JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D  production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO  were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors.  The primary site of FGF23 action is the proximal renal tubules, where, by signaling through fibroblast growth factor receptor 1 (FGFR1) and the coreceptor KLOTHO, it inhibits renal phosphate reabsorption and 1,25‐dihydroxy‐vitamin D  production. The net result is chronic hypophosphatemia, leading to rickets in children and osteomalacia in adults, and associated muscle weakness, bone pain, deformity, and fractures.Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome that presents clinically with pain, weakness, and fractures. It is caused by ectopic fibroblast growth factor 23 (FGF23) secretion by phosphaturic mesenchymal tumors (PMTs).1, 2PMTs are typically solitary, benign lesions that are often difficult to locate. When the tumor is found, complete surgical resection is usually curative. Some patients with TIO are not amenable to surgery due to tumor nonlocalization, significant surgical risk, distant or local metastases, or patient preference. If surgery is not possible, other tumor‐directed therapies, such as cryoablation, radiofrequency ablation, or radiotherapy have been used, although long‐term efficacy from these approaches is lacking.6, 7 With current medical treatment options, there remains a risk of continued tumor growth or tumor metastasis.Conventional medical therapy, with either a combination of phosphate and calcitriol, or burosumab, an FGF23‐blocking monoclonal antibody, effectively treats the consequences of hypophosphatemia, but does not target the tumor directly.8, 9 The fusion protein presumably includes the extracellular fibronectin autodimerization domain, and the FGFR1 ligand‐binding, transmembrane, and intracellular signaling domains, which would suggest that FGFR1 signaling may have a prominent role in tumorigenesis and FGF23 secretion, and thus be a therapeutic target in TIO.Chromosomal translocations resulting in a fibronectin 1‐FGFR1 (FN1/FGFR1) fusion gene have been identified in approximately 40% of resected PMTs.12 The and was recently US Food and Drug Administration (FDA)‐approved for the treatment of previously treated cholangiocarcinoma with FGFR2‐gene fusions or rearrangements. In non‐TIO cancers, hyperphosphatemia is a common dose‐limiting side effect of infigratinib treatment due to blockade of FGFR1 and the associated inhibition of FGF23 signaling.Infigratinib  is an orally bioavailable, FGFR1‐3 tyrosine kinase inhibitor (TKI) that has been studied in phase 2 trials of cancers with FGFR molecular alterations,17 and Remarkably, pretreatment and posttreatment biopsies of PMT metastases showed evidence of infigratinib‐induced differentiation of the PMT into mature lamellar bone. Although the marked biochemical and structural responses reversed with cessation of therapy in this patient with diffuse metastatic disease, we hypothesized that in less aggressive forms of TIO, infigratinib may be either tumoricidal or induce the differentiation of benign PMTs to osseous tissue.We recently described the use of infigratinib in a patient with metastatic TIO. The patient experienced significant decreases in FGF23, normalization of blood phosphate levels, and a profound reduction in tumor burden while on therapy.19 RemIn this open‐label, phase 2, proof‐of‐principle trial, we treated a small cohort of patients with nonsurgical tumor‐induced osteomalacia with infigratinib for 24 weeks. The primary endpoint was the induction of biochemical remission, as indicated by persistent normalization of blood phosphate and FGF23 after discontinuation.ClinicalTrials.gov (NCT03510455).This was an investigator‐sponsored, open‐label, single site, phase 2 trial (NCT03510455) approved by the Institutional Review Board of the National Cancer Institute, National Institutes of Health (NIH). It was conducted in accordance with the principles established by the Declaration of Helsinki. Written informed consent was obtained from participants. The study is registered with 2). Pregnant or lactating women or patients under age 21 years with open growth plates were also ineligible.Adults with a clinical diagnosis of TIO due to nonlocalized, nonresectable, or metastatic tumor(s), or patients with resectable tumors that could not be removed by minor surgical procedures were eligible for participation. Patients were recruited from February 2019 to June 2019. Patients were excluded if they had genetic or secondary causes of hypophosphatemia, recent non‐TIO malignancy, current ophthalmologic disease, prior treatment with an FGFR inhibitor other than infigratinib, or use of interfering medications. Additional exclusion criteria included comorbid diseases that impair gastrointestinal absorption, prior history of corneal or retinal disorders, active cardiac or cerebrovascular disease, and insufficient bone marrow, hepatic, or renal function  was provided by QED Therapeutics. After a screening evaluation, subjects were admitted to the NIH Clinical Center. Calcitriol and phosphate supplements were discontinued 3 days prior to initiation of infigratinib. Phosphate and calcitriol were subsequently given only during dose interruptions, as needed. To prevent dry eyes and palmar‐plantar erythrodysesthesia, common TKI side effects, preservative‐free artificial tears (carboxymethylcellulose 0.5%), and ammonium lactate 12% lotion were provided to patients prophylactically.ClinicalTrials.gov NCT02160041). After 8 weeks on therapy, dose escalation and de‐escalation of drug was determined by investigators based on tolerability and changes in C‐terminal FGF23 (cFGF23) levels. Planned dose escalation would occur by 25 mg every 8 weeks to a maximum dose of 125 mg/d if cFGF23 levels were not suppressed to <100 relative units (RU)/mL. De‐escalations or interruptions would occur if a subject experienced an adverse event, including hyperphosphatemia. A cFGF23 assay that measures both the active intact FGF23 molecule and inactivated C‐terminal fragments was used for titration purposes rather than an intact FGF23 (iFGF23) assay because the cFGF23 assay was the only commercially available option at the time.Subjects received oral daily doses of infigratinib for up to 24 weeks. The initial dose of 75 mg daily was based on studies investigating infigratinib use in subjects with cholangiocarcinoma, as well as our clinical experience with two NIH patients with TIO who had previously participated in an infigratinib trial outside of the NIH , cFGF23 , iFGF23 , C‐telopeptide (CTx) , and procollagen 1 intact N‐terminal (P1NP) . Infigratinib levels were measured by Q2 Lab Solutions .Tubular reabsorption of phosphate (TRP) was calculated using the following equation: 100 × [1 – (urine phosphate × serum creatinine)/(serum phosphate × urine creatinine)] and maximum renal tubular phosphate reabsorption in mass per unit volume of glomerular filtrate (TmP/GFR) was determined using the following equations: for TRP ≤0.86 (86%): TmP∕GFR = TRP × phosphate; for TRP >0.86 (86%): TmP∕GFR = (0.3 × TRP)/[1 − (0.8 × TRP)] ×phosphate.20At the end of week 24, patients still on therapy were admitted again to the NIH Clinical Center to monitor off‐drug effects with daily blood and urine sampling × 7 days. Subjects with persistent biochemical remission after 7 days would be monitored as outpatients off therapy for 12 additional weeks. Subjects with normal phosphate levels on infigratinib but without persistent biochemical response on cessation were considered for an optional extension phase.Renal ultrasounds were performed at baseline and at 24 weeks, and echocardiograms were performed at baseline, 8 weeks, and 24 weeks. Electrocardiograms (EKGs) were performed at screening and every 4–12 weeks depending on risk factors for arrhythmia.In patients with identifiable tumors, recent prior imaging was obtained from the patient record. The imaging studies that best characterized their tumor prior to therapy (18Flouride‐Fluorodeoxyglucose (FDG) DG‐PET/CT and/or 68Gallium (68Ga)‐DOTATATE‐PET/CT) were repeated at the 24‐week visit, if clinically indicated, and the changes were assessed.Safety, tolerability, and efficacy were evaluated during in‐person visits every 4 weeks at the NIH Clinical Center and included a physical exam, ophthalmologic exam, patient‐reported outcome measures and strength assessments. The Disabilities of Arm Shoulder and Hand Outcome Measurement (DASH) questionnaire was used to measure self‐reported upper extremity symptoms and disability. The RAND 36‐item Short Form Health Survey (RAND SF‐36) version 1.0 was performed to determine effects of infigratinib on health‐related quality of life over the duration of the study. Patient Reported Outcomes Measurement Information System (PROMIS) item banks for fatigue (PROMIS SF v1.0‐Fatigue 8a), mobility (PROMIS Bank v2.0 – Mobility), and pain interference (PROMIS SF v1.1‐Pain Interference 8a) were also performed. Strength assessments included a Six‐Minute Walk Test, Grip Strength assessment, Pinch Strength assessment, and Five Time Sit to Stand. The Grip Strength assessment was performed on the dominant hand using a JAMAR Hand Dynamometer  and three successive trials were averaged to determine the final score. The Pinch Strength assessment was performed using the Exacta Hydraulic Pinch Gauge  with three successive trials averaged for the final score.Patients were monitored via telephone between NIH visits.The primary objective of the study was to induce a persistent metabolic remission, defined by normalization of FGF23 and phosphate after study drug discontinuation. Secondary objectives included evaluating the effects of infigratinib on mineral homeostasis, radiographic appearance of PMTs, quality of life, and muscle strength. Key biochemical end points included changes in iFGF23, cFGF23, phosphate, 1,25D, TRP, and TmP/GFR. Because the study closed prematurely with only four patients enrolled, results were primarily descriptive. Adverse events were summarized by frequency and percentage. Continuous variables were presented as mean ± standard deviation (SD). Linear mixed effects models were fitted to the repeated measures data collected from the 24‐hour serial sampling and the first 8 weeks of therapy when the patients were on the same infigratinib dose (75 mg daily) because, after this point, dose reductions and interruptions occurred. Analysis was performed using SAS . Graphs were produced using GraphPad Prism 8 .Four subjects were screened, and all were eligible. Three subjects completed the 24‐week on‐drug period. Of these, subjects 1 and 2 experienced intermittent dose interruptions due to AEs. Subject 1 experienced three dose interruptions for a total of 25 days off therapy, and subject 2 experienced one 16‐day dose interruption. Subject 3 stopped the trial early after 17 weeks on drug due to AEs and was not restarted due to a persistently elevated cFGF23 on therapy. Subject 4 was on drug without interruption for 24‐weeks. After she was discontinued, she was restarted in the extension phase and remained on drug for 44 additional days but stopped due to failure to follow up.PHEX and FGF23. Patients had the expected biochemical findings of FGF23 excess: elevated intact and C‐terminal FGF23, hypophosphatemia, and low or inappropriately normal 1,25D. All but subject 3 had a baseline TRP lower than the normal range of 85%–95%; however, it was still inappropriately normal for her level of hypophosphatemia. No patients had hyperparathyroidism at the time of enrollment. Baseline CTx was slightly elevated in subject 2 but otherwise normal in other subjects. P1NP was greater than twice the upper limit of normal for subject 3 but was normal in other subjects. Alkaline phosphatase was elevated in subjects 3 and 4, but