Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions.

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

Case of Incomplete Kawasaki Disease with No Symptoms Except Fever Causing the Development of Coronary Aneurysm.

Incomplete Kawasaki disease (iKD), which does not satisfy the standard KD diagnostic criteria because the required number of principal symptoms is not met, sometimes causes coronary aneurysms. Here we report the case of a patient with iKD who presented with only one principal symptom that resulted in the development of coronary aneurysm, as evidenced by angiography.

PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer.

The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.

Epithelial-mesenchymal transition is activated in CD44-positive malignant ascites tumor cells of gastrointestinal cancer.

Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.

10-year follow-up of congenital cytomegalovirus infection complicated with severe neurological findings in infancy: a case report.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection leads to sensorineural hearing loss (SNHL) and neurodevelopmental delays. However, the long-term outcomes of cCMV infection with severe neurological manifestations in infancy remain unclear. CASE PRESENTATION: The patient was a one-month-old girl visited owing to abnormalities in neonatal hearing screening. Central nervous system involvement including intracranial calcification and extensive white matter abnormalities was identified. Right SNHL (50 dB) was detected by auditory brain response (ABR) testing. The cause of her hearing loss was determined to be cCMV infection by polymerase chain reaction (PCR) using a dried blood spot. At 1.5 months of age, the patient was treated with intravenous ganciclovir (GCV) for 5 weeks followed by oral valganciclovir (VGCV) for an additional 6 weeks. Cytomegalovirus (CMV) loads in her urine continued to be detected until she was 10 years old. Fortunately, during this time, her right hearing loss did not deteriorate, and her left hearing remained normal. Furthermore, the extensive abnormal areas of white matter observed at 1 month of age mostly disappeared by the time the patient was 9 years old. Her neurodevelopmental score was normal, and motor milestones were not delayed as of 10 years of age. CONCLUSIONS: Here, we report the 10-year follow-up of a patient with cCMV who showed normal neurodevelopment, no progression of hearing loss, and ameliorating magnetic resonance imaging (MRI) findings, despite having various complications and severe neurological findings during infancy.

First Pediatric Case of Infective Endocarditis Caused by Serratia Liquefaciens.

Infective endocarditis (IE) caused by Serratia liquefaciens has been reported in only 2 adults. We experienced the first pediatric (neonatal) case of IE caused by S. liquefaciens, with mitral valve vegetation 4 days after a palliative heart surgery. This report underscores the importance of treating for both gram-positive and gram-negative bacteria in IE cases until the blood cultures elucidate the details.

Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer.

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R=0.429), whereas EETS and DPR were less correlated with OS (R=0.0682, 0.186). EETS was well correlated with DPR (R=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

Afebrile Kawasaki disease with coronary artery dilatation.

Herein we describe the cases of two afebrile patients who were thought to have Kawasaki disease (KD). Patient 1 was a 7-month-old-Japanese girl. She presented with bulbar conjunctival injection, diarrhea, skin erythema, and redness around the bacillus Calmette-Guerin (BCG) inoculation site. Thirteen days after the first symptoms, ultrasonic cardiogram (UCG) showed dilatations of the bilateral coronary arteries (CA). The dilatations had completely resolved 5 months later. Patient 2 was a 13-month-old Japanese boy. He first presented with bulbar conjunctival injection and redness around the BCG inoculation site. Twenty-two days after the first symptoms, UCG indicated bilateral and peripheral CA dilatations. The mild dilatations of the proximal CA remained. Although fever is the principal symptom of KD, some incomplete KD patients may be afebrile. Although it is difficult to diagnose these patients as having KD, redness at the BCG inoculation site may be a clue to the diagnosis.

Clinical analysis and outcome of interstitial lung disease complicated with juvenile dermatomyositis and juvenile polymyositis.

