Finally, we highlight the significant achievements of various MPNs for cancer theranostics, such as tumor imaging, drug delivery, photothermal therapy, radiotherapy, and chemo- and photo-dynamic therapy. This review provides a comprehensive background on the design and controllable synthesis, in vitro and in vivo biocompatibility evaluation, applications of MPNs as cancer theranostic agents, and presents an overview of the most up-to-date achievements in this field.In recent years, metal-phenolic networks (MPNs) have attracted increasing attention for the engineering of multi-functional platforms because of their easy fabrication processes, excellent physicochemical properties, outstanding biocompatibility, and promising theranostic applications. In this review, we summarize recent progress in the design, synthesis, shape-control, biocompatibility evaluation, and potential theranostic applications of MPNs, especially for cancer theranostics. First, we provide an overview of various MPN systems, relevant self-assembly procedures, and shape-controllable preparation. The  OH) groups directly attached to an aromatic hydrocarbon group. Phenols and polyphenols normally exist in plant foods such as vegetables, fruits, spices, herbs, tea, and wine, and are associated with various biological functions, including chemical defense, structural support, metal sequestration, pigmentation, and prevention of radiation damage Figure 1) Phenols, also called phenolics, are a class of organic compounds consisting of one or more hydroxyl (-Phenols (and polyphenols) possess various cardioprotective, anti-inflammatory, anti-aging, antioxidant, anticancer, and antimicrobial activities, have kidney protective, lung protective, and neuroprotective effects, and are also effective against UV irradiation and prevention of osteoporosis IIIPolyphenols are excellent raw materials to prepare multi-functional inorganic-organic hybrids for biomedical applications and are considered potential candidates for applications in many fields, such as energy, transportation, optics, microelectronics, environment, housing, health and diagnostics III-tannic acid (TA) platform for tumor-specific photoactivated utilizations, including T1-weighted magnetic resonance imaging (T1-MRI imaging), photoacoustic imaging, photo-thermal imaging together with NIR photo-thermal therapy with complete tumor elimination in vitro/in vivo treatment. The second section of this review will discuss various cancer theranostic applications of MPNs, including tumor imaging, drug delivery systems for chemotherapy, photothermal therapy, radiotherapy, and chemo-/photodynamic therapy.MPNs are super-molecular network structures consisting of metal ions coordinated with phenolic ligands. Compared to metal organic frameworks (MOFs) or other metal polymer complexes, MPNs are environment-friendly for the green phenolic ligands Figure 2). By simply mixing TA with FeIII in phosphate-buffered saline for a few minutes at ambient temperature, large-scale FeIII-TA nanoparticles could be obtained with excellent physicochemical properties  III-TA capsule and film can be easily obtained by introducing different templates or substrates  III of a 3-dimensional multi-functional wound dressing cryogel  has been described for efficient wound healing Figure ) III formed MPNs, and Den-DOX-tannic acid-FeIII (DDTF) nanoparticles were obtained to overcome the multidrug resistance of tumor through the apoptosis/ferroptosis hybrid pathway MPNs consist of two parts: the central metal ions and phenolic ligands. A single organic ligand can coordinate with a variety of metals, or changing organic ligands for a specific metal ion are both significant strategies to design facile functionalized MPNs. The commonly used organic components are simple phenolic ligands, namely the monomeric building blocks of natural polyphenols Figure ) Figure ) Figure ) Figure ) Figure ) IIIco-DMA)/Fe MPNs for antimicrobial and antifouling applications Besides TA-based MPNs, many other natural plant phenols, including pyrogallol (PG), gallic acid (GA), pyrocatechol (PC) , iron (Fe), aluminum (Al), cobalt (Co), vanadium (V), copper (Cu), zinc (Zn), nickel (Ni), chromium (Cr), zirconium (Zr), molybdenum (Mo), rhodium (Rh), cerium (Ce), europium (Eu), cadmium (Cd), gadolinium (Gd), ruthenium (Ru), and terbium (Tb) III and TA was first reported by Caruso and colleagues III) in the water at ambient temperature. The original materials are readily available and inexpensive, and importantly, no other special equipment and devices are needed. During the one-step assembly of MPNs, the color of the mixture turns immediately blue upon addition of FeIII and TA, and small FeIII-TA networks form in the suspension and subsequently bind to the surface of the polystyrene substrate .The development of versatile and facile strategies for MPN engineering is of significant interest, especially the strategies for easily assembling MPNs on designed substrates with proper composition, structure, shape, and size. In 2013, the “one-step” assembly of MPNs consisting of FeIII and TA are removed during the incubation steps of “multistep” assembly, the formation of small FeIII-TA networks in the solution could be precisely controlled  III content (50 mol%) than those prepared through a one-step route (25 mol%). However, the one-step assembly strategy results in a higher Young's modulus Besides “one-step” assembly, “multistep” routes via coordination interactions are the most used procedures to prepare MPNs. In the “one-step” assembly, phenolic ligands and metal ions are mixed in one pot, or the substrate is immersed in separate phenolic ligand or metal ion solutions. However, “multistep” assembly has unique MPN performances as the substrates are sequentially incubated in separate solutions of excess phenolic ligands or metal ions. Since the unabsorbed Feet al.demonstrated rapid spraying of FeIII-TA-MOC nanofilms on gold-coated silicon wafer substrates  III solution for only 5 seconds. Alternatively, TA and FeIII solutions could be sprayed simultaneously to save time. Ellipsometric measurements revealed that the film thickness of MPN nanocoating was linear with spraying cycle, time and concentration. This rapid and simple spraying