Malignant melanoma is a tumor generated from the basal melanocytes of human epidermis. Primary malignant melanoma of the cervix (PMMC) is derived from cervical melanocytes. It is an uncommon disease, mostly occurring in perimenopausal women. PMMC has a bad prognosis and lacks a defined protocol or treatment standards. The aim of this study was to analyze the impact of different surgical procedures and different adjuvant treatment modalities on their prognosis and to find risk factors for their prognosis by integrating published case report data based on the Chinese population.This study included 165 patients with PMMC in the Chinese population. We used the Kaplan‐Meier method to build the survival curve, and the log‐rank test to examine the variations among the subgroups. Prognostic factors were examined utilizing the Cox proportional hazards regression model. We found that patients who underwent radical hysterectomy‐based surgery, those who underwent lymphadenectomy, and those who underwent other treatments in addition to surgery had significantly better survival rates. The overall analysis, showed that age, and FIGO Stage II, III, and IV, increased the risk of death. Moreover, radical hysterectomy (RH), total hysterectomy (TAH), lymphadenectomy, and adjuvant therapy were correlated with a decreased mortality risk.After summarizing the current data, we recommend radical hysterectomy, and lymphadenectomy treatment for patients with PMMC. For patients who had already undergone surgery, other treatment options had a positive effect on prognosis. For patients who had already undergone surgery, other treatment options had a positive effect on prognosis; therefore patient‐specific treatment options need to be further discussed. Melanocytes are formed from the neural crest, and are scattered throughout all skin and most mucosal areas. They are located in the epidermal basal layer and create the epidermal melanocyte unit. Most MM occurs on the surface of the skin, and less than 2% occurs in the female genitalia.22.1By searching CNKI, VIP, CSPD, and PubMed, we collected case reports/case series of PMMC in the Chinese population, from their inception until closure for this study on July 31, 2022.Keywords for the literature search were as follows:  AND (uterine cervix) OR (cervix) OR . Exclusion criteria included other sources of primary genital tract melanoma, genital tract melanoma of unknown source, reviews, books, and unrelated articles. In the case of duplication of study data, the studies with larger sample sizes were selected.2.2The following information was collected: publishing year, patients age at diagnosis, patients' symptoms, Federation Internationale of Gynecologie and Obstetrigue (FIGO) stage, whether surgery was performed, surgery pattern, with or without lymph node metastases, whether more treatments were used , overall survival (OS) in months, and the condition of human papillomavirus (HPV) infection. Missing and unrecognizable data were marked with NA if part of the patient's clinical data was omitted from mention in the article.2.3p < 0.05 indicates statistical significance.OS was based on case‐reported data, while missing and unidentifiable data were excluded from statistics. Categorical information is reported in terms of percentage and frequency. Continuous data with normal distribution are presented as mean and standard deviation (SD), while data without normal distribution are presented as medians. We used statistical software SPSS 25.0 to process the data, the Kaplan–Meier method to build the survival curve, and the log‐rank test to examine the variations among the subgroups. Prognostic factors were examined utilizing the Cox proportional hazards regression model, and 33.1Following the search, 71 articles in four databases were eligible, including 165 cases. Table 3.2Table Chemotherapy was given to 87 out of the 94 patients, including 6 patients who had preoperative chemotherapy, 7 patients who had both pre and postoperative chemotherapy, 16 patients who had chemotherapy without surgery, and the remaining 58 patients received postoperative chemotherapy. Of the 42 patients receiving radiotherapy, 5 patients had preoperative radiation therapy, and 1 patient received preoperative and post‐surgical radiotherapy; the remaining 36 patients had postoperative radiotherapy. For the 22 patients who received immunotherapy, their treatments included interferon (INF), interleukin‐2 (IL‐2), Bacille Calmette‐Guerin (BCG), and anti‐PD‐1.In total, 43 patients received more than one treatment in addition to surgery. Notably, among these 43, 15 cases were treated with chemotherapy + immunotherapy, 23 cases with chemotherapy + radiotherapy, 1 case with radiotherapy + immunotherapy, and 4 cases with chemotherapy + radiotherapy plus immunotherapy.3.3p < 0.001; Figure Survival time was available for 126 patients, and status information for 50 patients that had survived; 76 patients died (1–193 months). There was no corresponding information for 39 patients so their survival status could not be determined. OS was assessed by generating Kaplan–Meier survival curves, and the median OS was 20 months , while patients who underwent RH‐based surgery (median OS 38 months) had a better prognosis than for TAH‐based surgery (median OS 16 months)  Figure .After th) Figure .Althoughp = 0.548; Figure p = 0.240; Figure p = 0.819; Figure p = 0.222; Figure p = 0.188; Figure We also considered the possible influence of confounding factors , and the findings also indicated a non‐significant variation between their clinical characteristics Table . There w4PMMC is a very rare disease and, to date, specific risk factors leading to susceptibility have not been identified. Therefore, detection and diagnosis of this disease are still difficult. Cervical melanoma originates from cervical melanocytes,There are currently no clear guidelines for the treatment of PMMC. We checked the guidelines for cervical cancer and none of them specifically mentioned the diagnosis and treatment of PMMC. Although there is no agreement on the appropriate treatment for PMMC, surgery is still the default option.In the current study, most patients were treated with chemotherapy. In the treatment of melanoma, immune‐targeted therapy continues to make progress, with the most prominent being immune checkpoint inhibitors. Currently, most research is aimed at two types of targets: cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and programmed death receptor 1 (PD‐1) pathways. Several articles report the effectiveness of the anti‐PD‐1 antibody drug nivolumab in primary cervical and vaginal MM.In summary, this is the first comprehensive analysis of 165 cases of PMMC in the Chinese population, which has a high incidence of cervical cancer and a large sample size compared with other countries.Zhen Ma: Methodology . Yumei Chen: Methodology . Shibo Zhao: Methodology . Caiyun Chen: Methodology .This study was surpported by Study on the regulatory effect and mechanism of AGRN in malignant biological behavior of cervical cancer (2022A703‐3).All authors declare no financial interest and no conflicts of interest.This study involving human volunteers and did not require an ethical assessment and approval in compliance with the local legislation and institutional requirements. In compliance with national legislation and institutional regulations, this study did not need written informed consent for participation.Table S1.Table S2 Table S3 Table S4 Table S5Click here for additional data file.


Toxoplasma gondii in domestic cats, dogs and rabbits was evaluated. Samples from cats and dogs were collected from five veterinary practices from various parts of Poland - Poznan (wielkopolskie voivodeship), Przemysl (podkarpackie voivodeship), Kluczbork (opolskie voivodeship), Lublin (lubelskie voivodeship) and Deblin (lubelskie voivodeship). Moreover, the samples from rabbits were collected in Poznan. In total, serum samples from 193 cats, 204 dogs and 71 rabbits were randomly selected and tested for specific antibodies against T. gondii using a commercial ELISA test. Pathogen seroprevalence among cats and dogs was calculated at a 95% confidence interval (CI) for each sex and age category  and compared with a chi-squared test. The highest seroprevalence of T. gondii was noted in cats − 49.74% . In dogs, it reached 28.92% . Only 1 rabbit  was seropositive, and the seroprevalence in rabbits was 1.41% . A statistically significant correlation between seropositivity and age (p < 0.05) was observed in cats and dogs. No statistically significant difference in seroprevalence concerning gender or location was found in cats and dogs. Our findings indicate that cat and dog serum samples had a high frequency of anti-T. gondii antibodies, while rabbit serum samples had low frequency and that these species are exposed to T. gondii in Poland and develop humoral response due to infection.The seroprevalence of  Toxoplasma gondii is a widespread protozoan and the causative agent of toxoplasmosis – a zoonotic disease. T. gondii represents a wide range of host organisms . Rabbit sera came from animals from Poznan and their surroundings. Sera were stored at − 70 °C until analyses. In total, serum samples from 193 cats, 204 dogs and 71 rabbits were randomly selected and used in the study. For each sample, the following information has been available: species, gender, age at sampling, location and clinical presentation .A total of 468 serum samples collected between September 2020 and January 2022 in five veterinary practices located in various parts of Poland (Poznan 52°24′24″N 16°55′47″E (wielkopolskie voivodeship); Przemysl 49°47′05″N 22°46′02″E (podkarpackie voivodeship); Kluczbork 18°13′E 50°58′N (opolskie voivodeship); Lublin 22°34′E 51°15′N (lubelskie voivodeship); Deblin 21°52′E 51°34′N (lubelskie voivodeship) . The plate was washed three times, and the conjugate was added to each well. Then, the plate was incubated at the same temperature for 30 min and washed three times. Next, 100 µL of 3,3’,5,5’-tetramethylbenzidine (TMB) substrate solution was added to each well for 15 min, followed by 100 µL of stop solution. The optical density (OD) was measured at 450 nm in the Infinite® 200 PRO microplate reader  immediately after stopping the reaction. The mean value of the measured OD value for the Positive Control (ODPC) and the mean value of the measured OD value for the Negative Control (ODNC) was used to test validation. ODPC must be > 0.350 and ODPC/ ODNC must be > 3. The ratio of the sample OD to the mean OD of the positive control (S/P) was calculated using the following equation: S/P = (ODsample − ODNC)/(ODPC − ODNC). Samples with S/P ≥ 0.5 were considered positive, whereas samples with S/P ≤ 0.4 were considered negative. Samples with S/P ratio > 0.4 and < 0.5 were considered as doubtful.An ELISA  was used to detect anti-https://epitools.ausvet.com.au/ciproportion). CI for prevalence was calculated with the Wilson score method. Pearson’s chi-square (χ2) tests were used to analyze the data in different species, age groups, locations and genders. The odds ratio (OR) value was calculated with a 95% CI to analyze the risk of seroconversion in different age groups in dogs and cats. A p-value of < 0.05 was statistically significant. The map was created using an online program (https://www.mapchart.net) and canva (https://www.canva.com).The analyses were performed using RStudio (version 4.1.2), except for prevalence , which was available as an online program . The seroprevalence among dogs was 28.92% , while among rabbits it reached 1.41% . Only 1 rabbit  was seropositive.The highest seroprevalence of T. gondii antibodies and age observed in cats and dogs were statistically significant (p < 0.05). Detailed data on seroprevalence among each age group in dogs and cats and the association between age category and seroprevalence are presented in Tables The correlation between the presence of anti-p > 0.05). In dogs, the gender difference in seroprevalence was not statistically significant either (p > 0.05). The seroprevalence among males was 31.00%  and in females – 26.92% . The association between clinical picture and seropositivity is presented in Table Gender difference in seroprevalence was found between feline males  and females , however, it was not statistically significant (p > 0.05) and dogs (p > 0.05). Detailed data about samples that tested positive for anti-T. gondii antibodies in relation to samples obtained from cats, dogs and rabbits in each location in Poland are presented in Table Differences in seroprevalence in relation to location were not statistically significant in cats  and 48.4% (237/490) respectively  of pet rabbit samples , and 10.1% (99/981) in the 29 household farms , and the percentage of seroreagents increases with age. Additionally, dogs, cats and rabbits are exposed to the pathogen, can become infected and develop a humoral response as a result of infection with T. gondii. These results are beneficial to researchers, health workers and veterinarians. Control measures are required both to reduce the exposure of felids and intermediate hosts to infective oocysts and reduce the shedding of oocysts into the environment by definitive hosts. Careful handling and disposal of feline faeces and the use of disinfectant are suggested in living areas if they become contaminated with feline faeces. Moreover, prevention of infection in cats may reduce environmental pollution from T. gondii oocysts, which will have a positive impact on intermediate host animals and public health. This can be achieved by keeping cats indoors and feeding cats commercially prepared cooked foods. Cats should not be allowed to eat uncooked meat or hunt and eat intermediate hosts, such as rodents.Results of our study indicate that the seroprevalence of