normal in subjects 1 and 2.Baseline demographics and biochemical findings are shown in Table Overall, no subject achieved the primary objective of the study, enduring metabolic remission, defined as persistently normal FGF23 and blood phosphate following drug discontinuation. Subjects 1, 3, and 4 experienced a complete metabolic response while on therapy, although this reversed rapidly with drug cessation. Subject 2 achieved a significant biochemical response; however, neither his intact nor C‐terminal FGF23 ever normalized.p < 0.001, Fig. The intrasubject 24‐hour pharmacokinetic response to the first dose of infigratinib (75 mg) was highly variable Fig. A. SubjeFor the first 8 weeks of therapy, subjects were treated with infigratinib 75 mg daily Fig. A–F follDuring the rest of the trial, patient dosages and courses diverged due to adverse events with resultant dose interruptions and adjustments. Maintenance infigratinib doses at 24 weeks were as follows: subject 1, 75 mg daily; subject 2, 50 mg daily; subject 4, 25 mg daily. Subject 3 was on 50 mg daily at 17 weeks when infigratinib was discontinued. Only subject 4 continued into the extension phase for an additional 44 days. Detailed descriptions of each patient's course are included in the online Supporting Information .Patients had 68Ga‐DOTATATE‐PET/CT and 18F‐FDG‐PET/CT scans in the week following medication cessation. The previously identified tumors in subjects 1 and 2 had decreased relative uptake on both imaging modalities, when compared to pretreatment imaging Fig. . CausatiStrength and patient‐reported outcomes were limited by the small number of subjects, and intermittent dose interruptions that occurred starting at 8 weeks, precluding the utility of statistical analyses. Nevertheless, there was a suggestion of small improvements in the four strength assessments at 24 weeks Table .At the 8‐week time point, when patients had been on infigratinib 75 mg daily for 8 weeks, quality‐of‐life assessments appeared to improve, including a reduction in upper extremity disability using the DASH questionnaire, in the eight quality‐of‐life domains using the RAND SF‐36, and decreased fatigue, decreased pain interference, and improved mobility using PROMIS Table .By 24 weeks, patients had experienced dose reductions and subject 3 was no longer on infigratinib. At this time point, quality‐of‐life assessments appeared to be slightly worse compared to 8 weeks, and some were worse than baseline, including RAND SF‐36 quality‐of‐life domains: physical functioning, role limitations due to physical and emotional health, emotional well‐being, energy and fatigue, and bodily pain. There was wide variation in these quality‐of‐life assessments over time, which likely reflects small sample size, dose interruptions, and intermittent adverse events. Of note, on week 20, the RAND SF‐36 assessments were better than baseline across all domains.Subjects experienced mild to moderate treatment‐related adverse events on infigratinib. No subjects experienced serious adverse events. There were 111 AEs, with 87 considered possibly, probably, or definitely related to infigratinib. Most AEs were Common Terminology Criteria for Adverse Events (CTCAE) grade 1–2; the only grade 3 AEs were increased alanine aminotransferase and decreased neutrophil count in subject 2, both of which improved following drug interruption. A comprehensive table of adverse events is included in Table  To summarize, all patients developed corneal keratitis with blurred vision; drug interruptions were required in two patients. Vision normalized within 60 days of infigratinib discontinuation; however, two patients had residual corneal scarring, localized outside of the visual axis. Although vision was completely restored in these patients, corneal scarring has the potential to cause permanent vision loss. Because of the higher‐than‐expected rate and severity of corneal keratitis, and the lack of meeting the primary endpoint (permanent remission after 6 months of therapy), recruitment was halted and infigratinib therapy of the one subject in the extension phase was discontinued.Ocular AEs were common and the eye findings from this study were recently reported.21 To Other adverse events related to the drug were hyperphosphatemia, typical TKI side effects, or those determined to be unrelated to the study drug. TKI‐related adverse events included blurred vision, nail changes, dry eyes, dry mouth, weight loss, mucositis, dysgeusia, hair changes, trichomegaly, and decreased blood cell counts.Infigratinib resulted in a transient improvement of biochemical markers in four subjects with TIO; however, this response entirely reversed after drug cessation and no subjects achieved persistent biochemical remission. There was a mild reduction in radionuclide uptake on functional imaging but no change in tumor size in the patients with identifiable tumors. Strength assessments and patient‐reported outcomes were suggestive of small improvements at 8 weeks, that reversed by week 24. AEs were mild to moderate, with no serious events; however, ocular side effects were found in all subjects. The study ultimately closed early due to a greater‐than‐expected incidence of ocular keratitis, likely due to continuous dosing, and evidence that permanent remission was not achieved in the initial four subjects. Recently, fusion‐negative PMTs have been found to have increased expressions of KL mRNA, which encodes alpha‐KLOTHO, the coreceptor for FGF23‐FGFR1 binding, hinting at a third possible mechanism for PMT tumorigenesis, upstream of the FGFR1 pathway. All three mechanisms presumptively involve increased activation of FGFR1, causing PMT tumorigenesis and FGF23 excess. For this reason, it is plausible that TIO tumors may respond to FGFR1 blockade with certain TKIs. Of note, cases of nonlocalizable TIO do not have available pathologic material and the pathogenesis of this subset of TIO is still unknown. However, in this study, the two cases of nonlocalized PMTs also responded effectively to FGFR1 blockade, revealing that FGFR1 is indeed important in this subset of patients as well. The patients with localized PMTs did not have available pathologic tissue for fusion testing, but their robust biochemical response to the drug confirmed the importance of FGFR1 in their tumors.The identification of fusion genes in PMT surgical specimens was a pivotal step in understanding PMT pathogenesis. FN1‐FGFR1, the most common translocation, found in 40% of PMTs, first identified FGFR1 blockade as a promising potential therapeutic target for TIO. An additional 6% of PMTs harbor a FN1‐FGF1 translocation, which includes fibroblast growth factor 1, a ligand of FGFR1 and other FGF receptors. Although this fusion is unique, it likely results in increased activation of the FGFR1 pathway, similar to the FN1‐FGFR1 fusion.12 Rec This indicates that PMTs are likely derived from skeletal stem cells and that FGFR1 may hold a pivotal role in tumor differentiation.Our previous experience treating a patient with diffusely metastatic TIO with a known FN1‐FGFR1 fusion with infigratinib resulted in FGF23 suppression and normalization of phosphate, TRP, and 1,25D. Of note, a tumor adjacent to the scapula calcified during the first 3 months of infigratinib treatment. Pretreatment and posttreatment biopsies showed an apparent metaplastic redifferentiation from a sarcomatous‐appearing PMT to mature lamellar bone.19 Thi In studies of subjects with cholangiocarcinoma, infigratinib causes dry eye, including keratitis, in 44% of patients, and blurred vision in 21%, with no reactions above grade 2. The increased frequency and severity of the effect of infigratinib on the cornea in our study may be due to continuous dosing, which was unique to this protocol. The risk–benefit assessment in patients with benign TIO who are comparatively healthy precludes long‐term continuous dosing of infigratinib due to the potential of inducing permanent eye damage. In cases of TIO where the goal is not curative due to advanced metastatic disease, cyclical dosing might be preferable, as this may reduce the risk of ocular keratitis and scarring. Autologous serum eye drops, produced prior to initiation of FGFR1 blockade, may also be helpful in replenishing growth factors in the eye and avert keratitis; however, the efficacy of this therapy is still under investigation.In the current study, subjects developed ocular keratitis while on infigratinib, with corneal scarring occurring in 50%.19 In This study was limited by the small sample size due to the rarity of the underlying disease and early closure. Furthermore, adverse effects necessitated dose reductions or interruptions, limiting optimal drug exposure. Intersubject variability in pharmacokinetics as well as differing baseline disease severity likely contributed to a wide range of dose requirements and responses. Baseline PET scans were not standardized and, in one case, was performed at an outside facility limiting the ability to compare pretherapy and posttherapy imaging. The interpretations of quality‐of‐life outcomes and strength data were limited by the small sample size and high variability due to transient drug‐related AEs experienced by patients during the study.FGFR1 blockade with infigratinib effectively ameliorated the biochemical findings in TIO, decreasing tumoral FGF23 production and normalizing mineral metabolism. The biochemical response observed in this study confirms the role of FGFR1 signaling in PMT pathogenesis, including in cases of nonlocalized TIO for which the molecular drivers could not be assessed. However, infigratinib's effect reverses after drug cessation, suggesting that the drug is not tumoricidal with the regimen implemented. Although it is possible that a longer course of therapy at higher doses could induce a persistent remission, this approach would likely be limited by untoward treatment‐related AEs. Therefore, long‐term therapy should not be advocated given the side‐effect profile, except perhaps in cases of metastatic disease. In the future, more targeted therapeutics, such as monoclonal antibodies or a more specific TKI, that blocks FGFR1 with fewer off‐target effects, might allow for higher doses and longer continuous therapy in this population.Iris R. Hartley: Conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. Kelly L. Roszko: Conceptualization; data curation; investigation; writing – review and editing. Xiaobai Li: Formal analysis; writing – review and editing. Karen Pozo: Data curation; project administration; writing – review and editing. Jamie Streit: Data curation; project administration; writing – review and editing. Jaydira Del Rivero: Conceptualization; data curation; investigation; writing – review and editing. M. Teresa Magone: Conceptualization; data curation; investigation; writing – review and editing. Michaele R. Smith: Conceptualization; data curation; writing ‐ reveiw and editing. Roo Vold: Writing – review and editing. Carl L. Dambkowski: Writing – review and editing. Michael T. Collins: Conceptualization; data curation; formal analysis; investigation; methodology; supervision; writing – review and editing.NIDCR receives research funding from QED Therapeutics as a part of a Collaborative Research and Development Agreement (CRADA), RV and CD are employees of QED Therapeutics.https://publons.com/publon/10.1002/jbm4.10661.The peer review history for this article is available at Fig. S1. Markers of bone turnover over 24 weeks. (A) Alkaline phosphatase. (B) CTx. (C) P1NP. Individual lab values are represented by black symbols, while gray boxes represent the infigratinib dose averaged over the 4 patients. Male and female upper limit of normal is represented by horizontal dotted lines. Normal ranges were as follows: Alkaline phosphatase 35–105 U/L; CTx male 31–50 years: 93–630 