to form stable and uniform films on bulk substrates is suitable for application in agricultural technology. Similarly, Zhong et al.established a spray assembly method for patterned and homogenous MPNs by using appropriate conditions and building blocks  MPNs have a highly ordered network structure that allows layer-by-layer spray nanocoating. This “multistep” assembly strategy of MPNs for functionalization on various substrates has been widely studied et al.designed a new approach using rusted iron objects as solid-state iron sources for the continuous preparation of MPNs  The original preparation method for MPNs in the presence of solid substrates is inherently limited by the apparent discrete nature of the self-assembly procedure. Therefore, novel synthetic methods enabling continuous assembly of MPNs are required to improve processing flexibility and tunable properties. Caruso 3) particles are one of the most extensively used templates for preparing MPNs because of easy synthesis, size and shape control, and mild conditions for removing template3) by the co-precipitation method. Subsquently, the stable AlIII-TA self-assembly coordination films were formed in situ around the CaCO3 templates by vortexing AlIII ions and TA in the buffer solution (pH 8.0)  3 templates  et al.reported pH-responsive nanocarriers (DOX/GA-Fe@CaCO3-PEG) based on CaCO3 to enable effective intratumoral penetration and reversal of MDR II and FeII content in GA-Fe@CaCO3 was time-dependent with the extension of reaction time. These studies depicted a powerful strategy for the preparation of MPNs via template sacrifice.Template-mediated preparation is a well-known strategy for organic and inorganic nanoparticles. Calcium carbonate  II into FeIII, forming a confined gradient in the vicinity of the electrode and inducing localized self-assembly of a FeIII-TA film. The electro-triggered self-assembly of FeIII-TA confined FeIII ion buildup on the surface of the electrode, finetuning the coating thickness by switching on and off the electrical stimulus. Previous biphasic interfacial reactions required a cumbersome procedure for synthetic molecules. Kim et al.first reported biocompatible supramolecular coordination complexes through biphasic interfacial reaction  III-TA nanofilm strategy does not need complicated operating procedures, and the obtained products are biocompatible and even edible, providing great potential in the cell nanoencapsulation. Thus, the FeIII-TA networks synthesized in the biphasic interfacial system show high versatilities and can be seamlessly applied to various interfaces.Interfacial supramolecular self-assembly for MPNs proved to be simple, fast, and effective with a high degree of uniformity and was introduced to prepare the supramolecular coordination compound of TA and FeFigure ) III were used as raw materials for the template-mediated preparation. The investigators deposited FeIII-TA films on planar PS substrates  after completing the self-assembly coordination chemistry reaction. When spherical PS particles were used as a template, highly uniform FeIII-TA microcapsules were obtained after template removal  III  3·6H2O and 1,3,5-benzene tricarboxylic acid. The shape changed from spherical to ellipsoidal state during stretching of the spherical PS nanoparticles above their glass transition temperature. Thus, the ellipsoidal capsules of MPNs could be synthesized by sacrificing the ellipsoidal PS particles . Recently, highly ordered mesoporous metal-phenolic particles were prepared by sacrificial double cubic network polymer cubosomes  In recent years, besides the discovery of novel MPN systems for new functions based on different metal ions and special phenolic or polyphenolic ligands, shape- and size- controlled preparations of 0-, 2-, and 3-dimensional MPNs also attracted much attention. Various shapes of nanoparticles, mesoporous particles, capsules, ellipsoidal particles, films, and 2D-/3D- hydrogels have been successfully fabricated with precisely controlled methods. The first and most common strategy used a well-defined template to realize the designed shape control. In 2013, Caruso first reported the one-step assembly method to prepare various films and particles II, ZrIV, FeIII) and phenolic ligands -epigallocatechin gallate) . The average diameter of the MPN-coated PCs was about 2.4 ± 0.7 μm with uniform tetragonally distributed pores of ~40 nm.Precisely controlling the shape of nanomaterials by adjusting the synthesis parameters is significant as it usually creates unique and required functions. Efforts have been made to generate mesoporous holes within the MPNs through coordinating with different ligands et al.systematically explored the influence of ionic strength on FeIII-TA MPN precursors and the final morphology and capsule thickness of MPN films Figure 11). The molecular dynamics simulations demonstrated that the galloyl groups of FeIII-TA3 MPNs could extend further into the bulk solution away from the metal center at higher ionic strengths. This observation led to subsequent chelation with other FeIII ions and/or complexes, resulting in thicker and rougher films.The environmental conditions during the synthetic procedures are also adjusted for various shape-control. For example, Guo in vitro cytotoxicity and in vivo biocompatibility of MPNs in biological environment is of great significance.First discovered by Caruso in 2013, MPNs are being increasingly used in nanomedical science for fabricating multi-functional nanomaterials in various applications, including tumor imaging, drug delivery systems for chemotherapy, photo-thermal therapy, radiotherapy, chemo-dynamic therapy and photo-dynamic therapy. Therefore, understanding the III-TA networks have generated much interest for various biomedical applications. To evaluate the biocompatibility of both FeII and FeIII MPNs, Huang et al.used NIH-3T3 fibroblasts to systematically evaluate the cytotoxicity of all MPN coatings Figure ), indicating negligible cytotoxicity and good biocompatibility. Besides the relative cell viability, Li et al. explored the change in morphology of cells cultured on various MPN surfaces  As one of the most common components of MPNs, iron ions and TA are generally recognized as safe (GRAS) by