Klebsiella pneumoniae is a relatively recent cause, often affecting patients with low immunity. Endogenous endophthalmitis (EE), a rare and serious complication of PLA, may appear with eye symptoms before PLA. By reviewing a case of Klebsiella pneumoniae‐induced PLA complicated with EE, we want to summarize the information about the characteristics, causes, and complications of PLA based on the literature review.Pyogenic liver abscess (PLA) is a common surgical infectious disease caused by various pathogens. Klebsiella pneumonia. Blood and liver puncture drainage fluid were sent for microbial high‐throughput gene detection with next‐generation sequencing technology (NGS), which confirmed the diagnosis of Klebsiella pneumoniae‐induced PLA complicated with EE.This case report describes a 37‐year‐old male who had fever high to 39°C for 10 days experienced blurred vision followed by nonlight perception vision. He reported a history of diabetes irregularly taking oral medications and insulin therapy. Imaging examination found a large low‐density area in the right lobe of the liver with an unclear border and vague surrounding fat gap. The blood culture was not positive. The culture of the drainage fluid from the liver puncture showed The patient's surgical incision had healed well at discharge, and he could feel light at his left eye. But the patient was lost to follow‐up since the third month after discharge.By reviewing this case and summarize the information about the characteristics, causes, and complications of PLA based on the literature review, we concluded that it is necessary to promptly perform liver puncture drainage and empirically use antibiotics for patients with PLA, especially those with poor glycemic control, to avoid serious complications such as EE. It is important to promptly perform liver puncture drainage and empirically use antibiotics for patients with PLA, especially those with poor glycemic control, to avoid serious complications such as endogenous endophthalmitis. It can occur in various conditions such as biliary tract disease, colitis, pancreatitis, intravenous drug use, and trauma.Klebsiella pneumoniae is a type of Gram‐negative bacteria that is commonly found in the human gut and respiratory tract. In addition to PLA, K. pneumoniae infections can also cause pneumonia, urinary tract infections, and other types of infections.K. pneumoniae is a commensal bacterium that lives in the nasal cavity and gastrointestinal tract and is frequently responsible for community‐acquired pneumonia or urinary tract infections. When it causes liver abscesses, we call them invasive liver abscesses. This invasive PLA is caused by K. pneumoniae strains expressing serotypes K1 and K2 as well as mucoid phenotype A regulator.K. pneumoniae  strain and detected in an immunocompetent Chinese subject.K. pneumoniae‐induced PLA is not fully understood, but it is believed to involve bacterial invasion and destruction of liver cells, as well as the production of toxins and immune system activation.K. pneumoniae‐induced PLA include alcoholism, chronic kidney disease, and recent invasive procedures such as endoscopy or surgery.K. pneumoniae. Capsule, lipopolysaccharide, adhesin, and siderophores are among the virulence factors found in carbapenem‐resistant K. pneumoniae (CRKP)/hvKp, resulting in a variety of immune responses and related phenotypes in hvKp strains.In addition to diabetes and tumors, other risk factors for K. pneumoniae‐induced PLA is usually confirmed by imaging studies such as ultrasound or computed tomography (CT) scan, as well as blood cultures. They are useful tools for demonstrating a space‐occupying lesion and confirming the presence or absence of a liver abscess. CT scanning has a higher sensitivity (97% sensitive) for detecting liver abscess than ultrasound (85% sensitive).The presence of K. pneumoniae‐induced PLA, CT findings such as abscess location  and involvement of adjacent vessels, in addition to ocular symptoms, should be considered for an early diagnosis of EE.K. pneumoniae was still highly susceptible to ceftazidime and amikacin, and the multidrug‐resistant (MDR) K. pneumoniae isolates were not common in EE.In patients with Klebsiella pneumoniae pyogenic liver abscess. K1 capsular serotype infection was an independent risk factor.K. pneumoniae‐induced PLA.Endogenous endophthalmitis (EE) is a rare and serious complication of PLA and often appears with eye symptoms before PLA.1.1A 37‐year‐old male was admitted to the hospital 1 day after left eye surgery and more than 10 days of fever. He reported having a fever more than 10 days ago, accompanied by chills and shivering, with the highest body temperature being 39°C. He purchased fever‐reducing drugs from a pharmacy without seeking medical attention. Two days before admission, he began to experience blurred vision in the left eye, followed by nonlight perception vision. He went to Eye & Ent Hospital of Fudan University for emergency treatment and underwent left lens and vitreous body removal under local anesthesia. During the surgery, vancomycin and cefotaxime were injected, and silicone oil was injected into the eyeball. The surgery was successful, and a large area of retinal necrosis, large temporal hiatus in macular area, and extensive vascular occlusion were observed during the surgery. The bacterial smear of purulent secretion during surgery indicated Gram‐positive bacteria, and no fungi were found. The patient was immediately given Rocephin for anti‐infective treatment after surgery.On the second day after surgery , he was admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. His body temperature was 39.3°C, and he had no chills. He had a good appetite but poor sleep, normal bowel, and urine habits, and had lost 5 kg in weight in the past month.1.2The patient had a history of diabetes for more than 3 years, irregularly taking oral medications and insulin therapy. He denied a history of hypertension and chronic diseases. He had a history of hemorrhoids and had bleeding from hemorrhoids 1 week before the fever.1.3On examination, the patient had a body temperature of 39.3°C, R22 breaths/min, BP124/85 mmHg, HR96 beats/min, and the left eye was covered with gauze. No abnormalities were found in heart and lungs, and the abdomen was soft and flat. The liver was palpable one finger breadth below the ribs, with mild tenderness upon gentle pressure.1.41.4.19/L , with neutrophils accounting for 86.2%; erythrocyte sedimentation rate (ESR) 74 mm/h; C‐reactive protein (CRP) 276.1 mg/L; procalcitonin 1.06 ng/mL; serum 1, 3‐beta‐d‐glucan level (G tes) (−); endotoxin (−); 2‐h postprandial blood glucose 16.13 mmol/L; and glycated hemoglobin (HbA1c) 10.2%. The patient was started on antibiotics including Vancomycin 1.0 g q12h, Piperacillin‐Tazobactam 4.5 g q8h, and Metronidazole 0.5 g q12h after the blood culture specimen was collected.Upon admission, a blood culture specimen was collected and yielded the following results: white blood cell count (WBC) 13.3 × 101.4.2An abdominal ultrasound, which involved an abdominal ultrasound that specifically targeted the right posterior lobe of the liver, was conducted upon admission. and showed a mixed echoic area with a thick wall and internal partitions, about 95 × 80 mm in size, with an unclear border and slightly enhanced posterior echo signal, and a few blood flow signals were seen in the wall on color Doppler flow imaging (CDFI) Figure . On the A head CT scan was performed and showed increased density in the left eye and swelling of the subcutaneous tissue around the left eye Figure . After c1.4.3Klebsiella pneumonia, and the results of the drug sensitivity test showed that it was not sensitive to ampicillin but moderately sensitive to vancomycin, cephalothin, and meropenem. Blood and liver puncture drainage fluid were sent for microbial high‐throughput gene detection, which confirmed the diagnosis of K. pneumonia induced‐PLA with EE.The blood culture was not positive. The culture of the drainage fluid from the liver puncture showed 1.5The patient received antibiotic treatment and blood sugar control  during a 2‐week hospital stay. Ten days into the hospitalization, the patient reported feeling better and requested to be transferred to a hospital near their residence for continued treatment of the infection. Upon discharge, the patient had been afebrile for 10 days and a follow‐up CT scan of the upper abdomen showed a significant reduction in the size of a large low‐density lesion in the right lobe of the liver, measuring approximately 4.6 × 2.5 cm. The patient's surgical incision had healed well, and he could feel light at his left eye. The patient was discharged and transferred to a local hospital for convenient nearby medical treatment on October 12, 2020. One month after transfer, the patient reported via telephone follow‐up that he had been discharged from the local hospital after recovery with light perception of left eye (no specific vision was reported at this follow‐up). We tried to contact the patient via telephone at the 3rd, 6th, and 12th months, but the patient was lost to follow‐up since the 3rd month after discharge.2Escherichia coli to K. pneumoniae, which now accounts for the majority of cases.K. pneumoniae is the most common pathogenic bacteria, and most early cases of K. pneumoniae‐induced PLA with concomitant EE have been reported in Taiwan.K. pneumoniae was responsible for 55.8% of cases of EE.EE is an ocular infection that occurs secondary to sepsis, with an incidence of 0.04%–0.5% in cases of bacteremia or fungemia.K. pneumoniae endophthalmitis is increasingly reported globally and is a primary cause of EE in Southeast Asian countries, where Gram‐negative bacteria are the primary causative agents. In contrast, Western countries report Gram‐positive bacteria and fungi as the most common pathogens. This type of endophthalmitis has a higher incidence among East Asian populations, particularly in patients with poorly controlled diabetes, with PLA being the most common source of infection.K. pneumoniae can occur through four pathwaysStaphylococcus aureusK. pneumoniae‐induced PLA is seldom associated with liver and biliary diseases, previous liver surgery, abdominal trauma, or biliary or portal vein infections caused by malignant tumors,K. pneumoniae have varying invasive abilities through different genes. Type III mutants, for example, can penetrate the intestinal barrier and cause PLA.PLA caused by K. pneumoniae and Gram‐positive bacteria can lead to the formation of PLA in the right lobe through the blood supply pathway of the hemorrhoid plexus.K. pneumoniae.The patient in this case had a history of bleeding hemorrhoids 1 week before developing a fever. Intestinal colonization by both K. pneumoniae is a common Gram‐negative bacterium and is typically susceptible to carbapenems, gentamicin, and cefotaxime.The clearance of Gram‐positive bacteria by vancomycin could have contributed to the inconsistency with the results of liver puncture drainage fluid culture, which was taken after empirical antibiotic treatment for Gram‐positive bacteria.During the patient's surgery, vancomycin and cefotaxime were injected into the eye, and vancomycin combined with meropenem was administered after the operation. Following 2 weeks of antibiotic treatment, the patient no longer had a fever, and follow‐up CT scans showed a significant decrease in the PLA, indicating that the chosen antibiotic treatment was effective.K. pneumoniae‐induced PLA is 4–6 weeks, with the duration of treatment being based on control of the primary focus.Antibiotics should be adjusted based on drainage fluid and/or blood culture results.3It is important to promptly perform liver puncture drainage and empirically use antibiotics for patients with PLA, especially those with poor glycemic control, to avoid serious complications such as EE.Yunjiang Chen: Conceptualization; data curation; investigation; methodology; writing—original draft; writing—review and editing. Yanchun Gong: Conceptualization; data curation; investigation; methodology; project administration; writing—original draft. Bei Song: Data curation; investigation; methodology; resources; writing—review and editing. Yueling Du: Investigation; methodology; project administration; supervision; writing—review and editing. Kaiyu Cai: Conceptualization; investigation; methodology; supervision; validation; writing—review & editing.The patient has signed a copy of written informed consent for the notice of this case research and publication.


