., Results: The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF., Conclusions: We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

The amino acid sequences of human, porcine, and bovine erythrocyte cytochromes b5 which are soluble and present in the cytosol have been determined. In addition, the partial sequences of microsome-bound liver cytochrome b5, namely the sequence of the N-terminal region and joint region between the heme-containing and membranous part, have been established for human and porcine sources. All the cytochromes b5 from erythrocyte and liver contained N-acetylated N-termini. Of the 97 amino acid residues of erythrocyte cytochrome b5, residues 1-96 were identical with those of the liver protein of the same species. However, residue 97 (C-terminal residue) was proline for human erythrocyte cytochrome b5 and serine for the porcine protein, while residues 97 (joint region) of human and porcine liver cytochromes b5 were threonine. These findings indicate that the two forms of cytochrome b5 are encoded by two different but closely related mRNAs.