pg/mL; CTx female premenopausal: 25–573 pg/mL; P1NP male: 22–87 mcg/L; P1NP female: 19–83 mcg/L.Figs. S2–S5: Pharmacokinetics and pharmacodynamics of individual subjects over the course of the study including follow up. Measurements include (A) Infigratinib concentration, (B) iFGF23, (C) cFGF23, (D) phosphate, (E) 1,25D, and (F) TRP. Individual values are represented by black icons while gray boxes represent daily infigratinib dose. Reasons for dose reductions and dose interruptions are noted (A). Normal ranges are represented by horizontal dotted lines.Figure S2: Subject 1 experienced relatively low absorption of infigratinib. He experienced normalization of iFGF23 and cFGF23 during weeks 18–20 after the dose was increased to 100 mg daily, however, he subsequently developed hyperphosphatemia, which prevented him from being maintained on this dose. After adjusting his dose down to 75 mg daily, his phosphate remained elevated until he was discontinued at week 24. On cessation of therapy, cFGF23 rebounded above baseline, and subsequent measurements iFGF23 and cFGF23 returned to baseline.Figure S3: Subject 2 had the highest blood levels of infigratinib on 75 mg daily dose. His dose was limited by high ALT and low ANC on infigratinib 75 mg per day requiring dose cessation. He was then maintained on infigratinib 50 mg daily until 24 weeks. Although his iFGF23 and cFGF23 decreased 95% and 89% respectively from his baseline, both remained above the normal range with an iFGF23 nadir of 171 RU/mL  and cFGF23 nadir of 241 RU/mL . In response, blood phosphate increased only to the low‐normal range, and vitamin D 1,25 generally remained in the normal range. Although TRP increased, it never normalized.Figure S4: Subject 3 responded within 24 hours to infigratinib, with normalization of iFGF23, phosphate elevation, and vitamin D 1,25 elevation even with very low blood infigratinib levels. However, cFGF23, although initially decreased, subsequently remained at or above the normal range. Since cFGF23 was used for dose adjustments, when subject 3 developed blurred vision requiring a dose interruption, the persistently high cFGF23 made it appear that the patient's tumor was not adequately responding to therapy. Elevated phosphate and 1,25D was attributed to the blockade of non‐tumoral FGFR1 resulting in a FGF23 resistance. After a discussion of risks and benefits, the investigators and patient decided not to resume infigratinib therapy.Figure S5: Subject 4 developed hyperphosphatemia at 8 weeks requiring dose reduction to a final dose of 25 mg of infigratinib per day. On this dose, phosphate remained in the normal range without need for supplementation and 1,25D remained at or above the normal range. TRP increased initially to the normal range but subsequently decreased on lower doses. Although cFGF23 and iFGF23 dropped substantially initially, and cFGF23 normalized, on the lower infigratinib dose, both increased the rest of the treatment course. On cessation, phosphate and 1,25D decreased and iFGF23 increased to baseline. The patient enrolled in the extension period, however, was ultimately taken off the protocol after an additional 44 days on therapy due to loss to follow up.Click here for additional data file.Table S1. Patient reported outcomes and strength assessments.Table S2. Adverse Events.Click here for additional data file.


It is a priority for public health professionals to improve global breastfeeding rates, which have remained low in Western countries for more than a decade. Few researchers have addressed how maternal perceptions of birth experiences affect infant feeding methods. Furthermore, mixed results have been shown in research regarding breastfeeding and mother-child bonding, and many studies are limited by small sample sizes, representing a need for further investigation.We aimed to examine the relationship between subjective birth experiences and breastfeeding outcomes, and explored whether breastfeeding affected mother-infant bonding.3,080 mothers up to three years postpartum completed a cross – sectional survey.Mothers who had more positive birth experiences were more likely to report breastfeeding their babies. Moreover, mothers who perceived their birth as more positive were more likely to breastfeed their child for a longer period (over 9 months) than those who had more negative experiences. In line with recent research, breastfeeding behaviours were not associated with reported mother-infant bonding.Mothers who reported better birth experiences were most likely to breastfeed, and breastfeed for longer. We find no evidence to suggest that feeding methods are associated with bonding outcomes. Further, we aimed to explore whether mothers in different feeding groups varied in their perceived relationships with their children. Our research questions were as follows: [RQ1] Do mothers’ feeding methods differ depending on their feelings about their birth experience? [RQ2] Is birth experience associated with the length of time an infant receives breast milk? [RQ3] Do mothers’ feelings about their relationship with their child differ depending on infant feeding method? [RQ4] Do mothers’ feelings about their relationship with their child differ depending on the length of time an infant received any breast milk?The target population were mothers who had given birth in the last three years, with a view to later separating cohorts . Following other researchers e.g., , mothersBefore data cleaning, 3,416 responses were collected. Some mothers indicated that their child was over 36 months old, and thus were excluded. Responses from duplicate IP addresses were also removed before data anonymisation. After data cleaning, 3,080 responses were retained. All participants were required to be mothers of children under 36 months of age, and no further exclusion criteria were applied. Maternal age ranged from 16–49 years, and the mean age of mothers was 28.17 years.a priori G*Power analysis (f = .10) with three feeding groups, a sample size of 1,548 (or 516 per feeding group) was required.To assess infant feeding and the mother-child relationship, as well as infant feeding and birth experiences, an analysis  for analAs we were interested in multiple categories within the population, we employed an oversampling strategy. This was required due to significant feeding method disproportions within the population, particularly for breastfeeding and long-term breastfeeding mothers .Respondents reported maternal age, ethnicity, location, and the age category of their child (0–12 months or 12–36 months).The Childbirth Perception Scale CPS;  was usedr = .51 .Finally, participants indicated whether they fed their child with formula milk (FF), breast milk (BF), or a combination of the two (CF). If the child was not exclusively fed formula, mothers reported how long their child received any breast milk using predetermined categories  . Howeverwww.qualtrics.com). After giving consent, respondents completed the questionnaire.Data were collected over 6 consecutive weeks in April 2020. The questionnaire was hosted through Qualtrics . All ethical requirements for work with human participants were followed. Participants were introduced to the study prior to participation, and were debriefed upon completion.Data were analysed using SPSS version 24.0 , R , and JASP . One-wayTo assess feeding group differences for mother-child bonding as measured by the CPRS, one-way, between-subjects ANOVAs were performed for each of the CPRS subscales .A Bayesian ANOVA was conducted as a confirmatory test for findings related to breastfeeding and bonding outcomes, and a linear regression was conducted to determine the relationship between SSQ and CPS scores.Seventeen mothers reported that they exclusively breastfed their child, without formula inclusion, for 1–9 months. As guidance states that mothers should feed their infants either breast, formula milk, or a combination of both, for at least 12 months, these mothers may have mis-categorised themselves or changed feeding methods. To avoid the inclusion of miscategorised data, we excluded these responses from our analysis.All items from the CPS were reverse coded during analysis for clarity, so that higher scores indicated better experiences.Participants were all female as assigned at birth. Descriptive statistics for participants are presented in Table S1 in the Supporting Information file.Most mothers fed their children formula milk or breastfed their children for over 12 months . Feeding categories and reported incidence are illustrated in F = 102.08, p < .001, Cohen's f = .69. Those who exclusively breastfed their infants were the oldest group in the cohort . The CF group younger than BF , and younger still were the FF group . All ps < .001.Analyses exploring age differences across feeding groups revealed a significant main effect, F = 63.00, p < .001), with a large effect (Cohen's d = 1.00).When controlling for age, depression, and anxiety, and CPRS subscales, a multiple regression showed that satisfaction with care (SSQ) significantly predicted better birth experiences (CPS), The data for this analysis are summarised in , F = 26.94, p < .001, Cohen's f = .30. Post-hoc Tukey HSD comparisons revealed that the ‘BF’ group reported significantly higher scores on the CPS, representing a better birth experience , in comparison with both the ‘CF’ group  and the ‘FF’ group . There were no significant differences in CPS scores between the formula and combination feeding groups (p = .802).First, we compared feeding groups and CPS birth experiences. Results showed a significant main effect of feeding methodF = 13.42, p < .001, Cohen's f = .31. Those who exclusively breastfed reported higher levels of satisfaction with clinical care  in comparison with both those who combination fed  and those who formula fed their children , both ps < .001. In this case, only the ‘breast versus formula’ comparison yielded a practically significant effect size. There was no significant difference in satisfaction with care between the ‘combination’ and ‘formula’ feeding groups (p = .337).For satisfaction with clinical care, a main effect of feeding type was found, 2χ(2) = 53.29, p < .001.Given that birth experiences precede infant feeding, we conducted a multinomial logistic regression to establish the predictive and clinically relevant nature of birth experiences. Results are outlined in The odds ratios outlined in The data for this analysis are summarised in F = 9.93, p < .001, Cohen's f = .38. Post-hoc tests showed that the only ‘durations’ group which differed significantly from others for CPS scores was the ‘exclusive breastfeeding->12 months’ group, which differed from the formula group (p < .001), the ‘CF- 1–3 months’ (p < .001) and ‘CF- 8–12+ months’ (p = < .001) groups. Cohen's f effect sizes and significance varied for comparisons between this group and other feeding duration groups. (See Table S2 for between-group comparisons and more information.)For birth experience (CPS) scores and ‘feeding duration’ groups, a significant main effect was found, F = 5.05, p < .001, Cohen's f = .40. Again, the only group which significantly differed from others was the ‘breastfeeding- >12 months’ group (M = 32.63) Mothers in this category differed from the ‘formula’ group  and the ‘combination- 1–3 months’ group. . Table S3 shows detailed between-group comparisons and effect sizes.Next, we compared infant feeding duration groups’ satisfaction with clinical care as measured by the SSQ. A significant main effect was found, ps > .05), suggesting that age did not influence this relationship.We next sought to identify how age might influence the relationship between breastfeeding and birth experiences. As we found an association between the three feeding methods and age, the assumption of independence between independent