This study aimed to investigate the validity of pathological diagnosis of early CRC (E‐CRC) from the genetic background by comparing data of E‐CRC to colorectal adenoma (CRA) and The Cancer Genome Atlas (TCGA) on advanced CRC (AD‐CRC).MLH1 was also performed. The presence of oncogenic mutation according to OncoKB for the genes of the Wnt, MAPK, and cell‐cycle–signaling pathways was compared among CRA, E‐CRC, and AD‐CRC.TCGA data on AD‐CRC were studied in silico, whereas by next‐generation sequencer, DNA target sequences were performed for endoscopically obtained CRA and E‐CRC samples. Immunohistochemical staining of mismatch repair genes and methylation of The study included 22 CRA and 30 E‐CRC lesions from the Chiba University Hospital and 212 AD‐CRC lesions from TCGA data. Regarding the number of lesions with driver mutations in the Wnt and cell‐cycle–signaling pathways, E‐CRC was comparable to AD‐CRC, but was significantly greater than CRA. CRA had significantly more lesions with a driver mutation for the Wnt signaling pathway only, versus E‐CRC.In conclusion, the definition of E‐CRC according to the Japanese criteria had a different genetic profile from CRA and was more similar to AD‐CRC. Based on the main pathway, it seemed reasonable to classify E‐CRC as adenocarcinoma. The pathological diagnosis of E‐CRC according to Japanese definition seemed to be valid from a genetic point of view. Regarding the number of lesions with driver mutations in the Wnt and cells‐cycle–signaling pathways, Early CRC was comparable to Advanced CRC. It seemed reasonable to classify Early CRC as adenocarcinoma. Written informed consent was obtained from all patients in this study.2.3Pathological diagnosis was followed by Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma ver 9.0.2.4We designed the panel with Ion AmpliSeq designer software (Thermo Fisher Scientific) as previously reported.2.5Target sequencing was performed with an Ion PGM . Multiplex polymerase chain reaction (PCR) was performed with the CRC panel using the Ion AmpliSeq Library Kit 2.0 (Thermo Fisher Scientific). The library was barcoded, purified, and quantified according to prior report.2.6MLH1, MSH2, MSH6, and PMS2) was judged on formalin‐fixed paraffin‐embedded specimens of endoscopically resected samples for CRA and E‐CRC in accordance with previous report.Immunohistochemical analysis (IHC) was performed and deficiency of MMR proteins  or the MethylCode Bisulfite Conversion Kit . The Real‐time PCR and electrophoresis using 2% agarose gel were conducted with the EpiScope MSP Kit . The primers used in this analysis followed the prior report.Methylation‐specific PCR was performed to assess the methylation of 2.8http://oncokb.org/).Each mutation was analyzed whether it was putative‐driver or not according to the OncoKB , we performed PyClone analysis.2.12The raw data of target sequencing was processed and analyzed with Torrent Suite version 5.0.4. Detailed filter setup was conducted almost the same as previous reports.2.13p < 0.05, and all statistical analyses were performed using SPSS version 22.0 .Fisher's exact test or chi‐square test was used for comparisons between driver mutations in each pathway among cases of CRA, E‐CRC, and AD‐CRC in TCGA. Statistical significance was set at 33.1The characteristics of the patients and lesions are summarized in Table 3.2RNF43 and APC were mutually exclusive. KRAS, NRAS, and BRAF were also mutually exclusive within each case. Almost all of the mutation of APC and RNF43 identified in this study were putative‐driver. APC was the most frequently putative‐driver gene in E‐CRC  and CRA . In CRA, only one lesion had a putative‐driver mutation of TP53  in contrast to E‐CRC. Putative‐driver mutation of RNF43 was observed in 1 CRA and 2 E‐CRC with MMR deficiency. One case in E‐CRC with an RNF43 putative‐driver mutation had MLH1 methylation.Oncogenic mutations of Wnt, MAPK, and cell‐cycle–signaling pathway of CRA and E‐CRC are shown in Figure 3.3CTNNB1, AXIN2, and RNF43  were identified. Furthermore, putative‐driver mutations of BRAF were frequently observed in these tumors. Conversely, in the MSI‐low and microsatellite stable (MSS) tumors, most of the tumors were located in the left side. Almost all these tumors had a putative‐driver mutation of APC. In AD‐CRC, KRAS, NRAS, and BRAF were also mutually exclusive within each case, similar to E‐CRC.There were 212 cases of AD‐CRC in TCGA, which are illustrated via an oncoplot in Figure 3.4p = 0.052). The ratio of lesions with putative‐driver mutations in Wnt and cell‐cycle–signaling pathways were also not significantly different between AD‐CRC and E‐CRC , but they were significantly different between E‐CRC and CRA (36.6% vs. 4.5% p = 0.008). Lastly, the ratio of lesions with putative‐driver mutations in only the Wnt signaling pathway were significantly higher in CRA than in E‐CRC .The comparisons of the ratios of putative‐driver mutations among the Wnt, MAPK, and cell‐cycle–signaling pathways via Fisher's exact test are shown in Table 3.5There were two patients with double E‐CRC. The results of PyClone analysis are shown in Figure 4In this study, we examined the genetic profile of CRA, E‐CRC with clinical samples obtained from EMR, ESD, and AD‐CRC based on TCGA data. We also investigated the validity of Japanese pathological diagnosis for E‐CRC from a genetic aspect. To the best of our knowledge, these points have not been extensively discussed in the literature, and thus our study can be considered novel.APC, RAS, and TP53 mutations occur for an adenoma to progress to CRC. APC is often mutated in tubular or tubulovillous adenomas.The adenoma–carcinoma sequence is widely accepted as a model of carcinogenesis of CRC.TP53 instead of the genes for the MAPK signaling pathway, unlike in the typical adenoma–carcinoma sequence. And some E‐CRC with oncogenic mutations for the Wnt, cell‐cycling pathway may progress to AD‐CRC by acquiring oncogenic mutations for the MAPK signaling pathway . These mechanisms seem crucial to comprehensively understand the carcinogenesis of E‐CRC. Based on these results, CRA, and E‐CRC of the Japanese definition are genetically different profiles. E‐CRC, including IMC (which is defined as a high‐grade dysplasia in the WHO classification), already has a genetic background similar to that of AD‐CRC.To summarize, it may be true that CRA first obtains driver mutations for the genes of the Wnt signaling pathway (mainly APC) in a typical adenoma–carcinoma sequence. However, in order to progress into an E‐CRC, approximately 40% of tumors may secondarily obtain a driver mutation of MLH1 methylation) had a putative‐driver mutation of RNF43.The two identified mutations of RNF43 in E‐CRC were both p.Gly659fs ; writing – original draft (lead); writing – review and editing (lead). Yosuke Hirotsu: Data curation . Makoto Arai: Data curation . Kenji Amemiya: Data curation . Naoki Akizue: Data curation . Yuki Ohta: Data curation . Takashi Taida: Data curation . Keiko Saito: Data curation . Hiroshi Ohyama: Data curation . Tomoaki Matsumura: Data curation . Motoi Nishimura: Data curation . Kazuyuki Matsushita: Data curation . Keisuke Matsusaka: Conceptualization . Toshio Oyama: Data curation . Hitoshi Mochizuki: Data curation . Tetsuhiro Chiba: Writing – review and editing . jun Kato: Writing – review and editing . Junichiro Ikeda: Writing – review and editing . Osamu Yokosuka: Writing – review and editing . Naoya Kato: Conceptualization ; writing – review and editing . Masao Omata: Writing – original draft .This report received no sources of external funding.The authors have no conflicts of interest to declare.Table S1.Click here for additional data file.