OBJECTIVES: The aim of this study was to determine the clinical phenotype and outcome of interstitial lung disease (ILD) complicated with juvenile dermatomyositis (JDM) or juvenile polymyositis (JPM). METHODS: This was a single-center retrospective study. From 1984 to 2015, we retrospectively reviewed 29 patients who were diagnosed with JDM/JPM, among whom eight cases were ILD and 21 were non-ILD. The clinical features and laboratory findings included chest computed tomography (CT) images that were compared between the patients with ILD and non-ILD. RESULTS: Eight cases (27.6%) were complicated with ILD. The mean age was 6.3 years, and 75% of the patients were women. We found that high fever, arthralgia, muscle weakness, and high serum Krebs von den Lungen-6 (KL-6) level were significantly associated with the presence of ILD (p < 0.05). Two patients were positive for the anti-Jo-1 antibody, and two other patients were positive for the anti-MDA5 antibody. Three cases were identified as rapidly progressive (RP)-ILD. The chest CT images of the ILD patients appeared to show ground glass opacity (GGO) with a lower lobe predominance, reticulation, and traction bronchiectasis consolidation. Three patients with RP-ILD showed random subpleural GGO with/without consolidation patterns. Further, three patients with RP-ILD died of respiratory failure (p < 0.01). CONCLUSION: ILD is one of the most serious complications of JDM/JPM. In the early phase of ILD, high levels of serum KL-6 can be detected, regardless of the respiratory symptoms. Additionally, RP-ILD can be predicted based on the presence of anti-MDA5 antibodies and the chest CT findings, including random subpleural GGO with/without consolidation patterns.

Current perspectives of viral hepatitis.

Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. There remain few options for treatment, in spite of the increasing prevalence of viral-hepatitis-caused liver disease. Furthermore, chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality, even though effective treatments are available that could reduce or prevent most patients' complications. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030, along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. However, future therapies must be extremely safe, and should ideally limit the period of treatment necessary. A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize the current state of knowledge on each type of viral hepatitis, together with major innovations.

Clinical and immunophenotypic features of atypical complete DiGeorge syndrome.

BACKGROUND: DiGeorge syndrome is a congenital malformation characterized by variable defects of the thymus, heart and parathyroid glands. Athymic patients are classified as exhibiting complete DiGeorge syndrome. Some of these patients may also exhibit oligoclonal T-cell expansion, generalized rash and lymphadenopathy at some point after birth. This rare condition is known as atypical complete DiGeorge syndrome, resembles Omenn syndrome, and has not been fully characterized. METHODS: The clinical and immunophenotypic features of atypical complete DiGeorge syndrome were assessed in two affected Japanese infants. T-cell receptor (TCR) Vß repertoire was analyzed on flow cytometry and complementarity-determining region 3 spectratyping. RESULTS: Both patients had no detectable thymus tissue and profound T-cell lymphopenia soon after birth. Progressive increase of activated T cells, however, as well as eosinophilia, high serum IgE level, generalized rash, and lymphadenopathy were observed during early infancy. A highly restricted TCR Vß repertoire was demonstrated both in CD4(+) and CD8(+) T cells. CONCLUSIONS: The Omenn syndrome-like manifestations might be associated with the oligoclonal proliferation of activated T cells. Analysis of the immunophenotype and TCR Vß repertoire is helpful to establish the early diagnosis of atypical complete DiGeorge syndrome.

[A case of portal hypertension after 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy].

A 46-year-old man with cancer of the sigmoid colon with hepatic metastasis underwent sigmoidectomy, partial hepatectomy, and cholecystectomy in May 2008. He subsequently received 10 cycles of a modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) regimen as adjuvant chemotherapy from June 2008 to December 2008, following which he developed thrombocytopenia and splenomegaly. In May 2011, upper gastrointestinal endoscopy was performed, which revealed esophageal and gastric varices. The varices were treated endoscopically with ligation and balloon-occluded retrograde transvenous obliteration. A liver biopsy was performed to determine the cause of the portal hypertension in the absence of severe hepatic dysfunction or liver cirrhosis. The biopsy revealed obliteration of the peripheral portal veins with sinusoidal dilatation without fibrosis or inflammatory cell infiltration in the hepatic lobules. Oxaliplatin-based chemotherapy has been associated with hepatovascular injury, such as sinusoidal dilatation and fibrosis, resulting in non-cirrhotic portal hypertension as seen in this case.

High doses of dextromethorphan induced shock and convulsions in a 19-year-old female: A case report.