the U.S. Food and Drug Administration, and FeFigure 13). Furthermore, the mesenchymal stem cells grown on the MPN-coated Ti implants showed superior adhesion and the highest cell viability after 7 days of seeding compared with the bare Ti substrates. The enhanced biocompatibility of TA or MPN coatings might originate from the free radical scavenging capability of phenolic hydroxyl in phenolic molecules. Also, the biocompatibility assays of FeIII-based MPN hydrogels indicated that the potential cytotoxicity of some metal ions is tempered by the strong coordination between metal ions and phenolic ligands Similarly, Cai et al. prepared MPNs on pure Titanium (Ti) substrates to form Ti-based implants and explore their biocompatibility  in vivo biocompatibility of a material is a mandatory prerequisite for its clinical use, requiring well-planned preclinical and clinical trials et al. systematically evaluated the in vivo biocompatibility and immunogenicity of the metal-phenolic gelation for 14 weeks Figure ) Figure ). The overall low Ti concentration in main organs including the brain, heart, kidney, liver, lung, and spleen exhibited excellent in vivo biocompatibility of metal-phenolic gelation.The assessment of in vivo toxicity and in vivo inflammatory response of nebulized metal-phenolic capsules in mice III-TA capsules with different thicknesses (108 nm for (FeIII-TA)1, 162 nm for (FeIII-TA)3, 207 nm for (FeIII-TA)6) were systematically examined, including the serum levels of liver enzymes and proteins. The major hematological parameters, total number of cells and levels of inflammatory cytokines in the BAL fluid, and lung histology after 4 and 24 h post-administration were examined . After 30 days' administration with (FeIII-TA)1, 162 (FeIII-TA)3, and (FeIII-TA)6, no signs of lethargy, higher levels of inflammatory cytokines, higher BAL cell numbers, lung inflammation, or alveolar damage were observed compared with the control group. Furthermore, hematological parameters showed no significant changes of liver enzymes and protein levels. These results indicated high in vivo biocompatibility of FeIII-TA capsules.Caruso et al. investigated the III, GA and PVP in vivo biodistribution investigation exhibited that Fe-CPND excretion from the body after intravenous injection was via renal clearance. Pharmacokinetic measurements of Fe-CPNDs in blood showed that the blood-elimination half-time was about 5.5±1.9 h. No significant differences were observed between Ge-CPNDs-treated and control groups during 30 days of treatment by histochemical, hematological, and blood biochemical analyses, confirming the nontoxicity of Fe-CPNDs. Although appropriate MPN concentrations were biocompatible in vivo, extensive in vitro and preclinical studies are required before future clinical applications of MPNs.In 2015, Wang and colleagues demonstrated a gram-scale preparation strategy to synthesize a class of renal-clearable nanodots (Fe-CPNDs) via the self-assembly coordination of FeTheranostics provides a transition from conventional medicine to personalized medicine and has emerged as a safe, targeted, and efficient pharmacotherapy Molecular imaging of tumors has generated wide attention for its ability to interrogate and diagnose tumor tissues without biopsies or surgical procedures npFeIII-TA RPs) were fabricated via the self-assembly coordination complexation of FeIII ions and TA, and the nanoporous CaCO3 particles. The FeIII chelated in the npFeIII-TA RP networks could catalyze H2O2 into O2 and act as an agent for ultrasound imaging . Also, TbIII-TA and EuIII-TA capsules have been shown to be excellent fluorescence imaging agents; acetylacetone (AA) and 2-thenoyltrifluoroacetone (TTA) were employed as co-ligands to impart fluorescence intensities of TbIII-TA and EuIII-TA complexes, respectively. Due to the 5D0-7F2 transition, TbIII-AA-TA exhibited green fluorescence around 545 nm and EuIII-TTA-TA red fluorescence around 613 nm  64CuII-TA capsules were fabricated by doping 64Cu in the MPNs. PET phantom images and PET images in vivo in healthy BALB/c mice suggested that 64CuII-TA capsules were efficient PET-active agents, and could be used to track the bio-distribution of theranostic platforms or drugs .Due to the intrinsic performance of metal ions and the porous network structure, MPNs are excellent candidates as imaging agents or carriers. For example, nanoporous metal-phenolic particles . MnII-TA capsules exhibited the greatest MRI performance with relaxivity of 60 s-1 mM-1, which is generally sufficient for in vivo use Figure ) In vivo PAI measurement in HeLa cells tumor-bearing mice showed an imaging signal peak at 24 h post-injection, suggesting the considerable PAI ability of MPNs. These results demonstrated that MPNs are a potential platform for tumor imaging due to the excellent encapsulation capacity for loading imaging agents and the intrinsic performance of tumor imaging.GdFigure ) cis-diol responsiveness of boronate complexes and pH responsiveness of MPNs were brought together by the dynamic boronate covalent bonding of reversible boronate ester based on the multivalent coordination chemistry. Due to the controlled release of the boronate-phenolic network, the DOX release from networks could be dramatically accelerated when the pH decreased from 7.4 to 5.0 or 100 × 103 M mannitol was added. Furthermore, the combination of acidic pH and cis-diols could further accelerate the release kinetics of DOX from the networks due to the synergistic effect between the dual-responsive strategies.Approaches for delivering therapeutic agents to tumor sites typically include systemic administration of therapeutic drug delivery systems or localized delivery of therapeutics to the target tissue III nanoparticles, DPPF NPs) via a self-assembly process based on FeIII-MPNs for co-delivery of platinum prodrugs and DOX O2.-) to kill tumors . The polyphenols in DPPF NPs could catalyze  generation from (O2.