Parents of children treated for cancer may experience mental health difficulties, such as depression and anxiety. There is a lack of evidence‐based psychological interventions for parents, with psychological support needs unmet. An internet‐administered, guided, low‐intensity cognitive behavioral therapy‐based (LICBT) self‐help intervention may provide a solution.The feasibility and acceptability of such an intervention was examined using a single‐arm feasibility trial (ENGAGE). Primary objectives examined: (1) estimates of recruitment and retention rates; (2) feasibility and acceptability of data collection instruments and procedures; and (3) intervention feasibility and acceptability. Clinical outcomes were collected at baseline, post‐treatment (12 weeks), and follow‐up (6 months).The following progression criteria were met: sample size was exceeded within 5 months, with 11.0% enrolled of total population invited, study dropout rate was 24.0%, intervention dropout was 23.6%, missing data remained at ≤10% per measure, and no substantial negative consequences related to participation were reported. Intervention adherence was slightly lower than progression criteria (47.9%).Findings suggest an internet‐administered, guided, LICBT self‐help intervention may represent a feasible and acceptable solution for parents of children treated for cancer. With minor study protocol and intervention modifications, progression to a pilot randomized controlled trial (RCT) and subsequent superiority RCT is warranted. A single‐arm feasibility trial showed overall acceptability and feasibility of an internet‐administered, guided, low‐intensity cognitive behavioral therapy intervention for parents of childhood cancer survivors, and progression criteria were met for recruitment, retention, missing data, and harms, indicating methods, study procedures, and the overall the trial and intervention was feasible and acceptable. However, completion of assessments at each timepoint and intervention adherence were under progression criteria, meaning some modifications to the study protocol intervention are required before commencing a pilot randomized controlled trial. EJDeR is delivered via the U‐CARE‐portal , a web‐based platform, designed to deliver internet‐administered interventions and support the execution of study procedures.2.2Eligible participants were: (1) parent of a child diagnosed with childhood cancer (0–18 years) who completed treatment 3 months to 5 years previously 2.32.3.1Personal identification numbers of children who had completed treatment 3 months to 5 years previously were provided by the Swedish Childhood Cancer Registry (CCR), and linked to parents' names and addresses via NAVET, a population registry from the Swedish Tax Agency. The first recruitment block was pre‐selected with parents of children who had ended treatment near to 5 years previously. The following four blocks were randomly selected by a member of the Portal team, independent to the research team, using a computer‐generated simple randomization procedure. Postal study invitation packs, sent to parents' home addresses, included a: (1) study invitation letter; (2) study information sheet and link to a secure website on the Portal (information in text and video format); (3) paper reply‐slip to register interest in participation; (4) paper‐based opt‐out form and reasons for non‐participation questionnaire; and (5) freepost envelope. Parents could register interest in participation and request more study information via the Portal, post, telephone or e‐mail. ENGAGE included an embedded recruitment RCT, investigating the effect of personalized versus non‐personalized study invitations on recruitment and retention2.3.2Advertisements were placed on social media sites, websites, and newsletters of 12 cancer organizations and interest groups.2.3.3Parents invited via the post could opt‐out of ENGAGE via the Portal, post, telephone, or e‐mail. Up to five reminder telephone contact attempts were made if parents did not respond within 4 weeks of invitation. Telephone numbers were identified using internet search engines. Contact attempts were documented in paper‐based case report forms (CRFs). If a telephone number was not identified, a postal study invitation reminder letter was sent.2.3.4Parents opting out of ENGAGE were asked to complete a reason for non‐participation questionnaire including a closed, multiple choice question and an open question for other reason(s).2.4Parents provided consent via the Portal. Parents who registered interest in participation but did not provide consent, or opt out, within 2 weeks, were contacted to confirm interest in participation .Parents providing consent were contacted to organize a telephone eligibility interview with a licensed psychologist. Interviews included: 1) questions concerning eligibility criteria; with those eligible completing specific modules of the M.I.N.I., and; (2) questions concerning parent and child sociodemographic and clinical characteristics  checklist.EJDeR is a guided internet‐administered LICBT intervention delivered over 12 weeks on the Portal and includes text, illustrations, film, audio files, in‐module exercises, and homework exercises. EJDeR includes two LICBT techniques: behavioral activation (BA) for depression, and worry management (WM) for generalized anxiety disorder (GAD).E‐therapist guidance is provided via an initial assessment session ; weekly support via written messages via the Portal (≈20–30 min/week), and a mid‐intervention booster session  following structured protocols.2.6Feasibility outcomes are informed by the CONSORT 2010 statement extension for randomized pilot and feasibility trials,The post‐treatment time‐point was set at 12 weeks, immediately after the EJDeR intervention had finished. A 6‐month follow‐up time‐point was selected to examine the feasibility of longer‐term data collection.Sociodemographic data on parents and children, specific modules of the M.I.N.I. assessing current and past psychiatric disorders and suicidality, and psychological and health economic measures are reported in Table Semi‐structured interviews were conducted at baseline and post‐treatment with licensed psychologists (data reported elsewhere).2.7Following recommendations for feasibility trial sample sizes the target sample size was 50.2.8Paper‐based CRFs were used for data collected outside the Portal, with data independently entered onto a Microsoft® Access database by two research assistants, exported into Microsoft® Excel spreadsheets, with accuracy checked using Microsoft® Spreadsheet.2.9A prompt (SMS and/or e‐mail) was sent when it was time to complete Portal assessments with automatic reminders (SMS and/or e‐mail) sent if not completed within 1 week. Participants who did not complete Portal assessments within 2 weeks, were offered to complete over the telephone, with up to six reminder attempts made via telephone, SMS, or email. Informed by evidence suggesting study newsletters can improve retention2.10The minimum treatment dose (MTD)  was defined as: (1) attendance of the initial assessment session; (2) completion of the introduction and psychoeducation module; (3) completion of one LICBT module (BA or WM); and (4) attendance of the mid‐intervention booster session.2.11A 15% random sample of initial assessment and mid‐intervention booster sessions and written messages via the Portal from e‐therapists were marked for adherence, with each item within the structured support protocols marked as absent/present.2.12Feasibility outcomes relating to recruitment and eligibility, data collection, attrition, resources needed to complete the study and the intervention, participants' adherence to the intervention, participants' use of the intervention, e‐therapists' adherence to the intervention, and participants' sociodemographic characteristics are reported using descriptive statistics. Numbers and percentages (and 95% CIs where appropriate) are reported for categorical variables, means and SDs for continuous variables. Numbers and percentages of participants meeting criteria for each M.I.N.I. diagnosis is reported at each time‐point. Means and SDs for continuous variables and numbers and percentages for categorical variables are reported for all outcomes at each time‐point. Mean change scores (with 95% CIs) are reported for Portal assessments of psychological outcomes at each time‐point, to describe the study sample.2.13Participants scoring >0 on PHQ‐9 (depression) question 9 , or a total score >20 (severe depression) were risk assessed by a licensed psychologist within one working day. If needed, participants were directed to appropriate support and excluded.2.14A Parent Research Partner (PRP) group was established consisting of four parents with lived experience of being a parent of a child treated for cancer . The PRP group was involved in optimizing the acceptability of EJDeR e.g., relevancy, ease of understanding, content, language, and structure.3Data supporting feasibility objectives pertaining to recruitment and eligibility, data collection, attrition, and resources needed to complete the study and intervention are available in Zenodo.3.1Participant flow is summarized in an adapted CONSORT diagram Figure . RecruitAmbiguities regarding eligibility arose in six cases. In three cases, parents met criteria for PTSD according to the M.I.N.I. but were included as symptoms were mild. In one case a parent met criteria for Alcohol Use Disorder, and was included due to being in early remission. One was attending a psychological support group; study inclusion was delayed until the group ended. One reported their child had recently relapsed, however, as treatment had not started, the parent was included.Out of 509 parents identified via the CCR and NAVET, 164 (32.2%) opted out, and 137 provided a response to the multiple‐choice question regarding reasons for non‐participation. Not experiencing any need for psychological support  was most commonly reported Table . Full re3.2N = 75) are summarized in Table Baseline sociodemographic and clinical characteristics for participants , had been diagnosed with Leukemia  and treated with chemotherapy . The children's mean age at the time of the eligibility interview was 10.6 years . Baseline sociodemographic and clinical characteristics for children are provided in Table Participants' internet usage is reported in Table 3.3Data collection  took place between 24‐07‐2020 and 04‐10‐2021. Percentage completing assessments at each time‐point are reported in Table Missing data ranged from 0.01%–4.1% items missing per measure, bettering progression criteria (≤10%). Missing data from the M.I.N.I. is reported in Table 3.4In total, 18/75  of participants enrolled into the study dropped out of the study, bettering progression criteria (≤30%). In total, 17/72  of participants gaining access to EJDeR, dropped out of EJDeR, bettering progression criteria (≤30%).3.5Length of time for participants to work through EJDeR and complete assessments at each time‐point are provided in Table n = 10) supported 27 participants  and spent a mean of 76.9 h  delivering EJDeR, attending training, supervision, and administration, equating to a mean of 2.9 h per participant each week . Due to students not having adequate time to support participant caseloads, the majority were supported by a CBT‐therapist internal to the research team (n = 32), a licensed psychologist in the research team (n = 5), and a licensed psychologist external to the research team (n = 7). The clinical supervisor worked for 155 h, including training, supervision, and administration.Seventy‐two participants gained access to EJDeR and 71 were allocated to an e‐therapist . Psychology program students (n = 7) and e‐therapists (n = 10). Paper‐based CRFs for study data were considered time and resource intensive, as was coordinating external study personnel.Difficulties recruiting research personnel was identified as a challenge.3.6Seventy‐two participants gained access to EJDeR. One was excluded shortly after access  and 34/71 (47.9%) adhered to the MTD, nearly meeting progression criteria of 50%. The mean number of modules opened was 2.3 , parents completed a mean of 1.7 modules , and a mean of 2.7 homework sheets . Initial assessment sessions were attended by 61/71 (85.9%) and mid‐intervention booster sessions were attended by 44/71 (62.0%).Visual inspection of data indicated differences in adherence rates by first LICBT module started and by gender. A post hoc descriptive analysis was performed. In total, 54/71 (76.1%) started a LICBT module, with 26 starting with BA and 28 with WM. In total, 20/26 (76.9%) starting with BA, and 14/28 (50.0%) starting with WM adhered to the MTD.Of the 71 participants, 25 were fathers, and 46 were mothers. For fathers: 8/25 (32.0%) started with BA and 7/8 (87.5%) adhered to the MTD; 12/25 (48.0%) started with WM, and 5/12 (41.7%) adhered to the MTD. For mothers, 18/46 (39.1%) started working with BA and 13/18 (72.2%) adhered to the MTD; 16/46 (34.8%) started with WM and 9/16 (56.3%) adhered to the MTD.3.7A mean of 20 participant logins were made . A mean of 8.5 participant written messages were sent to e‐therapists , and a mean of 28.8 e‐therapist written messages  were sent to participants.3.8Adherence rates were 90.5% for initial assessment sessions, 85.2% for mid‐intervention booster sessions, and 87.5% for written communication between participants and e‐therapists.3.9Reasons for study dropout are reported in Figure 3.10M.I.N.I. data at baseline, post‐treatment, and follow‐up are provided in Table 4The ENGAGE feasibility trial demonstrated it is possible to recruit and retain parents of children treated for cancer into a single‐arm feasibility trial of an internet administered, guided, LICBT based, self‐help intervention. In summary: (1) 12.0% of invited parents consented and 11.0% of invited parents were enrolled, exceeding progression criteria of ≥9%; (2) 24.0% dropped out of the study, and 23.6% dropped out of the intervention, bettering progression criteria of ≤30%; (3) missing items per questionnaire ranged from 0.01% to 3.9%, remaining under ≤10% for all measures, bettering progression criteria; (4) percentage of participants completing assessments ranged from 65.6% to 98.7%, bettering progression criteria of ≥70% for M.I.N.I interviews at all