variables for ANCOVA analysis was violated  = 1.94, p = .144, Cohen's f = .02, or ‘closeness’ subscales, F = 2.26, p = .105, Cohen's f = .02. A statistically significant main effect of feeding type for the dependence subscale was found, F = 3.54 p = .029, with breastfeeding mothers scoring higher  than mothers who fed their infants formula milk . However, the effect size was negligible (Cohen's f = .06). The combination and formula feeding groups did not significantly differ (p = .565), nor did the breast and combination groups (p = .219).First, we treated ‘feeding type’ as a trichotomous variable, comparing formula, breast, and combination feeding groups. Responses on the CPRS did not significantly differ based on feeding type for either the ‘conflict’, F = .99, p = .418 or CPRS ‘dependence’ subscales, F = 1.64, p = .145. A significant main effect was found for the ‘closeness’ subscale, F = 2.57, p = .025, showing that the ‘combination feeding- received breast milk for 0–3 months’ group received higher closeness scores. However, post-hoc Tukey tests did not show any statistically significant group differences. Further, effect sizes for between-group comparisons were statistically negligible, with Cohen's f effect sizes ranging from .00–.04. No significant between-group differences were found when assessing differences in our three ‘combined’ feeding groups  for scores on the CPRS subscales .Next, we explored whether mothers reported differences in their perceived relationship with their child based on the amount of time their infant received breast milk. Analyses showed no main effect for the CPRS ‘conflict’, moderate evidence for the null hypothesis, and the latter two, strong evidence  ANOVA was conducted, with breastfeeding groups as fixed factors, and the CPRS subscales as dependent variables. This analysis supported our previous ANOVA results, showing that the likelihood of the null hypothesis given the data for the ‘dependence’ subscale was 3.78 times greater than for the alternative hypothesis. For the ‘conflict’ subscale, the likelihood of the null hypothesis was 17.94 times greater, and for ‘closeness’, 13.04 times greater. The former represents evidence .perceptions of her birth experience and subsequent breastfeeding behaviours remains scant. We sought to address this gap in the literature by surveying a large sample of mothers, focussing on their subjective childbirth experiences. Moreover, we investigated whether mother-infant bonding was associated with different infant feeding methods.Researchers have shown that birth interventions may prevent breastfeeding initiation . HoweverFindings showed that mothers who were more satisfied with clinical care at the time of birth, and who perceived their birth experiences as more positive, were more likely to report breastfeeding their children. Better satisfaction and more positive perceptions were also associated with breastfeeding past the child's first birthday. Consistent with Our data suggest that a positive birth experience is associated with the care received by healthcare staff, therefore highlighting the importance of good clinical care for maternal birth satisfaction. This is in line with previous investigations e.g., . Our finOur analyses showed that mothers who had better birth experiences were more likely to breastfeed their children, and that those who breastfed their children for over 12 months had better birth experiences than formula feeding mothers and some combination feeding mothers. Odds ratios revealed a 9.5% increase in the likelihood of combination feeding for our cohort, and a 10.5% increase in the likelihood of formula feeding, based on lower average birth experience scores when compared with mothers who exclusively breastfed. Results from this study suggest that childbirth experiences may be an area of interest for predicting breastfeeding initiation. As suggested by As well as emotional consequences, the introduction of formula has various associated health risks. Breastfeeding decreases the risk of several illnesses for both mother and child, including maternal breast and ovarian cancers, and child allergies, asthma, and gastric issues  and access to resources. Mothers who have fewer economic barriers are more likely to have successful breastfeeding journeys than those with lower socioeconomic backgrounds . We did Maternal age may also contribute to both better birth experiences and longer-term breastfeeding . Howevern = 70 was sufficient to detect medium, but not small, differences between groups). Further research is necessary to determine any differences in experiences between longer-term breastfeeding and combination feeding mothers. More generally, very few explorations have assessed the behaviours of mothers who continue to offer breast milk alongside formula milk for longer periods, representing a clear need for further inquiry.Although we found that breastfeeding mothers and those who combination fed for 4–7 months did not differ in their birth experiences, this finding may be an issue of statistical power, rather than a true lack of differences . Caution should be applied when generalising these findings, though we provide support for Finally, mothers were recruited in April 2020, during the COVID-19 pandemic. Although our primary analyses did not include mothers who gave birth in the preceding 12-month period, some analyses  included mothers who may have given birth at the start of the pandemic. Although it is beyond the scope of this particular project to account for the effects of the pandemic on birth experiences, this remains an important area for exploration.The results from this study support research which shows that staff can influence birth experiences in several ways. Individualised care and continuity of care can be important for a mother's perception of her experience , and perGlobal breastfeeding rates in 2020 represent a significant public health issue. As well as the risks associated with breastfeeding cessation, mothers who wish to breastfeed but do not can be vulnerable to feelings of guilt related to their experiences . By idenClick here for additional data file.Supplemental material, sj-docx-1-cjn-10.1177_08445621221089475 for Birth Experiences, Breastfeeding, and the Mother-Child Relationship: Evidence from a Large Sample of Mothers by Abi M. B. Davis and Valentina Sclafani in Canadian Journal of Nursing Research


The overall incidence of gastric cancer in women is half that in men for most global populations. Sex hormone pathways may be involved in carcinogenesis and estrogens have been postulated to protect women against gastric cancer.To evaluate associations of gastric cancer with estrogen metabolites in postmenopausal women.p‐values >.05), with low between‐study heterogeneity  for all but two metabolites (2‐hydroxyestrone‐3‐methyl ether and 2‐methoxyestradiol).We performed an analysis of 233 gastric cancer cases and 281 age‐matched controls from three prospective cohorts and two case‐control studies of early‐stage gastric cancer, mainly conducted in high‐risk Asian populations. Fifteen estrogen‐parent (estrone and estradiol) and ‐metabolite analytes  were measured in spot urines using liquid chromatography–tandem mass spectrometry. Odds ratios for association with each marker were estimated by logistic regression. Heterogeneity was assessed by Cochran's Q test. Study‐specific odds ratios were pooled by fixed‐effects meta‐analysis. Urinary levels of estrogen‐related molecules were not associated with gastric cancer (adjusted odds ratios ranged from 0.87 to 1.27; To date, this is the first comprehensive assessment of endogenous estrogens with gastric cancer risk in women. Estrogens do not appear to have an etiologic role in gastric cancer risk among postmenopausal women. Given the complex network of sex steroid hormones and their extreme variation over the lifespan, further evaluation of this hypothesis is warranted. Our previous meta‐analysis of menstrual and reproductive factors identified decreased gastric cancer risk among women with a longer time between menarche and menopause or exposure to hormone therapy.22.1Our analysis included 216 women from three population‐based prospective studies  and 13 metabolites  were simultaneously measured in urine  using liquid chromatography–tandem mass spectrometry assay,2.32 concentration of each metabolite. We report the study‐specific odds ratios (OR) and 95% confidence intervals from models that stratify by batch and adjust for age (continuous), body mass index (continuous) and, when available, smoking (ever vs. never), alcohol use (ever vs. never), education (none vs. any) and family history of gastric cancer (yes vs. no). This information was collected at enrollment in prospective studies and pre‐treatment in case–control studies. Study‐specific ORs were averaged via fixed‐effects meta‐analysis using the “metafor” R package, with heterogeneity assessed by Cochran's Q test. A p‐value less than .05 was considered statistically significant, except for test of heterogeneity for which we used a p‐value cut‐off of .1. Given the exploratory nature of our study, results were not corrected for multiple comparisons.We calculated pairwise Spearman's rank correlation coefficients among urinary metabolites using the controls. We used logistic regression to evaluate the association between the risk of gastric cancer and the log3Baseline characteristics of gastric cancer cases and controls are presented in Table The percentage of urine samples with missing measurements  ranged between 4% (2‐methoxyestradiol) and 34% (4‐hydroxyestrone), with a median of 5%. Most estrogen markers had a statistically significant correlation with each other in controls .p‐values >.1) for all but two markers, 2‐hydroxyestrone‐3‐methyl ether (p = .03) and 2‐methoxyestradiol (p = .04).Figure 4The reasons for sex differences in gastric cancer are not well elucidated. Despite the plausible biologic evidence from epidemiologic,This study is the first epidemiologic analysis that directly evaluated estrogen metabolism in gastric carcinogenesis in women using samples collected prior to cancer diagnosis or asymptomatic localized disease . We also used a sensitive and specific mass spectrometry method to accurately quantitate estrogens. Our study is informative as it mainly included women from high gastric cancer risk populations in East Asia. Despite these strengths, our study was limited by small numbers for subgroup analyses.In conclusion, our study did not find evidence of associations between postmenopausal estrogen levels and gastric cancer risk. Future studies should consider estrogen effects through the lifespan as well as associations with gastric preneoplastic conditions, particularly intestinal metaplasia. Notably, premenopausal estrogen levels are highly dynamic, thus studies of their associations are extremely challenging. A better understanding of sex hormone effects on gastric cancer may reveal common mechanisms of carcinogenesis responsible for other estrogen‐related malignancies.The authors have stated explicitly that there are no conflicts of interest in connection with this article.Concept and design, M.C.C.,M.S., and C.S.R.; Acquisition, analysis, or interpretation of data, X.X., A.E., H.B., H.‐W.L., B.T., B.H., B.S., K.S., S.M.D., S.L., T.S., S.K.P., R.M., and D.K.; Drafting of the manuscript, M.C.C., M.S., I.Z., and C.S.R.; Critical revision of the manuscript for important intellectual content: All authors; Statistical analysis, I.Z., and J.N.S.; Supervision, C.S.R.All individuals provided informed consent. The original studies were approved by the corresponding Institutional Review Boards. The present case‐control analysis was exempted from institutional review board evaluation by the U.S. National Institutes of.Health Office of Human Subjects Research.