-) due to their superoxide dismutase-like activity, and the ·OH generated by Fenton reaction could improve the chemotherapy efficiency via a cascade of synergistic bioreactions. In vivo antitumor evaluation based on the U87MG xenograft tumor model exhibited highest tumor growth inhibition by DPPF NP treatment, indicating the synergistic effect of ROS-promoted chemotherapy.Similarly, Chen et al. developed a ROS-promoting combination drug delivery system  in vitro and in vivo results revealed that EIN restricted tumor metastasis and also eliminated EMT-type cancer cells. The study provides a novel strategy to develop MPNs as chemotherapeutic agent carriers. Especially, MPNs exhibit selective gating performance under different pH environments to switch permeability, which is important for smart drug delivery III, AlIII, CuII self-assembly coordination with tannic acid, gallic acid, and pyrogallol revealed that the synthesized MPN capsules could switch between “closed” and “open” states in response to the pH change between 4 and 9 . These phenomena indicated that the designed MPNs could be precisely controlled for dynamic cargo encapsulation and release for drug delivery.It is well-established that tumor metastasis and multidrug resistance are the core challenges for cancer treatment. Emerging evidence has demonstrated that epithelial-mesenchymal transition (EMT) is associated with drug resistance and also an essential step in tumor metastasis Near-infrared (NIR) absorbing materials, namely photosensitizers, have attracted considerable interest in recent years for phototherapy of malignant tumors due to their ability to convert NIR light into heat. So far, photothermal agents, including carbon nanomaterials, metal nanoparticles, transition metal dichalcogenides, upconversion nanoparticles, black phosphorus-based complexes, and photosensitizer-based polymers are still scarce. In this context, MPNs were found to have excellent photo-thermal conversion performance III, RuIII, FeIII, CuII, NiII, MnII, and VIII  III-TA nanospheres with a concentration of 200 μg mL-1 increased about 44.5 °C compared to 3.8 °C of water. Further measurements showed that VIII-TA and RuIII-TA nanospheres exhibited considerably broad absorption in the NIR window and NIR-activated photo-thermal conversion, while GdIII, CuII, NiII, MnII-based MPNs. Besides TA, pH-sensitive MPNs with excellent degradability-based on FeIII and trimesic acid were combined with curcumin and PDA-modified hyaluronic acid for imaging-guided chemo-/photo-thermal treatment of tumors  -2 with the photo-thermal conversion efficiency of about 21.0%, close to that of Au nanorods (23.7%). Furthermore, a simple and scalable procedure was performed to prepare pH-activated nanodots (Fe-CPNDs) based on the self-assembly coordination of GA, FeIII, and poly (vinylpyrrolidone) -1 [Fe] increased to 50 °C, enough to kill cancer cells . Similarly, by mixing GA and FeIII solutions, Cheng et al.prepared polyethylene glycol-modified ultra-small Fe-GA self-assembly coordination nanoparticles for phototherapy of cancer  -1 showed temperature increase by 20 °C under NIR 808-nm laser irradiation (0.8 W cm-2) for 5 min. The photo-thermal efficacy of the ultra-small nanoparticles was confirmed by in vivo photo-thermal therapy experiments in 4T1 tumor-bearing mice.Feng et al. systematically explored the photo-thermal capability of MPNs by inducing different metal ions, including GdFigure ) 2+-induced T1-weighted MRI contrast enhancement, and photo-thermal properties. As excellent photosensitizing agents and photosensitizing agent carriers, various MPNs have demonstrated their efficient tumor killing ability in vitro and in vivo. Future studies should focus on designing new MPN systems with greater abilities and clinical application potential.As discussed above, various metal ions have been explored for multi-functional applications. Yang et al. directly used Mn-TA networks to coat black phosphorus nanosheets and obtained Mn-TA chelated-coated BPNSs   1O2 could be generated from Hb@Hf-Ce6 NPs under irradiation of 8 Gy X-ray compared to Hb@Hf-Ce6 NPs without irradiation. Quantitative fluorescence intensity detection exhibited 7.29 times higher 1O2 level under X-ray irradiation than free Ce6.Nanotechnology is a potential approach to address challenges, like intensity-modulated, imaging-guided, and dose-guided radiotherapy, deep inspiration breath-hold (DIBH), and combination therapy in vivo antitumor efficacy and showed significant growth inhibition on both primary and distant tumors in a 4T1 orthotopic and bilateral tumor model. Furthermore, treatment efficacy of the combination strategy of RT-radiodynamic therapy (RDT) and PD-1 checkpoint blockade immunotherapy based on the Hb@Hf-Ce6 NPs was demonstrated in the lung metastasis model in which the experimental group of NP(+) and programmed cell death protein 1 (PD-1) (+) exhibited delayed metastasis without mouse death. These results indicated that Hb@Hf-Ce6 NPs could improve the therapeutic effect of RT-RDT, enhance modulation of hypoxia TME and promote antitumor immune response in combination with PD-1 immune checkpoint blockade.The Hb@Hf-Ce6 NP-based X-ray irradiation was used to evaluate the Figure ) in vivo combined PDT and RT showed 98.8% tumor inhibition with the smallest tumor sizes, while the tumor inhibition rates for PDT or RT alone groups were 50.5% and 43.8%, respectively. These properties demonstrated that GRDs could be effectively applied to MRI-/enhanced-fluorescence-imaging-guided PDT and radiotherapy for cancers.Similarly, gadolinium (Gd)-rose Bengal (RB) coordination polymer nanodots (GRDs) based on their self-assemble coordination  of tumors is considered a great potential treatment with minimal side effects. The decomposition of hydrogen peroxide could be catalyzed by transition metal ions like Fe, Cu, Mn, Ni, and Co to produce hydroxyl radicals III, platinum prodrug polyphenols, hydrophobic DOX, and polyethylene glycol polyphenols were chosen as raw materials to construct DOX@Pt prodrug Fe nanoparticles (DPPF NPs) 2Ÿ-, the polyphenols could act as a SOD-like enzyme to catalyze O2Ÿ- to H2O2, and finally the ferric ions could react with H2O2 to generate highly toxic ·OH killing cancer cells by Fenton reaction. In vivo evaluation using the U87MG xenograft tumor model revealed that the DPPF NPs-treated group had tumor growth inhibition and high survival rate.To fabricate a synergistic combination therapeutic platform based on MPNs enhanced by toxic reactive oxygen species, FeFigure ) 2O2 level through