time‐points and Portal assessments at baseline, and marginally under progression criteria of ≥70% for Portal assessments at post‐treatment and follow‐up; (5) intervention adherence was 47.9%, marginally under progression criteria of ≥50%; and (6) no participant reported a substantial negative consequence related to the study and/or intervention, meeting progression criteria. This study was not designed to detect differences in parental depression or anxiety at follow‐up, however reductions in depressive and anxiety symptoms were observed via visual inspection.4.1To the best of our knowledge, ENGAGE is first trial worldwide designed to test the feasibility of an internet administered, guided, LICBT based, self‐help intervention for parents of children treated for cancer. Robust methods examined a range of feasibility objectives, alongside a priori specified progression criteria. The intervention protocol is published in accordance with TIDieR guidelinesThe study also has limitations. E‐therapists adherence to the intervention was examined by only one licensed clinical psychologist with adherence marked as absent/present. Future studies should develop an intervention adherence checking tool, examining both adherence and quality.4.2n = 101) may be anticipated to experience at least mild symptoms of depression and/or anxiety.While we successfully recruited our target sample size with an enrolment rate of 11.0%, confidence intervals ranged from 8.4% to 14.1% and in a future pilot RCT we will continue to identify participants via additional sources such as cancer organizations and interest groups. Further, we targeted parents of children treated for cancer with a self‐reported need for psychological support. Lack of recognition of one's psychological difficulties and lack of acknowledgement for the need of support, are commonly identified barriers to seeking help.Our study dropout rate of 24.0% bettered progression criteria of ≤30%. Confidence intervals ranged from 14.9% to 35.3% and we aim to minimize study dropout in the forthcoming future pilot RCT by continuing to use retention strategies, including telephone remindersOur intervention adherence rate of 47.9% was slightly lower than progression criteria (≥50%) and there was no evidence of harm. Results suggest the intervention may be feasible and acceptable for the population and are in line with other research suggesting internet‐administered delivery mechanisms are acceptable to parents of children on cancer treatmentRecruitment of experienced research personnel was challengingPsychology program student e‐therapists did not have time to support caseloads and more experienced licensed psychologists and a CBT‐therapist supported the majority of participants. Further, psychology program student e‐therapists spent a mean time of 2.9 h per participant, per week, which is more therapist time than reported in other studies on guided internet‐administered CBT interventions.In summary, the following modifications to the study protocol and EJDeR are warranted before commencing a pilot RCT: (1) collection of outcome assessment data via telephone; (2) reducing the number of measures; (3) adaptation of the intervention to improve the feasibility and acceptability of EJDeR; (4) recruitment of a trial coordinator; (5) recruitment of part‐time employed e‐therapists to increase caseloads and decrease time spent on each participant; (6) use of electronic CRFs to facilitate data collection and entry; and (7) training of research team members to collect research data over the telephone.5Using robust methods, including a priori specified progression criteria, the use of novel recruitment strategiesElla Thiblin: Data curation ; formal analysis ; investigation ; validation ; visualization ; writing – original draft . Joanne Woodford: Formal analysis ; methodology (supporting); project administration (supporting); supervision (supporting); writing – original draft . Christina Reuther: Data curation ; formal analysis ; investigation ; validation ; visualization ; writing – review and editing (supporting). Johan Lundgren: Supervision (supporting); writing – review and editing (supporting). Nina Lutvica: Data curation (supporting); investigation ; validation (supporting); writing – review and editing (supporting). Louise von Essen: Conceptualization (lead); funding acquisition (lead); methodology (lead); project administration (lead); resources (lead); supervision (lead); writing – review and editing (lead).This work is supported by the Swedish Research Council , the Swedish Cancer Society (grant number 15 0673 and 17 0709), the Swedish Childhood Cancer Foundation (grant number PR2017‐0005), and funding via the Swedish Research Council to U‐CARE, a Strategic Research environment (Dnr 2009‐1093). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of interest: none.The ENGAGE feasibility trial was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr: 2017/527) and was conducted in accordance with the Helsinki Declaration, ensuring the welfare and rights of all participants, and Good Clinical Practice (GCP) guidelines. Ethical amendment was obtained from Swedish Ethical Review Authority August 07, 2019, ref: 2019‐03083.Not applicable.Not applicable.ISRCTN 57233429.Data S1Click here for additional data file.


Real‐world evidence on immune‐related adverse events (irAEs) are relatively insufficient. Herein patterns and outcomes of irAEs after administration of anti‐programmed cell death 1 (PD‐1) and its legend 1 (PD‐L1) antibodies were investigated.Patients treated with anti‐PD‐1/PD‐L1 drugs from January 2018 to September 2021 at Huadong Hospital, Fudan University were included. Common Terminology Criteria for Adverse Events (CTCAE) was used for irAEs evaluation. The primary endpoints were the clinical description of irAEs.p = 0.013) and overall survival (OS) (p = 0.007), respectively, than patients without irAEs. In addition, patients with skin toxicities (p = 0.012) or blood toxicities (p = 0.015) had achieved a longer PFS, than those without corresponding toxitities, respectively.Two hundred and forty‐one solid tumor patients were included, with lung cancer as the most common tumor type (56%). 187 (77.6%) patients presented any kind of irAEs. The median time to any irAE onset was 28 (95% CI 24–32) days. Skin toxicities are the most common irAEs (46.1%) and the irAEs (36.5%) occurred earliest after immune‐checkpoint inhibitors. The most frequently occurred all‐grade irAEs were rash (23.7%), myelosuppression (20.7%), and hepatic injury (19.5%). 23 (9.5%) patients died of severe irAEs, which consists of 10 patients with pneumonitis, four colitis, four myocarditis, and one each for gastritis, pulmonary embolism, myelosuppression, hypophysitis, and encephalitis. Patients with any irAE onset had significantly longer progression‐free survival (PFS) (Most irAEs are mild and manageable, while some irAEs can present at later time or can be life‐threatening, especially pneumonitis as we observed. Patients with any irAE onset may achieve a better prognosis than those without irAEs, and presentation of skin or blood toxicities will indicate a better PFS. Firstly, irAEs can affect any organ system, especially organs with extensive environmental interfaces or harboring presumed pre‐existing autoimmunity.Currently, most knowledge of our understanding of irAEs comes from clinical trials, which have rigorous inclusion and exclusion criteria. Charateristics of irAEs, such as incidence, patterns of time to onset, and time to recovery in real‐world settings, are relatively unknown. In this real‐world observational study, we investigated the patterns and outcomes of irAEs presented in a pan‐cancer cohort treated with PD‐1/PD‐L1 inhibitors. Relationships between irAEs onset and patients' progression‐free survival (PFS) and overall survival (OS) were also studied.22.1A monocentric real‐world study was conducted at Huadong Hospital, Fudan University. Patients who received at least one administration of anti‐PD‐1/PD‐L1 drugs from January 1, 2018 to September 30, 2021 were included. Patients eligible for inclusion were those who were histologically diagnosed with non‐metastatic or metastatic solid tumors, aged ≥18 years (except for lymphoma which may develop at earlier ages), treated with ICIs as a single agent or in combination with other standard antitumor strategies such as chemotherapy. ICIs used in the perioperative period or for advanced stages were both allowed. Exclusion criteria were patients who developed multi‐site primary tumors, received systemic corticosteroids , or other immunosuppressive drugs within 14 days prior to initial ICI administration, previously treated with antitumor vaccine or immune‐stimulating agents (including ICIs), or those with insufficient information . This study was performed in accordance with the Declaration of Helsinki.2.2Data regarding patient demography and clinical characteristics were collected from electronic medical records. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. All irAEs were recorded and classified based on the affected organ. In addition, subtypes of irAEs were classified according to the organ/system and the degree of affectation according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (version 5.01).All irAEs were analyzed, according to medical notes and our follow‐up data by phone and/or outpatient service. Two reviewers (Ge X and Cui S) evaluated the irAEs based on medical records and will have a discussion with all authors if inconsistences occur. In order to homogeneously record the adverse events, all were classified according to the CTCAE (version 5.01), such as gastrointestinal disorders, respiratory disorders, skin and subcutaneous disorders, and endocrine disorders, and etc. Additionally, each adverse event is graded as Grade 1 to Grade 4 (or Grade 5) according to CTCAE criteria. Of note, myelosuppression is recorded as one type of irAE in this study as we would like to provide information on the occurrence of myelosuppression after the use of ICIs combined with chemotherapy in real‐world settings, considering most patients in our study cohort received a combination regimen containing an ICI plus chemotherapy. Cutoff date of this study was September 30, 2022.2.3The primary endpoints were the clinical descriptions of irAEs after anti‐PD‐1/PD‐L1 treatment. Secondary endpoints were PFS and OS descriptions, and the correlations between irAEs onset and PFS or OS. Time to onset was defined as the time between the date ICI was first administered and the date of first clinical, radiographic, or biological abnormalities of irAEs. Time to recovery was defined as the date from the initiation of irAEs to the date when irAEs were resolved. PFS was calculated as the time from the date ICIs were first administered until the date of objective progressive disease (PD)  according to RECIST, or all‐cause death. OS was defined as the time between the date ICIs were first administered until date of death from any reason.2.4IrAEs were evaluated in the whole cohort. Incidence rate, grade, median onset time, clinical management, proportions of recovery with median recovery time, proportions of irAEs leading to ICIs discontinuation, dose reduction, delayed prescription, or death were analyzed. PFS and OS was evaluated in the population whose survival were more than 90 days after ICIs treatment. Any irAE, specific irAEs with an incidence of ≥10% were included in survival analysis. For the correlation of any irAE onset and PFS or OS, analysis was also done in the whole cohort as a sensitivity evaluation.Enter method was used to estimate hazard ratios (HRs), and to compare differences between groups. Adjusted p values and HRs were given after adjustment for gender, age, smoking status, ICI drugs, treatment timing, combinations, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS). p values less than 0.05 were considered statistically significant. Statistical analysis was performed with IBM SPSS Statistics . Density plots and boxplots were generated using R (version 4.2.0).Categorical variables were described with the use of frequency counts and percentages, while continuous variables were described with the use of mean or median and range. The Kaplan–Meier method was applied to estimate time‐to‐event variables. For PFS and OS, a Cox regression model with 33.1A total of 241 patients received at least one administration of anti‐PD‐1 or anti‐PD‐L1 inhibitors at our center were enrolled Figure . The mea3.2General information for irAEs is shown in Table 3.3IrAEs stratified by systems/organs are summarized in Table The time to onset of each irAE is also calculated Table . In the In our cohort, most irAEs were managed with symptomatic treatment and finally recovered Table . The med3.4p = 0.013) and OS (719 [568–870] vs. 626 (371–881) days, aHR = 0.58 [95% CI 0.38–0.89], p = 0.007), respectively, than patients without irAEs  and 86  patients had PFS and OS events, respectively. Median PFS and median OS of the cohort were 459 (95% CI 364–554) and 656 (95% CI 553–759) days, respectively. Patients with any irAE onset had significantly longer PFS (461 [95% CI 336–586] vs. 371 (173–569) days, aHR = 0.58 [95% CI 0.38–0.89], Es Table . SensitiEs Table .p = 0.012) and blood toxicities , compared with patients without corresponding toxicities ; data curation ; formal analysis ; validation ; writing – original draft ; writing – review and editing . Weiping Jiang: Data curation ; formal analysis ; validation . Hongqing Li: Data curation ; formal analysis ; validation . Yanxu Wu: Data curation ; formal analysis ; validation . Xiangyang Li: Data curation ; formal analysis ; methodology (lead); supervision (lead); validation . Shaohua Cui: Conceptualization (lead); data curation ; methodology ; project administration (lead); supervision (lead); writing – original draft ; writing – review and editing .This work was supported by the Key Discipline Project of Huadong Hospital, Fudan University (grant number: ZDXK2216), and the Key Project of Huadong Hospital, Fudan University (grant number: 2019jc028). The funders had no role in the planning or execution of the study.The authors have no conflict of interest.This study was approved by the Ethics Committee of Huadong Hospital, Fudan University, Shanghai .Table S1.Click here for additional data file.