Cystatin‐C (Cys‐C) is a predictor of several malignancies. However, whether Cys‐C levels predict prognosis in patients with papillary renal cell carcinoma (PRCC) remains uncertain. The aim of this study was to assess the correlation between Cys‐C and clinical outcomes in patients with PRCC.The medical records of 137 patients with PRCC who underwent surgery at our institution from January 2008 to December 2020 were retrospectively analyzed. Data were divided into two subgroups based on cutoff values and the relationship between the Cys‐C group and their clinical outcomes was assessed.n = 92) and high Cys‐C group . Pathological classification and serum Cys‐C levels were shown to be independent prognostic factors affecting clinical outcomes, according to multivariate Cox regression analysis (p < 0.05). After adjusting the Cox proportional hazards model, the risk of death was elevated in the high Cys‐C group. The results of the area under the curve for time‐dependent receiver operating characteristics analysis indicated that Cys‐C is a stable and reliable prognostic biomarker for predicting survival in patients with PRCC. Forest plots, constructed to better reflect the comparison of hazard ratios between the two groups, confirmed that Cys‐C levels were significantly associated with worsening overall survival.By the last follow‐up, 62 patients had died of various causes, 53 of whom died from PRCC. Sixty patients suffered recurrence or metastasis during follow‐up. Based on the cutoff value, the patients were divided into two groups: low Cys‐C group (Cys‐C < 1.25 mg/L, This study is the first to examine the relationship between preoperative serum Cys‐C levels and prognostic overall survival in patients with PRCC. Cys‐C may be a useful biomarker for preoperative screening of high‐risk patients who may require adjuvant therapy. 1. This study is the first to examine the relationship between Cys‐C levels and OS in patients with PRCC. 2. Cys‐C may be a useful preoperative screening biomarker 3. Elevated Cys‐C levels were significantly associated with worsening OS. Previous studies have shown that abnormal serum Cys‐C levels can be used as a prognostic and diagnostic indicator for breast cancer, myeloma, colon cancer, renal cell carcinoma, and non‐Hodgkin's B‐cell lymphoma.22.1The medical records of 165 patients with PRCC, who underwent surgical treatment at our hospital from January 2008 to December 2020, had been retrospectively analyzed. The inclusion criteria were as follows: (1) pathologically confirmed PRCC, (2) the surgical approach was radical or partial nephrectomy, (3) no preoperative adjuvant therapy was administered, and (4) the medical records were complete. The exclusion criteria for data collection were as follows: (1) concomitant other cancer or a history of other cancers, (2) no treatment with partial or total nephrectomy, (3) patients received radiotherapy or chemotherapy before surgery, and (4) incomplete clinicopathological features and follow‐up data. After screening, the final cohort for further analysis included 137 individuals  were used to evaluate the grade and tumor stage, respectively.2.3Follow‐up assessments included laboratory tests, physical examinations, and radiological examinations, in accordance with the clinical practice guidelines of the National Comprehensive Cancer Network (NCCN). Physical and laboratory examinations were performed every 3 months, and magnetic resonance imaging (MRI) or enhanced CT was examined every 3–6 months. Local recurrence or distant metastasis was diagnosed by CT, bone scan, MRI, PET‐CT, and other imaging techniques. The primary outcome was overall survival (OS); secondary outcomes included progression‐free survival and cancer‐specific survival.2.4U test and chi‐square test were used to test the correlation between the groups of variables. Initially, we developed Cox proportional risk models of univariate and multifactor analysis. In this study, covariates were included in a Cox regression model; by comparing regression coefficients, we assessed the impact of confounding factors. The models we set up were as follows: covariates unadjusted model; model 1–adjusted for age, BMI, sex only; model 2–adjusted for age, BMI, sex, initial symptoms, laterality, smoking history, diabetes, hypertension, and coronary heart disease; and model 3–adjusted for all covariates. The area under the curve (AUC) and time‐dependent relative operating characteristic (ROC) curve analysis were also performed to assess the predictive accuracy of Cys‐C for survival prediction. The Kaplan–Meier curve (log rank test) was adopted to analyze the impact of Cys‐C on survival outcomes. A subgroup analysis using the Cox proportional risk model assessed the survival differences between the two Cys‐C groups. Further, a forest plot was constructed to better reflect the comparison of hazard ratios (HRs) between the two groups, in each subgroup.Continuous variables and categorical variables were expressed as median and interquartile range (IQR), and frequencies (percentage), respectively. The X‐tile software (version 3.6.1) was used to calculate the optimal cutoff point of preoperative Cys‐C levels, based on which we could treat continuous Cys‐c as a categorical variable and classify the entire cohort into two groups. The Mann–Whitney http://www.R‐project.org, The R Foundation) and Free Statistics software versions 1.3, were used for statistical analyses. All tests were two‐tailed. Statistical significance was set at p < 0.05.The statistical software package R v.4.0.2 (33.1n = 92) and high Cys‐C group . The correlation between various levels of Cys‐C and clinicopathological features is shown in Table p > 0.05). In the high Cys‐C group, patients tended to be older and with a higher pathological grade (p = 0.037) than those in the low Cys‐C group. In addition, patients with high levels of Cys‐C developed distant metastases (p = 0.040), most of which were pathological type‐2 PRCC (p = 0.035).A retrospective analysis was performed using the data from 137 patients with PRCC, who had received surgical treatment at Shengjing Hospital of China Medical University from 2008 to 2020. The mean follow‐up time was 24 months. At the final follow‐up, 62 patients died due to various causes, 53 of whom died of RCC. Sixty patients experienced recurrence or metastasis at follow‐up. This study's optimal cutoff value for Cys‐C, obtained by X‐tile software, was 1.25 mg/L . Using the significant prognostic factors identified in the univariate analysis to determine a multivariate Cox regression analysis, it was determined that pathological classification and Cys‐C levels were independent prognostic factors affecting clinical outcome (p < 0.05).Univariate and multivariate Cox regression analyses were used to explore independent risk factors for OS Table . Univari3.3p < 0.001). In adjusted model 1, after adjustment for age, sex, and BMI, high serum Cys‐C levels remained an independent risk factor for OS . In adjusted model 2, after adjusting for age, sex, BMI, initial symptoms, laterality, smoking history, diabetes, hypertension, and coronary heart disease, the HR for the effect of high serum Cys‐C levels on OS was 9.5 . In fully adjusted model 2, after adjusting for age, sex, BMI, initial symptoms, laterality, smoking history, diabetes, hypertension, coronary heart disease, pathological classification, tumor size, tumor grade, lymph node status, T‐stage, distant metastasis, surgery, serum creatinine levels, and eGFR, high serum Cys‐C levels remained independently associated with OS .We investigated the association between serum Cys‐C levels and OS by constructing unadjusted and adjusted Cox proportional hazards models Table . In the In addition, Kaplan–Meier analyses showed that OS times were shorter in patients with high levels of serum Cys‐C than in those with low levels of serum Cys‐C Figure . As show3.4To investigate the effect of serum Cys‐C levels on prognosis in different subgroups with PRCC, we performed subgroup analyses. As shown in Figure 4The primary aim of this study was to analyze the association between preoperative serum Cys‐C levels and the oncological prognosis in patients with PRCC. Our findings demonstrated that patients whose serum Cys‐C levels were high had worse prognosis than those with low Cys‐C levels. After adjusting for other prognostic variables, preoperative Cys‐C was defined as an independent risk factor of OS in this particular subgroup. Therefore, we recommend preoperative Cys‐C levels to be a prospective predictor of patient survival, for clinicians.Pretreatment Cys‐C levels have been shown to be an independent prognostic biomarker in various malignancies, such as nasopharyngeal, breast, and uroepithelial cancers.Cys‐C is widespread in the cells and tissues of various human tumors, although its expression is not consistent.Serum Cys‐C levels have been proved to be a valuable biomarker to indicate renal function, and estimate eGFR more sensitively than that by serum creatinine levels.p < 0.001). Similarly, we observed that the risk of postoperative mortality and OS decreased as Cys‐C levels increased, in the adjusted model. In this study, the cutoff values were determined using the X‐tile program. Notably, the optimal cutoff value for Cys‐C to predict tumor prognosis may vary with the tumor type, which might be related to tumor specificity, as well as to different sample sizes, survival endpoints, and follow‐up time. Conspicuously, our study incorporated time‐dependent ROC curves to estimate the predictive power of the factors and can be used to group continuous variables. In survival analysis, both, the factor values and the disease status change over time, whereas traditional ROC curve analysis treats individual factor values and disease status as smooth values, and time was not considered in the analysis. In this case, using the time‐dependent ROC is certainly a better alternative. Our findings are of interest from a clinical standpoint. Serum Cys‐C levels are one of the most common markers of renal function, routinely tested on hospital admission and area low‐cost and accessible preoperative predictor. Therefore, we recommend that preoperative Cys‐C levels should be considered by surgeons during preoperative evaluation or consultation when predicting patient survival post‐surgery. The opportunity provided by preoperative Cys‐C for earlier and more accurate prediction of tumor prognosis. In addition, preoperative Cys‐C levels may provide valuable suggestions for clinical anticancer treatment, or even the development of different treatment regimens, and monitoring of treatment effects. PRCC patients with high preoperative Cys‐C values should be followed up more aggressively and rigorously postoperatively.The present study findings showed that, in patients with PRCC patients, higher pretreatment Cys‐C levels were correlated with poorer clinical outcomes. Survival curves revealed a statistically significant discrepancy in survival between the two groups (Several limitations of this study warrant discussion. First, it is restricted by its retrospective character and confined to a single center, which may lead to a selection bias. Second, only patients with PRCC who received surgery were included in this study, which cannot represent other patients with PRCC who do not receive surgical treatment. Third, the primary endpoint of this study is OS, and further studies are needed to investigate the association of Cys‐C levels with tumor recurrence and tumor‐specific survival. Fourth, the cutoff value of Cys‐C was not based on the literature or previous studies, which might have an impact on the results. Fifth, since both eGFR and Cys‐C are factors in renal function, there is homology between Cys‐C and eGFR, which means that the effect of Cys‐C on the prognosis of PRCC may be influenced by eGFR. Finally, the sample size of this research was relatively small. Large prospective randomized trials are needed to validate the study findings.5This study explored the association between preoperative serum Cys‐C levels and prognostic OS in patients with PRCC. Serum Cys‐C levels can be considered a useful biomarker for preoperative screening of high‐risk patients, requiring adjuvant therapy. Patients with PRCC having high serum Cys‐C levels should be monitored more frequently postoperatively. Multicenter prospective cohort studies to further confirm the importance of Cys‐C in PRCC are warranted.The authors declare no conflict of interest.This study was approved by the Ethics Committee of Shengjing Hospital of China Medical University. The clinical research registry number is 2021PS692K.SjL and SyL conceived and designed this research. SyL and SjL made contributions to the data gathering and analysis of this data. The original manuscript was drafted and revised by SyL. SjL prepared the figures and/or tables. The manuscript was edited by SjL and SyL. All authors have made contributions to this essay and endorsed the submitted version.