cascade reactions inside cells. Then FeIII catalyzed to produce toxic ROS, thus boosting the therapeutic efficacy by introducing CDT. Similarly, to overcome the low Fenton reaction efficiency and insufficient H2O2 levels in TME, FeIII, TA, glucose oxidase (GOx), human serum albumin (HSA) and tirapazamine (TPZ) were used to synthesize a self-amplified nanoreactor termed HSA-GOx-TPZ-FeIII-TA (HGTFT). The nanoreactor HGTFT could realize starvation therapy by consuming oxygen, CDT via converting oxygen into ·OH for CDT, and TPZ radical-mediated chemotherapy with one injection, indicating a sustainable cascade antitumor performance Mao et al. synthesized theranostic nanoparticles (PTCG NPs) for synergistic cascade cancer chemotherapy and chemo-dynamic therapy using polyphenol-modified block copolymer, phenolic platinum (IV) prodrug, and epigallocatechin-3-gallate  in vivo results showed that the increased ROS concentration generated by DOX-induced apoptosis could make cancer cells more sensitive to Fenton reaction-induced ferroptosis, improving the chemo-dynamic therapy effect.Recently, inspired by the ROS-producing and ferroptosis-inducing agents for CDT, Wu et al. prepared MPN nanocomplexes based on Fe1O2) induced by photosensitizers  Similar to CDT, photo-dynamic therapy (PDT) is another efficient strategy to eliminate tumor cells via ROS-like singlet oxygen , was fabricated for combined treatment of breast cancer with photo-thermal therapy, chemo-dynamic therapy, and chemo-therapy  III to FeII, which could react with intracellular H2O2 to generate ·OH for chemo-dynamic therapy. The photothermal conversion property of ICG under NIR 808-nm laser enabled PID@Fe-TA to generate heat and promote more ROS concentration, leading to photo-thermal therapy and enhanced chemo-dynamic therapy. Finally, with additional chemotherapy of DOX, PID@Fe-TA offered attractive pH-responsive multi-functional nanotheranostics.Besides the single treatment strategy alone, MPNs are also excellent candidates for designing multi-functional nanomaterials as combined therapeutic platforms due to their functional metal ions, various phenolic ligands, easy modification, and high efficiency for loading theranostic agents. A metal-phenolic network-based multi-functional platform (PID@Fe-TA), consisting of Fein vitro and in vivo biocompatibility, multi-functionality, and unique physicochemical properties are potential candidate for cancer theranostics. MPNs also act as a platform for tumor imaging, drug delivery carriers, and agents for photo-thermal therapy, radiotherapy, and chemo-/photo-dynamic therapy. The traditional theranostic nano-platforms represent sophisticated nanostructures requiring a combination of physical and/or chemical procedures for diagnostic and therapeutic components MPNs with simple self-assembly synthesis, excellent in vivo metabolism and toxicity in vivo biological interactions of MPNs for their theranostic applications. MPNs have heralded new avenues for designing functional materials for cancer theranostic applications and future research is expected to further advance this field.An important prerequisite to realize the promising potential of theranostic metal-phenolic structures as nano-platforms is to extend their circulation time in the blood for controlled and targeted treatment


Tumor necrosis factor (TNF)-α inhibitors are known for the reactivation of latent tuberculosis (TB). As a paradox, it has been reported to have a role in the treatment of immune reconstitution inflammatory syndrome (IRIS) from anti-TB therapy.We report a case of paradoxical worsening of central nervous system TB after initiation of anti-TB medications, which was treated successfully with infliximab (TNF-α inhibitor).Mycobacterium Tuberculosis which was pan-susceptible. Repeat MRI of the brain 6 months into therapy revealed worsening of brain lesions. Moxifloxacin and linezolid were added to the regimen given clinical progression on first-line therapy. 6-months into this enhanced regimen he started experiencing blurring of vision. Visual field mapping showed left homonymous hemianopia. Repeat MRI of the brain confirmed extensive changes of basilar meningitis completely enveloping the optic chiasm. IRIS from TB was suspected. His prednisone dose was increased, and 3-doses of infliximab infusion were, 2-weeks apart were administered which showed clinical and radiological improvement.A 34-year-old man from Nepal with a history of untreated latent TB presented with complaints of occipital headache, slurred speech, and witnessed seizure. His physical exam was consistent with hyperreflexia. MRI of the brain revealed multiple small contrast-enhancing lesions in cerebral hemispheres. CT Chest showed bilateral centrilobular nodules suggestive of miliary TB. Cerebrospinal fluid (CSF) analysis showed pleocytosis, high protein, and low glucose. He was started on isoniazid, rifampin, ethambutol, and pyrazinamide along with high-dose dexamethasone for TB meningitis. Later, MTB DNA probe from bronchioalveolar lavage and CSF detected MRI BrainMRI Brain  shows hyperintensities in multiple locations including the involvement of the left optic nerve and the left occipital region.Exacerbation of pre-existing clinical symptoms, formation of new lesions, or cavitation of prior pulmonary infiltrates is known as tuberculosis IRIS or paradoxical reaction. Despite the clinical and radiological exacerbation, mycobacterial cultures usually stay negative. Continuation of anti-TB medications and high-dose corticosteroids are the backbone of treatment but in refractory cases, immune modulation is needed with anti-TNF-α agents.All Authors: No reported disclosures