The COVID‐19 pandemic worldwide has caused varying degrees of severity of lung damage in patients, with acute respiratory distress and death in severe cases. However, this is not directly caused by the virus itself, but by the production of inflammasome by monocytes in the body, leading to a systemic inflammatory response, which results in a very poor clinical prognosis for patients with COVID‐19.The purpose of this meta‐analysis was to look at the relationship between hypernatremia and mortality in COVID‐19 patients.We searched the PubMed, Web of Science, Embase, and Cochrane databases for articles published from the inception of the database until August 27, 2022. Three researchers reviewed the literature, retrieved data, and assessed the quality of the literature, respectively. A meta‐analysis was performed using State 17 software to assess the value of the effect of hypernatremia on mortality in patients with new coronavirus pneumonia.p = .002, I² = 66.7%] with a sensitivity of 0.36  and a specificity of 0.88 . The posterior probability of mortality was 42% in patients with COVID‐19 hypernatremia and 15% in patients who did not have COVID‐19 hypernatremia.A total of nine publications was finally included in this study, including a total of 11,801 patients with COVID‐19, including 1278 in the hypernatremia group and 10,523 in the normonatremia group. Meta‐analysis showed that hypernatremia was associated with mortality in patients with COVID‐19 [OR = 4.15, 95% CI (2.95–5.84), According to available data, hypernatremia is associated with death in patients with COVID‐19. Hypernatremia is associated with death in patients with COVID‐19. And as of September 4, 2022, the novel coronavirus has spread greatly in the population and has spread in more than 200 countries worldwide, and the World Health Organization has reported more than 600 million confirmed cases of novel coronavirus pneumonia and more than 6.4 million deaths.Although mild to moderate symptoms are now common in patients infected with COVID‐19, critical care or respiratory support is still required for patients in a critical state. Disturbances in electrolyte levels are a common clinical phenomenon in patients suffering from COVID‐19,2This is a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines compliant meta‐analysis. This meta‐analysis is registered at PROSPERO (PROSPERO ID: CRD42021233592).2.1Studies meeting the following criteria were included: (1) retrospective and prospective cohort studies, (2) patients with confirmed diagnosis of novel coronavirus pneumonia (3) hypernatremia and normonatremia (4) patients ≥18 years of age. Studies meeting the following criteria were excluded: (1) review‐type literature, (2) case reports, (3) conference abstracts, (4) duplicate reports, (5) literature with missing data, and (6) pregnant women. Pregnant women were excluded to reduce bias due to physiological status and changes in glomerular filtration and renal plasma flow that are specific to the general population.2.2Two researchers systematically searched PubMed, Web of Science, Embase, and Cochrane literature databases for studies of hypernatremia associated with patients with COVID‐19 through August 2022, and we used a combination of subject terms and free words to search for keywords including: “COVID‐19, 2019‐nCoV Disease, COVID‐19 Virus Infection, etc., Hypernatremia, hypernatraemia, Hypernatremias, hypernatriaemia, hypernatriemia.” The retrieved articles were managed using EndNote X9.1, and the relevant literature cited in these articles was read.2.3First, three researchers independently read the document titles and summaries, reviewed the required documentation against inclusion and exclusion criteria, and extracted the data for analysis. If disagreements were identified during the screening process, the issues were addressed through discussion or expert advice. Data were noted using a Microsoft Excel worksheet, including first author, country, time of publication, type of study design, sample size, age (Mean ± SD), male (%), hypernatremia cutoff range, length of stay, ICU admission, and mortality.2.4Two investigators independently assessed the quality of the referenced literature using the Newcastle‐Ottawa scale (NOS), and consulted a third party to solve the problem when there was bias in the results. NOS consisted of three main aspects: study population selection, comparability between groups, and exposure evaluation or outcome evaluation. The score is 9 out of 9. Studies of low quality: 0–3, studies of average quality: 4–6, and studies of high quality: 7–9.2.5p < .05 indicating a statistically significant difference. For the test of heterogeneity I2 > 50%, p ≤ .1, suggesting significant heterogeneity, Meta‐analysis was performed using the random‐effects model, considering the source of their heterogeneity and dealing with it; for the test of heterogeneity I2 ≤ 50%, p > .1, indicating relatively little heterogeneity among studies, the fixed‐effects model was used. The included documentation was analyzed for release bias using the State 17 software Egger test.We conducted a statistical analysis of the included literature using the State 17 software. Effect value indicators for the effect of hypernatremia on mortality in patients with novel coronavirus pneumonia were expressed using the ratio (OR), 95% confidence interval (95% CI), with 3Initially, 253 publications were researched, including 24 in PubMed, 48 in Web of Science, 168 in Embase, and 13 in Cochrane, with articles published up to August 27, 2022. Seventy‐eight duplicates were removed using Endnote software, then the titles and abstracts of the literature were read according to the inclusion and exclusion criteria, 142 irrelevant papers were excluded, and finally, the contents of the remaining 33 papers were carefully read, and a total of 9 matching papers were includedThe definition and extent of hypernatremia were measured in seven of the nine included studies that measured blood sodium levels on admission, and one study recorded peak blood sodium levels during hospitalization in patients with COVID‐19.3.1p = .002, I² = 66.7%] showed significant heterogeneity between the included studies by heterogeneity test. Consequently, the included studies were reanalyzed using a randomized model, and the results showed that hypernatremia was associated with mortality in COVID‐19 patients , With a significant statistical difference, as illustrated in Figure Analysis of the association between hypernatremia and mortality in patients with novel coronavirus pneumonia using a fixed effects model [OR = 4.31, 95% CI (3.78–4.90), 3.2To explore the source of heterogeneity, we have plotted Galbraith using Stata 17 software, see Figure 3.3I² = 66.6%), we performed separate subgroup analyses for sample size (>200 cases) and study type (retrospective cohort study), which showed a significant decrease in heterogeneity. Analysis of subgroups of studies that have a sample size greater than 200 cases is presented in Figure p < .05). We then analyzed subgroups from seven retrospective cohort studies, see Figure p < 0.05). We did not perform subgroup analyses prospective studies alone, as these two original papers were the main source of heterogeneity.Given the large study heterogeneity (I² = 85.7%), a random‐effects model analysis was used, which showed an association between hypernatremia and ICU admission ,  was much lower than the proportion of deaths in the hypernatremia group of patients with COVID‐19 (622/1278). The occurrence of hypernatremia was associated with mortality in COVID‐19 patients compared with COVID‐19 patients who did not develop blood sodium abnormalities during hospitalization [OR = 4.31, 95% CI (3.78–4.90), COVID‐19 pandemics around the world are primarily caused by SARS‐CoV‐2 infections, and the clinical presentation can range from asymptomatic to mild upper respiratory tract infections or severe lung injury. SARS‐CoV‐2 infection induces a cytokine storm (CS) leading to the release of proinflammatory cytokines, such as interleukin (IL)−6, IL‐1β, and tumor necrosis factor (TNF)‐α, which play an important role in the progression of COVID‐19, and the mechanism is mainly related to the interaction between SARS‐CoV‐2 and immune cells.Studies have shown that SARS‐CoV‐2 can cause damage to the respiratory, neurological, cardiovascular, gastrointestinal, and genitourinary systems of patients, and its most common clinical symptoms include fever, cough, malaise, anorexia, and shortness of breath.Second, COVID‐19 patients are predisposed to gastrointestinal problems, with major symptoms including diarrhea, nausea, vomiting, and abdominal pain.Insensible water loss due to fever and shortness of breath can cause the development of hypernatremia in patients. The respiratory tract and skin are the main sources of insensible water loss, a normal adult loses approximately 1000 mL of water per day through the respiratory tract and skin, and in the case of fever, fluid loss through the skin will increase by 3‐5 mL/kg/day for every 1°C rise in body temperature. The most common symptom in patients with COVID‐19 is fever, which is prevalent in up to 90% of cases,Studies have shown an association between the development of hypernatremia in COVID‐19 patients and admission to the ICU. A large number of previous studies have shown that hypernatremia is a common clinical phenomenon in the ICU,Of the nine original papers we included, because the definition of patient mortality in Atila's literature was different from the rest of the literature, which may have influenced the results of the study,This study also has some limitations; first, although our findings showed an association between hypernatremia and mortality in patients with COVID‐19, this does not indicate a causal relationship. Second, this study mainly involved retrospective clinical studies, and we were unable to analyze the severity of the disease in admitted patients and postadmission treatment measures, so there may be heterogeneous in the severity of disease and treatment options, which may affect the results of meta‐analysis.In conclusion, the available data suggest a relationship between hypernatremia and mortality in patients with novel coronavirus pneumonia and an impact on ICU admission in patients with COVID‐19. In the future, it is important for physicians to identify risk factors for hypernatremia at an early stage in clinical practice, and patients who are already hypernatremia at the time of admission should be monitored and treated with a view to reducing hypernatremia in patients and decreasing mortality in patients with COVID‐19.Yongzhi Ma: Study design; data collection; data analysis; writing. Panjuan Zhang: Data collection; data analysis; writing. Ming Hou: Study design.The authors declare no conflict of interest.