Fagus mexicana Martínez (Mexican beech) is an endangered Arcto‐Tertiary Geoflora tree species that inhabit isolated and fragmented tropical montane cloud forests in eastern Mexico. Exploring past, present, and future climate change effects on the distribution of Mexican beech involves the study of spatial ecology and temporal patterns to develop conservation plans. These are key to understanding the niche conservatism of other forest communities with similar environmental requirements. For this study, we used species distribution models by combining occurrence records, to assess the distribution patterns and changes of the past , present (1981–2010), and future (2040–2070) periods under two climate scenarios (SSP 3‐7.0 & SSP 5‐8.5). Next, we determined the habitat suitability and priority conservation areas of Mexican beech as associated with topography, land cover use, distance to the nearest town, and environmental variables. By considering the distribution of Mexican beech during different periods and under different climate scenarios, our study estimated that high‐impact areas of Mexican beech forests were restricted to specific areas of the Sierra Madre Oriental that constitute refugia from the Last Glacial Maximum. Regrettably, our results exhibited that Mexican beech distribution has decreased 71.3% since the Last Glacial Maximum and this trend will for the next 50 years, migrating to specific refugia at higher altitudes. This suggests that the states of Hidalgo, Veracruz, and Puebla will preserve the habitat suitability features as ecological refugia, related to high moisture and north‐facing slopes. For isolated and difficult‐to‐access areas, the proposed methods are powerful tools for relict‐tree species, which deserve further conservation. Suitability habitat Climatic effect on Mexican beech forests The ext Biaggi, . This is Biaggi, .2; Figure https://www.iucnredlist.org/species/62004694/62004696#population). The Mexican beech forests occur at altitudes of 1509–2034 m above sea level (asl) on northern steep‐ravines with high moisture, on vitric slopes, and near streams harboring unique floristic assemblages with a specific microclimate , but rarely Acer saccharum Marshall and certain conifer species such as Pinus patula Schltdl. & Cham., Podocarpus reichei J. Buchholz & N.E. Gray, Picea martinezii T. F. Patterson and Taxus globosa Schldl. Additionally, tree ferns such as Cyathea fulva  Fée and Dicksonia sellowiana var. arachneosa Sodiro  model the present Mexican beech potential distribution range as a function of particular environmental variables; (3) explore the future Mexican beech forests' potential distribution under climate change scenarios; and (4) determine Mexican beech suitability habitat models and priority areas (hotspots), environmental ranges, and anthropic effects. The exploration of the past, present, and future ecological refugia has the potential to explain their importance for conservation.We tested the hypothesis that the mountains of eastern‐central Mexico have been sufficiently stable climatically to be considered a long‐term Arcto‐Tertiary Geoflora refuge for many taxa such as Mexican beech. In addition, we theorized that there will be a decline in the extent of suitable habitats for relict‐endemic tree species under future climate change. In this study, our aims were to (1) describe the 22.1To determine the current natural distribution of Mexican beech, we conducted field studies of TMCFs from eastern Mexico over 14 years, from 2007 to 2021. We complemented these studies with satellite imagery observations , we used Paleoclimate Modelling Intercomparison Project 3 (PMIP3), supported by WCRP/CLIVAR/Working Group on Coupled Modelling (WGCM) and IGBP/PAGES , the aridity index, and the annual evapotranspiration variables from the CGIAR‐CSI website  of the WGCM  under two greenhouse gas concentration regimes and without implementing future climate policies , retaining those relationships. Additionally, we performed a Jackknife analysis that incorporated the following options: False discovery rate calculation, the multicollinearity degree, coefficient of determination of linear regression, tolerance, variance inflation factor, the Bayesian information criterion (BIC), and Akaike (AIC). Finally, we combined this with our knowledge of Mexican beech responses to specific environmental factors , assessing the surface variation among past, present, and future scenarios  and environmental variables to assess potential habitat suitability analysis. We achieved the analysis with the SDMtoolbox package in ArcGIS v. 10.8 . The environmental variables which influenced the presence of the species were altitude (31.5%), mean temperature of warmest quarter , annual precipitation , and precipitation of wettest quarter , accounting for almost 77.8% of the explained variation (Appendix 2), Tamaulipas (1550.71 km2), San Luis Potosí (351.43 km2), Querétaro (177.06 km2), Hidalgo (1039.16 km2), Veracruz (2397.81 km2), and Puebla . The Jackknife analysis detected that the mean annual temperature (BIO1), seasonality of temperature (BIO4), annual precipitation (BIO12), seasonality of precipitation (BIO15), precipitation of the driest quarter (BIO17), precipitation of the coldest quarter (BIO19), aridity index, and evapotranspiration as the most relevant environmental variables determining potential presence Appendix . Accordi3.32) under the SSP 3‐7.0 of the IPSL‐cm6a‐lr model and 38.06% (1310.49 km2) under SSP 5‐8.5 of the MRI‐esm2‐0 model . Climate change effects on future Mexican beech forest distribution from 2040 to 2070 were estimated under SSP 3‐7.0 and 5‐8.5 scenarios with both scenarios showing a significant decrease in suitable habitat. Mexican beech detected a loss of habitat suitability: 17.13% (1753.95 kmAppendix  and S6. future (>80.4%) were the maximum temperature of the warmest month , mean diurnal range , precipitation of driest month , and precipitation seasonality . Under the SSP 5‐8.5 scenario, the more representative environmental variables were (>84.8%) as follows: maximum temperature of the warmest month , precipitation of the driest month , precipitation of the wettest month , and mean diurnal range , Puebla (650.15–172.69 km2) and Hidalgo ; and (2) Sierra de Juárez in the state of Oaxaca  an area of 316.31 km2, highlighting the states of Hidalgo (145.5 km2), Puebla (55.27 km2), Veracruz (111.47 km2), Querétaro (3.66 km2), and San Luis Potosí (0.41 km2). Further, we identified hotspots covering the “Sierra Gorda” Biosphere Reserve , “Medio Monte” Natural Protected Area , and “La Cuenca Hidrográfica del Río Necaxa” Closed Forest Protection Zone . Our results showed that during the LGM, Mexican beech remained in possible refugia through projected past distributions, influenced mainly by precipitation of the wettest month, precipitation of the coldest month, and altitude. In this situation, the climate became cool temperate (~3°C) and climax forest communities were dominated by subtropical evergreen forests with Arcto‐Tertiary Geoflora genera such as Liquidambar, Acer, Meliosma, Tilia, Magnolia and Fagus having migrated to middle latitudes (from 19 to 23°N) during the Eocene  and Pahuatlán, Puebla , potentially suitable areas that remain to be explored, or locally where it has become extinct  and San Luis Potosí (>88.7%), as indicated in the SSP 3‐7.0 and 5‐8.5 scenarios. We developed these scenarios with information on the increase in gases such as carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) generating the greenhouse effect and having the effect of increasing temperature , that were once common during Oligo‐Miocene thereby protecting them from climatic change. In analyzing the SDMs, we have found a valuable tool that complements palaeoclimatic  and paleoecological effects  in understanding historical, current, and future distribution of Mexican beech. This has allowed us to identify suitable new areas with specific environmental conditions that can influence Mexican beech forest conservation.By assessing suitable habitat for Mexican beech, we have detected a restricted distribution in Hidalgo, Veracruz, and Puebla as projected by 4.1past, present, and future) can provide a realistic potential geographic range proxy, and habitat suitability to identify ecological refugia. Nevertheless, it is necessary to consider connectivity among fragments as reported by Rodríguez‐Ramírez et al. ; data curation (lead); formal analysis (lead); investigation ; methodology (lead); writing – original draft ; writing – review and editing . Isolda Luna‐Vega: Funding acquisition (lead); project administration (lead); writing – review and editing . Gregg Dieringer: Writing – original draft ; writing – review and editing . Ernesto C. Rodríguez‐Ramírez: Conceptualization (supporting); formal analysis (supporting); investigation (lead); writing – original draft (lead); writing – review and editing .The authors declare no conflict of interest.Appendix S1‐S6Click here for additional data file.