BACKGROUND: Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication. There has been a growing number of reported cases of toxicity in recent years. Generally, there are numerous instances of mild symptoms, with only a limited number of reports of severe cases necessitating intensive care. We presented the case of a female who ingested 111 tablets of dextromethorphan, leading to shock and convulsions and requiring intensive care that ultimately saved her life. CASE SUMMARY: A 19-year-old female was admitted to our hospital via ambulance, having overdosed on 111 tablets of dextromethorphan (15 mg) obtained through an online importer in a suicide attempt. The patient had a history of drug abuse and multiple self-inflicted injuries. At the time of admission, she exhibited symptoms of shock and altered consciousness. However, upon arrival at the hospital, the patient experienced recurrent generalized clonic convulsions and status epilepticus, necessitating tracheal intubation. The convulsions were determined to have been caused by decreased cerebral perfusion pressure secondary to shock, and noradrenaline was administered as a vasopressor. Gastric lavage and activated charcoal were also administered after intubation. Through systemic management in the intensive care unit, the patient's condition stabilized, and the need for vasopressors ceased. The patient regained consciousness and was extubated. The patient was subsequently transferred to a psychiatric facility, as suicidal ideation persisted. CONCLUSION: We report the first case of shock caused by an overdose of dextromethorphan.

Secondary pulmonary infection by Fusarium solani and Aspergillus niger during systemic steroid treatment for COVID-19: A case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated invasive pulmonary aspergillosis presents a diagnostic challenge due to its non-specific clinical/ imaging features, as well as the fact that the proposed clinically diagnostic algorithms do not necessarily apply to COVID-19 patients. In addition, Fusarium spp. is a rare cause of opportunistic life-threatening fungal infections. Disseminated Fusarium infection in an immunocompromised host is intractable, with a high likelihood of resulting mortality. To our knowledge, this is the first case of secondary pulmonary infection by Fusarium solani (F. solani) and Aspergillus niger (A. niger) during systemic steroid treatment for COVID-19. CASE SUMMARY: A 62-year-old male was transported to our hospital by ambulance with a complaint of fever and dyspnea. We established a diagnosis of pneumococcal pneumonia, complicated with COVID-19 and septic shock, together with acute renal failure. He was admitted to the intensive care unit, to be treated with piperacillin/tazobactam, vancomycin, and 6.6 mg per day of dexamethasone sodium phosphate, along with noradrenaline as a vasopressor, ventilator management, and continuous hemodiafiltration. His condition improved, and we finished the vasopressor on the fifth hospital day. We administered dexamethasone for ten days, and finished the course of treatment. On the eleventh day, patient respiratory deterioration was observed, and a computed tomography scan showed an exacerbation of bilateral ground-glass-opacity-like consolidation, together with newly appeared cavitary lesions in the lung. we changed antibiotics to meropenem plus vancomycin. In addition, a fungal infection was considered as a possibility based on microscopic findings of sputum, and we began coadministration of voriconazole. However, the pneumonia worsened, and the patient died on the seventeenth day of illness. Later, F. solani and A. niger were identified from sputum collected on the twelfth day. It was believed that he developed a cell-mediated immune deficiency during COVID-19 treatment, which led to the complication of pneumonia caused by the above-mentioned fungi, contributing to his death. CONCLUSION: Because early initiation of intense antifungal therapy offers the best chance for survival in pulmonary fusariosis, computed tomography scans and appropriate microbiologic investigations should be obtained for severely immunocompromised patients.

Penile and scrotal strangulation by stainless steel rings in an human immunodeficiency virus positive man: A case report.

BACKGROUND: Penoscrotal constriction devices are either used as autoerotic stimuli or to increase sexual pleasure or performance by maintaining an erection for a longer period, and a variety of metallic and non-metallic objects are used. On the other hand, penile strangulation is a rare urologic emergency that requires prompt evaluation and intervention to prevent long-term complications. The goal of treating penile incarceration is to remove the foreign object as soon as possible. On the other hand, removal can be very challenging, and often requires resourcefulness and a multidisciplinary approach. CASE SUMMARY: A 47-year-old man who has sex with men was transferred to our hospital for persistent phallodynia and scrotal pain, accompanying swelling due to strangulation by stainless steel rings. His medical history included acquired immunodeficiency syndrome. One day prior, he had put three stainless steel rings on his penis and scrotum before sexual intercourse. After sexual intercourse, he was unable to remove them, due to swelling of his penis and scrotum. The swelling persisted, and he felt pain in the affected area the next day, then he was transferred to our hospital by ambulance. The emergency department found that his penis and scrotum were markedly engorged and swollen. We established a diagnosis of penile and scrotal strangulation by stainless steel rings. We unsuccessfully attempted to cut the rings using a cutter, then requested a rescue team via emergency medical service. They cut through each ring in two places, using an electric-powered angle grinder, and successfully removed all of the pieces. Finally, he was discharged and went home. CONCLUSION: We report the first case of penile and scrotal strangulation by stainless steel rings in an human immunodeficiency virus positive person.