Background: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel (sb-PTX) in breast cancer patients of all stages.Method: Pubmed, Embase and Cochrane Library were searched for head-to-head randomized controlled trials of nab-PTX and sb-PTX in breast cancer. Risk ratio (RR) with 95% confidence interval was used for dichotomous variables while Hazard ratio (HR) was used for time-to-event outcomes.Results: Our review finally included 9 studies with 3508 patients. Nab-PTX showed a benefit on objective response rate (ORR)  as well as non-inferiority compared with sb-PTX in disease control rate (DCR) , overall survival (OS)  and disease free survival/progression free survival (DFS/PFS) . However, when it comes to toxicities , results favored sb-PTX . Patients with metastatic tumors or undergoing conventional schedule responses better to nab-PTX than the compared groups .Conclusions: Nab-PTX can improve ORR compared with paclitaxel and should be given priority to when aiming to reduce tumor load in breast cancer. Sb-PTX of dose dense schedule is recommended when toxicity of nab-PTX is hard to bear for breast cancer patients. There were 2,261,419 new cases of breast cancer, ranking first among all cancer types worldwide, according to the data of GLOBOCAN 2020 There are different forms of taxanes frequently used in clinical practice in breast cancer, including solvent-based paclitaxel (sb-PTX), docetaxel  and nanoparticle albumin-bound paclitaxel (nab-PTX), three of which are most frequently used worldwide. Sb-PTX is the first to be identified and should be dissolved in Cremophor EL which may lead to hypersensitivity reactions and make dexamethasone and H1 & H2 -receptor antagonists necessary as premedication. Nab-PTX, a solvent-free nanometersized form of paclitaxel which make castor oil caused toxicity avoidable, can be administered with shorter fusion schedule (30 minutes) than sb-PTX and no premedication is needed There are three meta-analyses To help make a wide choice between nab-PTX and sb-PTX, we performed this meta-analysis of data from all the head-to-head randomized controlled trials comparing nab-PTX and sb-PTX in breast cancer regardless of treatment settings. The following outcomes were compared: short term efficacy , long term efficacy  and toxicity (≥3 grade toxicity events and adverse effect related discontinuation). Subgroup analyses were done using available data and treatment settings/schedule/molecular subtype were all taken into account.This meta-analysis was done following recommendations of the Preferred Reporting Items for Systematic Review and meta-analysis (PRISMA) We only included randomized clinical trials comparing nab-PTX with sb-PTX in this study. Observational studies, case reports, animal studies, those with unclear data on outcomes or comparing nab-PTX with docetaxel, were all excluded. The selecting process was independently conducted by two authors (Bing-Xue Li & Yi-Hua Liu). Any disagreements between these two investigators were resolved by a third author (Xin-Jie Chen).We extracted data on study randomization methods, participants' baseline characteristics, chemotherapy regimens and outcomes together with outcome definitions both in printed papers and electronic files (excel). Outcomes were measured as follows: 1) objective tumor response rate ; 2) disease control rate ; 3) overall survival ; 4) progression-free survival/disease-free survival ; 5) grade 3/4 toxic events as defined by the original study. Two investigators (Bing-Xue Li & Xin-Jie Chen) independently extracted the data and resolved queries through discussion with a third researcher (Tong-Jing Ding). For trials with three arms including nab-PTX and sb-PTX, we only extracted data of this two arms. When there was more than one publication on the same study, we used the updated data for the long-time follow-up outcomes. As for missing data, attempts have been made to contact the original investigators but further details were not available and these data were excluded from the quantitative analysis.The Cochrane Collaboration's 'Risk of bias' assessment tool 2<50% and p>0.1 for Q test otherwise random effects model was used . Heterogeneity was measured by I2 and explored by subgroup analysis, baujat plot and sensitivity analysis (omitting each study once at a time). In tests of subgroup differences, fixed effect model was only used when there was no heterogeneity found in all the subgroups or overall results, otherwise random effects model would be used. Publication bias was evaluated by funnel plots and adjusted using trim-and-fill method. All the analyses were done using R version 4.0.2.Risk ratio (RR) with 95% confidence interval were used for dichotomous variables while hazard ratio (HR) for time-to-event outcomes. When HRs and SEs were not directly reported in the original paper, we used Engauge Digitizer to obtain the survival rate at different time points from Kaplan-Meier curves and calculated HRs and SEs using the spreadsheet shared by Jayne F Tierney After searching pubmed, embase and the cochrane library, we got 2026 records on January 23 2021. Finally we contained 11 records , 2  of which provided updated data for 2 previously included studies. The study flow diagram can be seen in Figure Overall, 3508 patients were included in the analysis. For trials including more than two arms For selection bias, 6 trials For performance bias, considering the shorter fusion schedule (30 minutes) and no premedication in nab-PTX group, there was no possible way to blind the participants and investigators, so we assessed all studies at high risk.Detection bias was grouped by outcomes with similar risk of bias:1) ORR, DCR, PFS/DFS:Untch 20162) OS, hematological toxicity:We perceived that these outcomes' assessments were unlikely to be influenced by blinding or not so we assessed them as at low risk of bias.3) Non-hematological toxicity:No details were provided so we assessed them as at unclear risk.We drew the conclusion that time-to-event outcomes (OS and PFS) were all incomplete because the specific censor method  was not explained and this would have an effect on the analyzed result. Ciruelos 2019 Considering the baseline characteristics of the included studies differed and the potential factors influencing the outcomes were not fully understood, all studies was assessed as at unclear sick of bias in the 'other bias' part.All the quality assessment could be referred in Figure Eight studies were available for us to estimate a risk ratio (RR) for objective response rate (ORR). Specially, for patients undergoing neoadjuvant chemotherapy, we analyzed the response rate before surgery other than pathological complete response rate (pCR) to evaluate the pure effect of chemotherapy. The ORRs were respectively 61.2% in nab-PTX group and 57% in sb-PTX group. There was