We present a case of self‐poisoning with a massive dose of paracetamol by a young Nepalese female patient who presented late to our emergency department. This report highlights the successful management of the patient with the extended use of N‐acetylcysteine over 4 days and continuous supportive therapy as required. The case is an example of the management of delayed presentation of a massive paracetamol poisoning in a resource‐limited setting, where intensive care units and hemodialysis facilities are not easily available. However, when available, massive poisoning should always be managed in continuous monitoring units under the expertise of a toxicologist. Paracetamol poisoning accounts for the majority of overdoses in Europe, North America, and Australia.2 N‐acetylcysteine (NAC) is the antidote of choice in paracetamol poisoning. Early use of activated charcoal, an increased dose of NAC, and early hemodialysis are suggested for a massive overdose of paracetamol.Acute ingestion of at least 7.5–10 gms in adults or 150–200 mg/kg in children above 6 years is considered a toxic dose of paracetamol, which is likely to produce hepatotoxicity.Herein, we present a 24‐year‐old patient who presented 40 h after the consumption of 50 grams of paracetamol. Despite delayed presentation, the patient was managed with the prolonged use of NAC and continuous supportive therapy without extracorporeal treatment, which sets this case apart from others.2a.m. on December 13, 2021 with an alleged history of ingestion of paracetamol tablets about 40 h ago. Our risk assessment revealed that the patient consumed a total of 100 tablets, each containing 500 mg , over 4 h. Different formulations, such as immediate‐release and delayed‐release, in unmeasured quantities, were supposedly consumed by the patient. After 6 h of acute single ingestion, she developed nausea and vomiting, along with abdominal pain. The patient was immediately rushed to a nearby local hospital where routine laboratory investigations were performed and symptomatic management was started. An intravenous (IV) line was opened to provide fluids, pantoprazole 40 mg, ondansetron 2 mg, and ceftriaxone 1gm. She received a referral to TUTH for further management due to the unavailability of antidote N‐acetyl cysteine (NAC) and intensive care unit (ICU) for monitoring. The reason behind her intentional overdose was not clear but she pointed toward the whole act being performed out of curiosity. She had planned the ingestion for a month before the event. During this time, she bought 100 tablets from nearby pharmaceutical dispensaries.A 24‐year‐old female patient presented to the Emergency Department (ED) of Tribhuvan University Teaching Hospital (TUTH) at 6:45 2 saturation: 99%. The patient was awake, alert, and well oriented to time, place, and person. The patient's general condition was fair, with mild pallor but no icterus, edema, or dehydration. Her per abdominal examination revealed generalized abdominal tenderness, predominant in the left iliac and left hypochondrium regions. However, other systemic examinations were unremarkable. The results of laboratory tests at admission to our ED (about 40 h post‐ingestion) are shown in Table The patient had no history of co‐morbidities requiring her to consume paracetamol. Similarly, she had no known psychiatric problems, and this was her first act of self‐harm. Her last menstruation was 2 days before the event. Her vital status was as follows: pulse rate: 74 beats/minute, blood pressure: 110/60 mmHg, temperature: 36.7°C, respiratory rate: 20/minute, and OHer initial investigations revealed anemia, thrombocytopenia, deranged liver function tests (LFTs), a raised amylase level, and slightly raised PT INR. Her serum paracetamol concentration was at 14.2 ugm/ml which was within the therapeutic range. Her urinalysis revealed hematuria (22–24/high power field) with trace albumin. Her electrocardiogram and ultrasonography of her abdomen and pelvis showed normal findings.At our ED, she received IV pantoprazole 40 mg and IV ondansetron 4 mg stat. In addition to this, she (weight = 40 kgs) also received IV NAC 6 gm (dose = 150 mg/kg) in 500 ml dextrose normal saline (DNS) over 30 min. Next, 2 gm (dose = 50 mg/kg)IV NAC was infused over 4 h. Finally, 4 gm (dose = 100 mg/kg) NAC was started for 16 h as a final dose of 21 h IV protocol.On the second day of hospitalization, she was shifted to the observation unit of the ED. The vitals were within normal range. However, she had icterus and mild generalized tenderness of the abdomen. Her liver enzymes, ALT and AST, were about eight times higher than the values on the first day of admission. Appropriate symptomatic management was provided along with an infusion of 10 ml of LOLA on the second day. Her vitals remained stable throughout her stay in the hospital. The LFTs were assessed every day of her stay in the hospital. The results of LFTs are presented in Table On the third day, her ALT level was the highest of all at 1150 U/L. On this background of high and increasing ALT levels, NAC infusion was resumed since it was stopped after completion of the 21 h treatment protocol. Therefore, an IV infusion of 4 gm of NAC was given to the patient over the course of 12 h. The same dose of NAC was continued for the next 3 days of her stay. The IV infusion of LOLA was also continued for the next 3 days. With persistent treatment, her clinical status and LFTs improved, and thus, NAC treatment was stopped. The pattern of liver enzymes throughout the hospital stay is shown in Figure 3Paracetamol is an effective antipyretic and analgesic that has been used comprehensively and globally for many years. The exact mechanism of action of paracetamol is not yet clearly understood. However, complex mechanisms involving cyclooxygenases, endocannabinoid system, serotonergic pathways, and nitric oxide synthesis pathways have been discussed in the literature.Paracetamol at the therapeutic dose (up to 4 gm/day for adults and 50–75 mg/kg/day in children) has a safety profile, but an overdose can induce life‐threatening adverse reactions like acute hepatic failure.Paracetamol poisoning leads to acute renal failure with oliguria and deranged renal function tests.IV NAC is the widely accepted antidote for paracetamol poisoning and is very effective when used early in the course of poisoning.This case management was challenging to us in many aspects. Since the patient presented after 40 h of ingestion of a massive dose, the Rumack–Mathew nomogram could not be used to guide the initiation of treatment.Massive paracetamol overdoses have been reported occasionally in the literature, with variable outcomes. Two case reports have described patients who were treated successfully with intravenous or oral preparations of NAC for three continuous days without significant adverse reactions.Our patient has received multiple infusions of LOLA which gets converted into glutathione and replaces the depleted source in the liver created by paracetamol overdose. LOLA has been shown to correct the glutathione loss with liver failure resulting from toxic liver injury.4This case highlights that recovery is possible in massive paracetamol poisoning with extended NAC treatment for days in resource‐limited settings where ICU or hemodialysis facilities are unavailable. Therefore, NAC should be started as soon as possible under the suspicion of significant ingestion despite delayed presentation. However, when available, patients should always be managed in the continuous monitoring units by a team with expertise in managing drug overdoses. Furthermore, this report has shed light on the ease of accessibility to large amounts of over‐the‐counter medications for the general public in Nepal. Public health measures that restrict the availability of paracetamol, such as reducing non‐prescription pack sizes, are needed to stanch such cases of massive paracetamol overdoses in Nepal.Pratik Lamichhane: Conceptualization; data curation; methodology; writing – original draft; writing – review and editing. Kailash Mani Pokhrel: Data curation; writing – original draft. Bijay Bhandari: Writing – original draft. Anushka Agrawal: Writing – original draft. Bhumika Ghimire: Writing – original draft. Olita Shilpakar: Writing – review and editing.None declared.Written informed consent was obtained from the patient to publish this report in a accordance with the journal's patient consent policy.


Fulminant lupus pneumonitis is a rare complication of SLE. We report a case of 75 years‐old male patient with SLE who developed pneumonia and severe respiratory failure requiring mechanical ventilation. Refractory respiratory distress complicating noninfectious fulminant lupus pneumonitis did not respond to methylprednisolone and intravenous immunoglobulin treatment. FLP in SLE of the elderly is a rare and severe condition. Each practitioner has to focus on respiratory failure, which is severe and life‐threatening. He was treated with 3 pulses of methylprednisolone (1 g/day) relayed by oral prednisone at 1 mg/kg/day in combination with cyclophosphamide. Initial evolution was favorable with clinical and biological improvement (Hb = 11 g/dL and proteinuria at 1 g/24 h). However, a month later, he presented acute dyspnea. On examination, he had no fever, tachycardia (HR 100/min), and tachypnoea at 24/min. On auscultation, loud crackles were audible over both lungs. Biological analyzes were normal . Blood arterial gases revealed severe respiratory failure with hypoxemia . There were negative repeated sputum and blood cultures. Bronchoalveolar lavage (BAL) cultures were also negative. The Golde score was under 100. Chest X‐ray revealed a bilateral alveolar syndrome. High‐resolution computed chest tomography showed bilateral ground glass opacities. Tests for HIV, CMV, EBV, and viral C, and B hepatitis were negative. Sputum examination for acid‐fast bacillus was negative. Although infectious pneumopathy was not very probable, we started empirical antibiotics (ciprofloxacin and spiramycin) with noninvasive ventilation and steroids (a pulse of intravenous methylprednisolone). Repeated blood gases evaluations showed no improvement and in two days, the patient progressed into severe respiratory failure. He required mechanical ventilation on volume support mode and we added intravenous immunoglobulin. Unfortunately, our patient deceased from refractory respiratory distress.A 75‐year‐old male presented with a history of weakness for a few months. He had a familial history of SLE (his daughter). On general examination, the patient was conscious, with stable cardio‐respiratory vitals. The joint examination was normal and pallor was present. His lab stix found proteinuria. Diagnosis of SLE was retained since the presence of 4 criteria of ACR was detected: kidney involvement with proteinuria (3.27 g/24 h), autoimmune hemolytic anemia (7.3 g/dL), thrombocytopenia .Written informed consent was not obtained from the patient because of his death.