Mycophenolate mofetil therapy for juvenile dermatomyositis with immune thrombocytopenic purpura.

A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease.

Estimation of a Suitable Number of Patients for Selective Safety Data Collection (ICH E19 Draft Guideline): When is the Safety Profile of a Drug Well Characterized?

PURPOSE: We propose methods to estimate a suitable number of patients for implementing selective safety data collection (SSDC) in clinical investigations based on a confidence interval of the incidence rate or risk difference using Monte Carlo simulation. METHODS: The incidence rates and risk differences of adverse events (AEs) were based on the safety outcome measures. A suitable number of patients for implementing SSDC was estimated based on the probability that the half-width of the two-sided 95% confidence interval of incidence rate or risk difference was equal to or less than a pre-specified cut-off value (0.5-3.0%). Monte Carlo simulation was used to estimate the suitable number of patients at probabilities of 70%, 80%, and 90%. The applicability of our proposed method for estimating a suitable number of patients for SSDC implementation was confirmed based on the incidence rates or risk differences from actual clinical trial data for panitumumab. RESULTS: We demonstrated the performance of our proposed method in estimating a suitable number of patients to implement SSDC in several situations. Furthermore, according to the safety datasets of three phase III clinical trials, the number of suitable patients for implementing SSDC using incidence rates or risk differences of common AEs with panitumumab could confirm the applicability of our proposed method. CONCLUSION: A suitable number of patients estimated based on our proposed method may be one of the foundations for implementing SSDC, as additional data accrual may not impact the precision of the estimates of the frequency of common AEs.

How Many Clinical Trials Exist that Have Adopted Selective Safety Data Collection? NEJM Literature Search Results: The Possibility of Harmonizing the ICH E19 Guideline.

BACKGROUND: The selective safety data collection (SSDC) proposed in The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E19 guideline is a more selective approach to collect safety data of medicinal products with well-characterized safety profiles. There has been no systematic survey of the implementation status of SSDCs. METHODS: A literature search was conducted on clinical trials using SSDC published in The New England Journal of Medicine from February 1, 2016, to December 31, 2019. By reviewing the retrieved texts, protocols, and statistical analysis plans, we identified the method of safety data collection and evaluated whether each trial adopted SSDC. RESULTS: Of the 459 trials of medicinal products searched, 44 clinical trials adopted SSDC. The common objectives of these studies were "to study additional endpoints" (31 trials, 70.5%) and "new indications of approved drugs" (8 trials, 18.2%). Participant number was more than 1000 in 33 trials (75.0%). Most trials adopted SSDC for the entire study population throughout the trial period. Death and serious adverse events (SAEs) were recorded in all trials. Twenty-nine (66.6%) recorded death, SAE, and AE leading to drug discontinuation, which were specified in the E19 draft guideline as the data that should be collected under all circumstances. CONCLUSION: There have already been cases where SSDC was used in clinical trials for regulatory application. It is desirable that the E19 guideline will harmonize the method for implementation of SSDC, making SSDC more common as an option for clinical trial design.

ST-Elevation Acute Myocardial Infarction in a Young Man.

Acute myocardial infarction (AMI) in young patients is very rare, but the incidence has increased over years past at younger ages, likely due to the presence of multiple risk factors. We present the first known case of ST-elevation AMI (STEMI) in a young man. A 22-year-old Japanese man was transferred to our hospital due to suddenly occurred anterior chest pain. An electrocardiogram revealed ST elevation in anteroseptal leads together with reciprocal ST depression in inferior leads. An emergency coronary angiogram was performed, revealing a 100% occlusion at segment 6 of the coronary artery and we established a diagnosis of STEMI. The lesion was expanded to 0% stenosis through plain old balloon angioplasty, after which a third-generation drug-eluting stent was installed there. Afterwards, the patient was discharged on day 17. In this case, a combination of mild six risk factors plus family history of hypertension might lead to this atypical event.

Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions.

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFß signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFß and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.