a significant difference in favor of nab-PTX with an RR of 1.22  which were reported by more than 2 studies. Differences were found in fatigue (nab-PTX vs sb-PTX: 7% vs 3%), nausea or vomiting (nab-PTX vs sb-PTX: 3% vs 1%), peripheral sensory neuropathy (nab-PTX vs sb-PTX: 11% vs 5%), adverse event related discontinuation (nab-PTX vs sb-PTX: 14% vs 7%) , DFS/PFS , fatigue  and PSN  while not found in DCR , OS , nausea or vomiting  and ARD   and different schedules (P<0.01). Patients with metastatic tumors or undergoing conventional schedule responded better to nab-PTX than the compared groups  in OS and DFS/PFS analyses but still no significant difference was found between nab-PTX and sb-PTX . However, HRs in TNBC tended to be lower than that of the total  were verified by baujat plot. Untch 2016 affected ORR, fatigue, PSN and ARD and only ADR was verified by baujat plot. Related results could be got in Sensitivity analysis & Baujat plot parts of Based on Q test results, for ORR and DCR, Guan 2009 contributed most to heterogeneity; for OS, DFS/PFS, nausea or vomiting, Rugo 2015 contributed the most; for fatigue, PSN and ADR, Untch 2016 contributed the most (Baujat plot parts of Funnel plots showed that publication bias might exist in all the analyses. And after using trim-and-fill method, RR of ORR was still higher than 1.00 and RRs of fatigue and nausea or vomiting became lower than before adjusted, which encourage the usage of nab-PTX. But HRs for OS and DFS/PFS became higher which discourage the usage of nab-PTX.We tended to compare nab-PTX with sb-PTX comprehensively in breast cancer patients of all stages in our study. We have confirmed the superiority in objective response to nab-PTX compared with sb-PTX but with higher occurrence of fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse event related discontinuation, while it showed non-inferiority in DCR, OS and DFS/PFS.Unlike previous meta-analyses No obvious advantage in DCR, OS and DFS/PFS was seen in nab-PTX in our study. But taking the higher adverse event related discontinuation in nab-PTX group into account, time-to-event outcomes might have been overestimated as censoring method in survival analysis could be informative and non-independent Results of TNBC group in OS and DFS/PFS still showed a trend to favor nab-PTX but no statistical significance was found. With the development of precision medicine, individual patient data with more molecular information might help dig deeper into the benefit population of nab-PTX in the future. SPARC For toxicity, risks at least doubled in analyses of fatigue Figure E, nauseaJust as Lee et al. mentioned All in all, the toxicity of nab-PTX should be taken seriously in clinical practice. Apart from publications bias, censoring method could also cause bias in efficacy evaluation of survival analysis which should be considered in further studies. And based on our review, nab-PTX outperformed sb-PTX in objective response rate and should be preferred in conditions when it is urgent to shrink the tumor burden. But nab-PTX can increase risks of fatigue, nausea or vomiting, peripheral sensory neuropathy and adverse-related discontinuation at the same time. The difference between nab-PTX and sb-PTX in dose dense group was not obvious, so when toxicity of dose dense scheduled nab-PTX are unbearable, change it directly into sb-PTX is ponderable.Supplementary methods and figures.Click here for additional data file.


Radioiodine (I-131) whole-body scintigraphy (WBS) is a useful modality for identifying functionally preserved thyroid tissue and metastases from differentiated thyroid cancer (DTC); however, the specificity of I-131 uptake is limited, and its accumulation in the pancreas has not been well described.18F-FDG) during subsequent 18F-FDG-positron emission tomography. A diagnosis of pancreatic metastasis from the DTC could not be excluded; therefore, local resection was performed for diagnostic certainty and treatment. Histopathology confirmed the mass to be an exophytic lymphoepithelial cyst (LEC) of the pancreas. The patient also had a transient pancreatic leak which spontaneously resolved after surgery, and he was discharged from the hospital on postoperative day 8.A 70-year-old male patient with DTC who had previously undergone total thyroidectomy (pT3N1bM0 Stage IV) received radioiodine treatment at our facility. After treatment, an I-131 WBS revealed abnormal I-131 uptake in the head of the pancreas. Computed tomography identified a round hypodense mass (10 × 20 mm) adjacent to the pancreas head that was impervious to fluorodeoxyglucose (To the best of our knowledge, this is the first reported case of an exophytic pancreatic LEC producing a false-positive result during I-131 WBS. Knowledge of all potential I-131 false-positive findings may help improve the management of patients with DTC and circumvent misdiagnoses. Radioiodine I-131) whole-body scintigraphy (WBS) is routinely used to detect remnants of functioning thyroid tissue, recurrent neoplasia, or distant metastases in patients with differentiated thyroid cancer (DTC) after undergoing postoperative radioiodine therapy 31 whole-. DTC hasIn the present case, a routine I-131 WBS of a 70-year-old patient previously diagnosed and treated for DTC revealed abnormal uptake of radioiodine in the pancreas. A hypodense mass identified near the pancreas head could not be excluded as a pancreatic metastatic neoplasm; however, pathological examination of the tumor tissue after resection confirmed a final diagnosis of pancreatic lymphoepithelial cyst (LEC). The patient recovered well with minimal surgical management. This case has been reported in line with the SCARE criteria .18F-FDG-PET). Retrospectively reviewed, the preoperative CT images before thyroidectomy showed the same lesion with slightly small size (10 × 18 mm). Serum levels of thyroglobulin (Tg) and CA 19-9 were normal . However, open surgical examination was decided to either confirm or exclude the possibility of metastasis from the original DTC.The patient in this case is a 70-year-old man who had previously undergone total thyroidectomy for papillary thyroid cancer with a pathological staging of pT3N1bM0 (stage IV). Treatment with I-131 (13.7 Gbq) commenced 11 