All patients were on stable background therapy with phosphodiesterase-5 inhibitor and endothelin receptor antagonist therapies at baseline. All patients reached their planned goal selexipag dose during admission without the need for changes to the titration schedule and without hemodynamic deterioration. In our experience, oral selexipag is safe and well-tolerated in young pediatric patients with pulmonary hypertension. Based on our favorable experience, we developed an institution-specific selexipag process algorithm for continued successful use in the pediatric population.Selexipag, a selective prostacyclin receptor agonist, is approved for treating pulmonary arterial hypertension in WHO Group 1 adult patients. Compared to parenteral prostacyclin formulations, selexipag offers a significant improvement in patient’s and caregiver’s quality of life because of its oral formulation, frequency of administration, and mechanism of action. Although experience in the pediatric population is limited and selexipag is not FDA-approved for use in the pediatric pulmonary hypertension population, many US pediatric centers are expanding the use of this therapy to this younger population. We report our institution's experience in the use of selexipag to treat pulmonary hypertension in children under 10 years of age, between 10 and 30 kg. Seven patients were initiated on selexipag therapy including  Current therapies target three main physiologic pathways: the nitric oxide, endothelin, and prostacyclin pathways. Oral agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic PH in adults include phosphodiesterase-5 inhibitors , endothelin receptor antagonists , prostacyclin analogs such as oral treprostinil, and soluble guanylate cyclase stimulators (riociguat). Oral agents are generally preferred by patients and families over parenteral or inhaled therapies due to lower treatment burden and are therefore associated with increased medication adherence. Selexipag, a selective prostacyclin receptor agonist, was approved by the FDA in 2015 as the second oral prostacyclin pathway-targeted therapy option for adult WHO Group 1 patients. Clinical trials demonstrated a lower incidence of side effects, less frequent dosing, and administration without regard to food compared to oral treprostinil . Using pictorial graphs and medication calendars, education was provided on different tablet strengths, the importance of adherence, and timely administration.de novo initiation in children <30 kg, selexipag was initiated at 50 μg every 12 h and rapidly titrated up in 50 μg per dose per day increments until the goal dose was achieved, roughly 4 days. To determine the goal dose, we utilized an equivalent of IV treprostinil; 10 ng/kg/min IV treprostinil was equivalent to 100 μg selexipag every 12 h for patients <30 kg and 10 ng/kg/min IV treprostinil was equivalent to 200 μg selexipag every 12 h for patients ≥30 kg. Upon reaching the goal dose, the patient was discharged to continue slower titration in the outpatient setting.For Similarly, to determine selexipag goal dose and titration increments for transitions from IV treprostinil to oral selexipag, we utilized an equivalent of IV treprostinil; 10 ng/kg/min IV treprostinil was equivalent to 100 mcg selexipag every 12 h for patients <30 kg and 10 ng/kg/min IV treprostinil was equivalent to 200 μg selexipag every 12 h for patients ≥30 kg. During the rapid transitions from IV treprostinil, selexipag was administered first and immediately followed by IV treprostinil dose reduction by an increment of 2–5 ng/kg/min per step. Selexipag 200 μg tablets were used to facilitate dose titrations and adjustments. For smaller-dose titration steps and/or patients who could not swallow tablets, 200 μg tablets were dissolved in 4 ml of water to yield a mixture of 50 μg/ml, as described by Koo et al. , right ventricular (RV) pressure estimate, and baseline mean pulmonary artery pressure (mPAP) as measured within the past year.3.3.1.3.1.1.A 3-year-old boy with WHO Group 1 PAH presented with the worsening disease despite dual-targeted therapy. The mPAP at diagnosis was 36 mmHg. However, 2 years later, when referred to our center, the RV systolic pressure estimate by echocardiogram was at least 61 mmHg. Past medical history was significant for persistent pulmonary hypertension of the newborn and bone marrow transplant in the context of MECOM mutation. Parenteral prostacyclin therapy was recommended but declined by the family due to the perceived treatment burden. Selexipag therapy was therefore agreed upon as an alternative.At the time of selexipag initiation, the patient weighed 14.6 kg. A baseline 6-min walk test could not be done due to age/developmental status. The baseline echocardiogram estimate of RV pressure was at least 70 mmHg. Cardiac catheterization had not been repeated since diagnosis 2 years prior. Selexipag was initiated at 50 μg (1 ml of 200 μg/4 ml solution) every 12 h. Over the course of the next 4 days, selexipag dosing was titrated by 50 μg per dose once daily up to the goal dose of 200 μg every 12 h. The patient tolerated the transition well without significant events. Six months after initiation, the family reported subjective improvement in activity and endurance. On serial assessments, the child was noted to have increased weight gain and a consistent increase in 6MWD. The echocardiographic estimate of RV systolic pressure was 77 mmHg. Although he was clinically progressing in a positive direction, since his echocardiogram was largely unchanged, the selexipag dose was increased without complication by 100 μg per dose weekly up to 400 μg every 12 h. Functional class improved from class III to class II. Cardiac catheterization was performed 19 months after selexipag initiation, and mean PAP was 56 mmHg, consistent with echocardiograms at that time. Concerns about consistent oral dosing administration and absorption prompted reconsideration of parenteral prostacyclin therapy, so the child was ultimately transitioned successfully from selexipag to IV treprostinil.3.1.2.A 5-year-old girl with trisomy 21 and PH associated with the late repair of atrioventricular septal defect (AVSD) presented with worsening PH. Comorbidities included a history of extracorporeal membrane oxygenation, tracheostomy, gastrostomy tube placement, adrenal insufficiency, factor V Leiden deficiency, and hypothyroidism. Although she had been classified as a Group 1 PAH patient, recurrent aspiration and associated chronic lung disease were suspected, prompting consideration for Group 3 exacerbating diseases. She had been on dual therapy; however, interval catheterization showed elevated PA pressures and indexed pulmonary vascular resistance. Selexipag was selected due to limited caregiver resources to support parenteral prostacyclin therapy in the outpatient setting.At the time of selexipag initiation, the patient weighed 15.1 kg. The baseline 6-min walk distance was 254 m. The baseline echocardiogram estimate of RV pressure was 44 mmHg. Baseline cardiac catheterization was 53 mmHg before selexipag initiation. Selexipag was initiated at a dose of 50 μg (1 ml of 200 μg/4 ml solution) every 12 h over 4 days. Selexipag dose was titrated by 50 μg per dose each day up to the goal dose of 200 μg every 12 h. Once outpatient, dose titration continued to 250 μg every 12 h. However, with this continued dose titration, the caregiver noted facial flushing, decreased appetite, intermittent diarrhea, and headache, so the dose was decreased back to selexipag 200 μg every 12 h. Six months after initiation, the child's functional status was judged to be improved to class I, and the family reported subjective improvement in activity and endurance. Her 6MWD was improved to 314 m. The echocardiographic estimate of RV systolic pressure was 43 mmHg. Interval cardiac catheterization had not yet been completed (elapsed time since initiation = 12 months) at the time of manuscript submission.3.2.3.2.1.A 5-year-old girl on triple combination therapy to treat severe hereditary PAH (Group 1 secondary to BMPR2+ and KCNA5+ mutations) was evaluated for conversion from IV treprostinil to selexipag due to repeated admissions for central venous line-related complications (damaged line and infections).At the time of selexipag initiation, the patient weighed 14 kg. The baseline 6-min walk distance was 190 m. The baseline echocardiogram could not estimate RV pressure; however, the septal motion was moderately to severely flattened with associated moderate RV dysfunction. Baseline cardiac catheterization measured mPAP 59 mmHg before selexipag initiation. The patient was started on selexipag 100 μg every 12 h and increased by 100 μg per dose daily while decreasing IV treprostinil by 5 ng/kg/min every 12 h. The transition from IV treprostinil 62 ng/kg/min to selexipag 600 μg every 12 h was completed in 6 days. The transition was well tolerated. Six months after initiation, the child's functional status was judged to be class II. The family reported subjective improvement, and at the time of this study, she has not had any more admissions since conversion to selexipag. Her 6MWD was 292 m at 6 months post-transition. The echocardiographic estimate of RV systolic pressure could not be quantified; however, the septum was noted to be flattened, and RV systolic function was judged normal. Interval cardiac catheterization has not been done due to social barriers affecting scheduling (elapsed time since transition = 23 months).3.2.2.An 8-year-old girl was newly diagnosed with Group 1 PAH after 1 year of worsening dyspnea with exercise, syncopal episodes, and severe right ventricular dysfunction necessitating extracorporeal membrane oxygenation support. Baseline cardiac catheterization data were obtained while on (clamped) extracorporeal support ad epinephrine, vasopressin, and calcium chloride infusions. The mean PA pressure on this support was measured to be 35 mmHg. She was able to come off mechanical support on upfront combination therapy of tadalafil, ambrisentan, and IV treprostinil 36 ng/kg/min. The patient had a surprisingly robust response to therapy, with complete normalization of the echocardiogram. Due to limited resources for the family and the normal echocardiogram, prostacyclin therapy was adjusted from IV treprostinil to selexipag.At the time of selexipag transition, the patient weighed 30.6 kg. Baseline 6MWD could not be done since the child was still admitted to intensive care and was judged to be too critically ill to participate in testing. A baseline echocardiogram performed on IV treprostinil prior to transition could not quantify the RV pressure estimate; however, septal motion and RV function were normal. She was started on selexipag 100 μg every 12 h. IV treprostinil was decreased by 4 ng/kg/min twice daily immediately after each selexipag dose. Selexipag was increased by 100 μg per dose daily in the morning until a goal dose of 800 μg every 12 h was achieved. She