Ischemic pain with no‐obstructive coronary artery (INOCA) is clinically significant and defined by nonobstructive coronary stenosis <50%. Coronary microvascular dysfunction (CMD) is a relevant cause associated with adverse outcomes.Investigated the effect of no‐stenosis (0% stenosis) and non‐obstructive (0% < stenosis < 50%) on the prognostic impact of CMD in INOCA.t‐test, Kaplan–Meier curve, and Uni‐multivariable Cox proportional models were used for analysis. Clinical outcomes were major adverse cardiovascular events (MACE) during a median follow‐up of 35 months.A retrospective study assessed the coronary microvascular function in 151 INOCA patients who underwent invasive angiography by the coronary angiography‐derived index of microcirculation‐resistance (caIMR). CZT‐SPECT was performed to evaluate myocardial perfusion imaging (MPI) abnormalities. Chi‐square test/Fisher exact test, Student p = .001), along with abnormal MPI . The MACE rates were not different between no‐stenosis and nonobstructive stenosis. CMD showed an increased risk of MACE for all INOCA. No‐stenosis with CMD had the worst prognosis. Cox regression analysis identified CMD and abnormal MPI as predictors of MACE in all INOCA and patients with no‐stenosis. However, no‐stenosis and nonobstructive stenosis were not predictors of MACE in INOCA.No‐stenosis was present in 71 (47%) INOCA patients, and 80 (53%) were with nonobstructive. CMD (caIMR ≥ 25) was more prevalent in patients with no‐stenosis than nonobstructive (76.1% vs. 48.8%, CMD was more frequently present in INOCA with no‐stenosis. However, there was no difference in long‐term clinical outcomes between no‐stenosis and nonobstructive stenosis. CMD could independently predict poor outcomes in INOCA, particularly in patients with no‐stenosis. It has been shown to have a predictive value for adverse outcomes in coronary heart diseases and INOCA.Thus, the objective of the current study was to investigate CMD by caIMR between no‐stenosis and nonobstructive coronary stenosis in INOCA and evaluate the effect of coronary stenosis on the prognostic impact of CMD in INOCA.2This retrospective, observational study followed the Declaration of Helsinki. The Shanghai 10th People's Hospital of Tongji University's ethical review board and committee  approved the study design. All enrolled patients signed informed consent.2.1The inclusion criteria were (1) age ≥18 years; (2) from February 2017 to June 2019, consecutive patients with chest pain suspected to be myocardial ischemia who underwent invasive CAG and stress‐rest MPI by CZT‐SPECT within 90 days; (3) all native epicardial coronary vessels and major branches (>2.0 mm) stenosis <50%; (4) adequate quality of CAG images for caIMR measurement. Myocardial ischemia is suspected based on the clinical likelihood of ischemia , a clinical assessment that suggests high coronary event risk, and ECG or echocardiographic findings.2.2CAG was performed with standard techniques. Coronary luminal stenosis was determined visually by interventionists at times of CAG and later confirmed by another interventionist. According to CAG analysis, the subjects were divided into (1) a no‐stenosis group when no luminal stenosis or luminal irregularities can be seen (0% stenosis) and (2) a nonobstructive stenosis group (0% < stenosis < 50%) in the major coronary arteries or any branch.The caIMR calculation and analysis were carried out by cardiologists who are well‐familiar and certified in using FlashAngio system software (Rainmed Ltd.). The methods of caIMR have been delineated in detail before.2.399mTc‐sestamibi (99mTc‐MIBI). If there was no contraindication, stress‐phase testing was carried out pharmacologically by administering adenosine triphosphate . The protocol applied to patients in the current study was described in detail in our group's previous study.A CZT‐SPECT cardiac scanner with a camera containing nine rotating pixelated locater columns of cadmium‐zinc‐telluride crystals was used to assess MPI . For all patients, a 1‐day rest/stress protocol was employed using Interpretation of all CZT‐SPECT images was achieved independently by two experienced nuclear readers of heart imaging blinded to the patient's features and outcomes data. The stress and rest phase images were interpreted visually utilizing the 17‐segments sample of the left ventricle and a five‐point measure .2.4The duration of follow‐up was decided from the time of the CAG to the time of the last examination. All participants were followed up by a physician's office visit or phone communication with the patients themselves or relatives and checked electronic hospital records to assess their clinical conditions. The follow up carried out by well‐trained physicians blinded to data every 6 months.The primary endpoint of the study was composite major cardiovascular adverse events (MACE), including (1) mortality caused by clear cardiovascular events; (2) nonlethal MI; (3) unprogrammed coronary revascularization; (4) heart failure, (5) stroke, and (6) anginal‐associated rehospitalization. Cardiovascular mortality was defined as death related to myocardial infarction, fatal cardiac arrhythmia, unresponsive heart failure, cardiogenic shock, or sudden unexplained death. MI was identified as the presence of at least two of the following criteria (1) ischemic symptoms, (2) elevated cardiac enzymes, and (3) ischemic ECG changes. After the exclusion of planned procedures on the fundamental CAG's result, any coronary revascularization (with ≥50% stenosis) at the segment due to clinical deterioration was considered unprogrammed coronary revascularization. Heart failure was diagnosed based on recommended guidelines.2.5t‐test were used for comparison. Kaplan–Meier curve was used to estimate the free survival of MACE, and the long‐rank test was used to detect the differences between survival curves. Uni‐multivariable Cox proportional hazard risk models were constructed to determine the risk factors of MACE. The covariates of the univariate model were age, gender, smoking, diabetes, prediabetes, hypertension, body mass index (BMI), hyperlipidemia, left ventricular systolic ejection fraction (LVEF), CMD, and abnormal MPI. The variables with p < .10 were adapted in the stepwise multivarieties model. The risk hazard ratio (HR) with a 95% confidence interval (CI) of the variables was calculated. Martingale residuals were used to confirm the proportional hazards assumption. The covariable numbers in the model were adjusted per the MACE number. A significant difference was considered when two‐sided p < .05. All statistical tests were accomplished by SPSS (version 20) and GraphPad software.Numerical and categorical variables were presented as mean ± SD and counted with percentages. Chi‐square test/Fisher exact test and independent Student 3From February 2017 to June 2019, of the 268 enrolled patients with INOCA, 172 were prospectively enrolled in the caIMR measurements. Finally, 151 patients who met the inclusion criteria and had readable data of caIMR and CZT‐SPECT were enrolled in the current study , 71 (47.1%) with no‐stenosis and 80 (52.9%) with nonobstructive stenosis were enrolled in the present study. Among all INOCA, 22 (14.6%) and 70 (46.4%) were diabetics and pre‐diabetes, respectively. caIMR measurements were carried out in 337 coronary arteries: in the left anterior descending artery was 131 (38.9%), in the left circumflex artery was 98 (29.1%), and in the right coronary artery was 108 (32.0%). Patients with nonobstructive stenosis were older, had more diabetic frequency, and had less female frequency than no‐stenosis patients. Aspirin, antidiabetic medications, and statin treatment were more frequent in nonobstructive stenosis patients than in no‐stenosis patients. There was no difference between the two groups in other clinical characteristics (Table 3.2p = .001). Rates of CMD were higher in no‐stenosis patients  than in nonobstructive stenosis patients. Concerning CZT‐SPECT, 46 (30.5%) patients showed abnormal MPI in all INOCA patients. The prevalence of abnormal MPI was higher in no‐stenosis  than in nonobstructive stenosis groups, Table The mean caIMR was 32.7 ± 12.8 in all INOCA patients. The caIMR was higher in no‐stenosis patients than in nonobstructive stenosis patients . Additionally, in all INOCA patients, the MACE rate was higher in patients with CMD  than without CMD. Similarly, in the no‐stenosis group, the MACE rate was higher in patients with CMD  than without CMD. However, in the nonobstructive stenosis group, the MACE rate was not different between patients with CMD  and without CMD.During the median follow‐up of 35 months Table , there wp = .176), Figure p = .002), Figure p = .008), Figure p = .010), Figure p = .145)  Figure .p = .021), abnormal MPI  and prediabetes  were independently associated with MACE in both the univariate model and multivariate model after adjusting for confounding factors. However, the no‐stenosis or nonobstructive stenosis were not associated with the prediction of MACE (p = .180) (Table p = .041), abnormal MPI , prediabetes  and LVEF%  were independently associated with MACE, Supporting Information: Table SThe Cox regression model in all INOCA patients showed that CMD  the rate of CMD was higher in patients with no‐stenosis than nonobstructive stenosis, along with abnormal MPI; however, (2) there was no difference in long‐term outcomes between patients with no‐stenosis and nonobstructive stenosis, neither the no‐stenosis nor nonobstructive stenosis was a predictor for MACE; (3) there is a strong relationship between CMD and MACE events in the overall INOCA patients, and this relationship is clearly demonstrated in patients with no‐stenosis.The nonobstructive CAD is not an uncommon finding in both acuteLogically one would have suspected a significantly higher percentage of adverse cardiovascular events in the nonobstructive stenosis (0% < stenosis < 50%) than in the no‐stenosis (0% stenosis) coronary arteries. Early studies showed that normal (0% stenosis) coronary lesions had a better prognosis in terms of mortality than mild (<30% stenosis), and that moderate narrowing (30%–50% stenosis) showed the worse prognosis.In our study, there was no difference in MACE rate when patients were stratified by the degree of stenosis (0% vs. 0% < stenosis < 50%), and coronary stenosis has no predictive value for MACE, whereas CMD assessed by caIMR and abnormal MPI were independent predictors of MACE for all INOCA. Our findings are consistent with a study by Cortigiani et al.,CMD is a major factor in the pathogenesis of myocardial ischemia among patients with INOCA.Interestingly, in our study, the incidence of CMD and abnormal MPI were higher in INOCA patients, which may be implicated in the increased MACE predicted in these patients. Especially in patients with no‐stenosis and CMD with the highest risk of MACE than other patients, it could be that visually normal CAG was considered as an excellent prognosis than nonobstructive stenosis by the physician since the undertreatments were common in the no‐stenosis group.Furthermore, in the current study, CMD and abnormal MPI were independent predictors of MACE in all INOCA patients, and this result is clearly demonstrated in patients with no‐stenosis. As previously demonstrated, CMD is strongly associated with MACE in INOCA patients. In the WISE study, the evaluation of CMD by CFR improved the prediction of MACE regardless of the presence or absence of obstructive (≥50% stenosis) CAD.In the same manner, this study revealed that no‐stenosis with CMD had a significantly higher MACE rate than with no‐stenosis without CMD. Because the total number of CMD in the nonobstructive group was relatively small, the prognostic effect of CMD in the nonobstructive was inconclusive; thus, further studies with a larger sample are needed to verify our findings. CMD is common among diabeticOur study has some limitations: (1) It was an observational, retrospective, single‐center study with a small sample size that investigated INOCA patients who underwent CAG and DSPECT MPI. Therefore, it may not represent general clinical practice. (2) In addition, we have only used visual estimation to determine the percentage of coronary stenosis, which is often difficult to distinguish patients with 0% stenosis from those with minimal CAD on CAG alone without intravascular ultrasound or optical coherence tomography, which may cause missed lesions in the no‐stenosis group. (3) The accuracy of caIMR measurement could be influenced by the image quality, causing patient exclusion. (5) In our study, the INOCA patients did not do the intracoronary acetylcholine test; therefore, microvascular vasospasm was not assessed. (6) The duration of follow‐up was relatively short, which may have caused the under‐reporting of the MACE rate. Multicenter prospective studies with intracoronary imaging testing to evaluate the degree of stenosis and assess microvascular endothelial (microvascular vasospasm) function, with a longer follow‐up, are necessary to ascertain our findings.5CMD was more frequently present in INOCA with no‐stenosis; however, there was no difference in long‐term clinical outcomes between no‐stenosis and nonobstructive stenosis. CMD could independently predict poor outcomes in INOCA, particularly in patients with no‐stenosis. In INOCA patients, further functional investigations for CMD are justified in risk stratification.Conception and design: Lu Liu, Ayman A. Mohammed, Hengbin Zhang, Wenliang Che; Administrative support: Fuad A. Abdu, Wenliang Che; Provision of study materials or patients: Shekhar Singh, Xian Lv, Tingting Shi; Collection and assembly of data: Redhwan M. Mareai, Abdul‐Quddus Mohammed, Guoqing Yin; Data analysis and interpretation: Lu Liu, Ayman A. Mohammed, Hengbin Zhang; Manuscript writing: All authors; Final approval of manuscript: All authors.The authors declare no conflict of interest.Supplementary information.Click here for additional data file.Supplementary information.Click here for additional data file.