transitioned over 6 days and tolerated the transition well with no side effects. At the 6-month follow-up, the child's functional status was judged to be class I. Her 6MWD at 6 months was 469 m. The echocardiographic estimate of RV systolic pressure was 33 mmHg. Interval cardiac catheterization showed an mPAP of 30 mmHg.3.2.3.An 8-year-old boy with idiopathic PH (due to ABCA3 point mutation), WHO Group 1, on triple therapy with ambrisentan, tadalafil, and SQ treprostinil dose of 100 ng/kg/min was identified for selexipag therapy to improve quality of life after 6.5 years of SQ therapy. At the time of selexipag initiation, the patient weighed 18 kg. The baseline 6-min walk distance was 391 m. The baseline echocardiogram estimate of RV pressure was 64 mmHg. Baseline cardiac catheterization, done on triple therapy 2 years before transition, measured an mPAP of 26 mmHg. Of note, it had been 35 mmHg on diagnostic catheterization 5 years prior. Selexipag was initiated at 100 mcg every 12 h. Intravenous treprostinil was decreased by 5 ng/kg/min twice daily immediately after every selexipag dose. Selexipag was increased by 100 mcg per dose once daily up to a goal of 600 μg every 12 h over 6 days. The patient tolerated the transition well during the admission. He was discharged 12 h after the last dose change without any adverse events. Selexipag dose was increased outpatient to 1,200 μg every 12 h over the following year. Six months after initiation, the child's functional status was still considered class I, and the family reported great energy levels as demonstrated by the child running laps with other children. His 6 MWD was 566 m. The echocardiographic estimate of RV systolic pressure was 52 mmHg. Interval cardiac catheterization 9 months after transition showed an mPAP of 29 mmHg.3.2.4.A 10-year-old boy with PH, WHO Group 1, on triple therapy with ambrisentan, tadalafil, and IV treprostinil 128 ng/kg/min, was identified for selexipag therapy. The treatment plan was tailored to encourage remodeling for the ultimate closure of a patent ductus arteriosus (PDA); however, cardiac catheterization data did not support intervention. Unfortunately, lung transplantation was not a good option because of the preserved right ventricular function. Therefore, in consideration for quality of life given the unlikely consideration for ductal closure, conversion from IV treprostinil to selexipag was offered.At the time of selexipag initiation, the patient weighed 23 kg. His baseline 6MWD was 547 m. The baseline echocardiogram showed a bidirectional shunt across the PDA. Baseline cardiac catheterization measured an mPAP of 52 mmHg before selexipag transition. He was on IV treprostinil 128 ng/kg/min, which was weaned down weekly outpatient to 100 ng/kg/min, with regular echocardiographic monitoring. The reason to decrease the treprostinil dose outpatient prior to transitioning to selexipag was to decrease overall hospital stay and start selexipag at a dose that fits within the approved adult dosing recommendation  When he reached the target IV treprostinil dose of 100 ng/kg/min, he was admitted and started on selexipag 100 μg every 12 h. Treprostinil was decreased by 5 ng/kg/min twice daily immediately after every selexipag dose. Selexipag was increased by 100 mcg per dose once daily up to a target dose of 1,000 μg every 12 h over 10 days. He was discharged 24 h after the last dose change. He had no side effects during admission, and his upper and lower extremity oxygen saturations were noted to be matched. Selexipag was increased outpatient to 1,200 μg every 12 h to address frequent leg cramps and tiring; however, he had increased side effects  with a morning dose of selexipag. This was treated with more consistent meals, ondansetron pretreatment, and oxygen supplementation during meals. As side effects improved, his dose was increased over 2 months to 1,600 μg every 12 h outpatient. After reaching the maximum dose, he reported a good energy level and fewer foot desaturations. Six months after initiation, the child's functional status was class II. His 6MWD was 577 m. Echocardiograms continued to demonstrate the bidirectional shunt (unchanged) at the PDA. Interval cardiac catheterization showed an mPAP of 51 mmHg.3.2.5.A 2-year-old boy patient with repaired D-transposition of the great arteries who was subsequently palliated with reverse Potts shunt procedure for continued severe disease presented for conversion from SQ treprostinil to selexipag in the post-Potts shunt period. The postoperative period was unremarkable; however, the child experienced frequent site changes and skin reactions to the subcutaneous dressing, so he was transitioned to selexipag. At the time of selexipag initiation, the patient weighed 10.5 kg. The baseline 6-min walk distance could not be done due to age and mobility. The baseline echocardiogram showed a bidirectional shunt at the level of the reverse Potts shunt. Baseline cardiac catheterization measured an mPAP of 76 mmHg before selexipag titration. The patient started titration at a dose of 50 μg selexipag (1 ml of 200 μg/4 ml solution) every 12 h. In contrast to the other treprostinil to selexipag transition patients, 2 ng/kg/min treprostinil steps were selected due to the patient's previous history of sensitivity with dose escalation of prostacyclin, during SQ treprostinil initiation. Treprostinil was decreased by 2 ng/kg/min twice daily immediately after every selexipag dose. Selexipag was increased by 50 mcg per dose once daily to a goal dose of 200 mcg every 12 h over 5 days. He tolerated the transition well, with no side effects. He was discharged 12 h after the last dose change. As an outpatient, he was transitioned to tadalafil, and the selexipag dose was increased to 600 mcg every 12 h over 4 months. Six months after initiation, the child's functional status continued to be class I. The family reported matched upper and lower extremity saturations. The child was noted to have consistent weight gain. At the time of this study, he remained developmentally too young for 6MWD. Echocardiograms were stable on selexipag, demonstrating the bidirectional shunt across the reverse Potts shunt. Interval cardiac catheterization was not sought post-transition (elapsed time = 15 months).3.3.de novo initiation, and five (71%) patients were transitioned on admission from intravenous treprostinil to oral selexipag. Four of seven (57%) patients were boys. Four of seven (57%) patients were 5 years old or younger. All patients were WHO Group 1 and were on stable background therapy with a PDE5 inhibitor and endothelin receptor antagonist. Selexipag dosing strategies and clinical characteristics before and after selexipag initiation are also represented in Patient demographics prior to selexipag therapy are displayed in 4.de novo initiation and rapid transition from treprostinil to oral selexipag in young pediatric patients aged 2–10 years old. Our experience allowed us to develop an institution-specific algorithm (This case series describes our experience with lgorithm  and selelgorithm  to help de novo selexipag initiation was 4 days. The median duration of the rapid transition to selexipag was 6 days (5–10 days) as it was dependent on the patient's initial treprostinil dose and goal selexipag dose. Patients were generally ready for discharge by 12 h after receiving the final titration dose and were either discharged the same day or the next day, depending on consideration of hour of the day. All patients in our cohort completed the transition as planned, without unexpected events, adverse side effects, and any deterioration in hemodynamic parameters.The dosing strategy and transition methodology were developed on principles of dose escalation of parenteral prostacyclin therapy, treprostinil and selexipag pharmacokinetics, and historical experience with transitions from IV to oral treprostinil. The median duration of via a nasogastric or gastric feeding tube.Clinical data to support the nasogastric or gastric feeding tube administration route of selexipag is lacking in this population; however, it was deemed successful based on subjective and objective improvement, supporting absorption, in both of our patients. We used the preparation method described in the 2021 case series by Koo et al.  with dosFactors we considered relevant for pediatric selexipag therapy were stable disease , stable prostacyclin doses, quality of life, and availability of resources to support parenteral prostacyclin therapy. Prior to selexipag, our patients were challenged by SQ site infections, SQ site pain, and central line complications. After the transition to selexipag, patients have remained hemodynamically stable and without disease progression, as documented by echo and 6MWD. We believe selexipag may play a role in reducing overall healthcare costs through reduction in unscheduled admissions as our patients admitted frequently for complications due to IV/SQ treprostinil therapy have not had an unscheduled admission since selexipag. All of our patients and their caregivers reported improvements in quality of life. We suggest that our institution-specific algorithm  and dosiA limitation of our case series is the size of the population. However, while our overall cohort was small, we described a consistent experience in using selexipag across a wide age and weight range. Since September 2021, we have applied this process to 10 more patients, all with the same level of success. It must also be noted that process implementation started in May 2020, during the COVID-19 global pandemic. This impacted our ability to directly monitor these patients closely for follow-up postinitiation in the outpatient setting. Due to clinical and access constraints, there were decreased encounters for in-clinic visits, 6MWD testing, echocardiography, and cardiac catheterization testing. Therefore, in some instances, follow-up may not be truly long-term or complete.5.de novo initiation and rapid transition from parenteral treprostinil to selexipag were well-tolerated and safe for children 2–10 years of age and 10–30 kg of body weight. With the support of continuous monitoring in the PICU and thorough education provided by the PH team, medical providers were able to effectively and confidently follow the titrations as planned, and each patient was successfully transitioned home to continue therapy. Follow-up data on selexipag were stable for every patient, without any evidence of clinical worsening. Given this favorable experience and follow-up, selexipag may be a reasonable oral therapy to consider in treating severe but stable pediatric PH. The process algorithm presented can be regarded as a pediatric-specific framework for successful selexipag initiation or transition in this population.This case series summarizes our center's experience in introducing selexipag therapy in young pediatric patients. Using a process specific to pediatric pharmacokinetics and pharmacodynamics,