months after initial surgery. After treatment, a routine I-131 WBS showed focal uptake in the thyroid bed and near the head of the pancreas Fig. , but no Intraoperative visual inspection revealed the cyst to be adhered to the pancreatic head. Tumor enucleation was performed, and the tumor was filled with cheesy, granular, and yellowish-white contents Fig. . The tumRadioiodine WBS is routinely used to screen for local or distant metastases in patients with DTC after having undergone thyroidectomy and subsequent radioiodine therapy . The scaThere are various possible causes of false-positivity on I-131 WBS after thyroidectomy for DTC: functional sodium iodide symporter expression in normal tissue, benign and malignant tumor, metabolism of radioiodinated hormone, retention of radioiodinated body fluids associated structural change, retention and uptake of radioiodine in inflamed tissue, contamination by physiologic radioiodine uptake , 12. Fal18F-FDG-PET [18F-FDG-PET avidity [The preoperative findings of abnormal I-131 uptake in the pancreas suggested the possible occurrence of metastatic DTC. Patients with DTC are known to experience unusual metastases; however, DTC metastasis to the pancreas is extremely rare, and only 24 cases have ever been reported in the literature . Several-FDG-PET . Relatin avidity . NeitherEctopic thyroid tissue in the pancreas may be a differential diagnosis based on the I-131 WBS findings. However, such an occurrence is exceedingly rare, and only 3 cases of intra-abdominal ectopic thyroid tissue have ever been reported at sites including the adrenal gland, gall bladder, porta hepatis, mesentery, liver, spleen, retroperitoneum, duodenum, and jejunum. Surgical resection is also commonly applied to ruling out malignancy when this rare occurrence is encountered in clinical practice –29. OverPancreatic LECs are relatively rare benign tumors; since first being described by Luchtrach and Schriefers in 1985, over 200 cases of pancreatic LECs appear in the literature, thereby accounting for approximately 0.5% of all pancreatic cysts . LECs mo18F-FDG-PET findings. Considering clinical policy for addressing pancreatic lesions, surgical resection was deemed necessary to rule out all possibilities of malignancy [Preoperative attempts at cytopathologic assessment usually involve endoscopic ultrasound-guided fine-needle biopsy (EUS-FNA) . The senlignancy , 41. In lignancy , 43. On In conclusion, we present a rare case of pancreatic LEC which produced false-positive radioiodine uptake during routine WBS of a patient previously diagnosed with DTC who had undergone total thyroidectomy and subsequent radioiodine treatment. A better understanding of the false-positivity patterns associated with I-131 WBS is critical for the proper management of patients with DTC.


Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic gain of function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.in vivo phenotype and validated findings in human primary alveolar organoids.We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.We show that wild-type SFTPC takes an unexpected indirect trafficking route These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development. Studying how SFTPC mutations cause familial pulmonary fibrosis may help us develop new therapies for IPF. By studying a pathogenic mutation, this study reveals new insights into SFTPC handling in alveolar cells and how this is perturbed in disease.https://bit.ly/344VUhm In idiopathic pulmonary fibrosis (IPF), pathological scarring of the lung impairs gas exchange to cause premature death . AlveolaAutosomal dominant mutations in surfactant protein C (SFTPC), which is expressed exclusively in AT2 cells, cause FPF . ExpressEn route, sequential C- then N-terminal cleavages yield mature SFTPC  which undergoes several proteolytic steps before being secreted, although surprisingly the location and precise nature of the maturation steps remain unclear. ProSFTPC is a type 2 transmembrane protein that comprises four domains : 1) an Nre SFTPC  17]. Ho. HoEn roitophagy , 19. Undvia the plasma membrane. Mislocalisation of SFTPC-I73T results from aberrant recycling of this protein to the cell surface owing to its failure to targeted to the MVB, resulting in its accumulation at the cell surface and recycling endosomes. Our investigation of a rare pathogenic variant thus provides fundamental insights into the biology of SFTPC and the mechanism of disease.Here, we present a detailed analysis of SFTPC trafficking that shows for the first time that both wild-type and I73T-mutant SFTPC unexpectedly traffic supplementary material.Detailed methods including details of chemicals, antibodies, cell lines, small interfering (si)RNAs, CRISPR guides, creation of expression vectors and cell-based assays are available in the −1 geneticin for stable cell lines). Transfection of DNA was achieved using FuGene 6 (Promega) and clonal transgenic cell lines generated by selection and single-cell sorting. Knockout cell pools were generated by liposomal transfection with vectors expressing Cas9, guide RNA, and a fluorescent marker used for fluorescence-activated cell sorting.HeLa cells were maintained in DMEM+10% fetal bovine serum . Briefly, tumour-free peripheral lung tissue was collected from patients undergoing cancer resection and subjected to enzymatic digestion. The use of lung tissue that was collected within the framework of patient care was in line with the Federation of Dutch Medical Scientific Societies code of conduct . This coTissue from inducible SFTPC-I73T-expressing mice  was a kiUnless stated, figures depict representative images from at least three independent repeats.When detected using N-terminal domain (Npro) antibodies, we confirmed that wild-type proSFTPC (SFTPC-WT) localises to punctate structures consistent with MVBs , 22 and supplementary figure S1a). Surface accumulation of GFP-SFTPC-I73T relative to GFP-SFTPC-WT could be detected by microscopy and flow cytometry using an antibody to the BRICHOS domain, although interestingly we could detect low levels of SFTPC-WT at the plasma membrane (supplementary figure S1b).To investigate the mechanisms responsible, a cell model of early SFTPC trafficking was established. Primary AT2 cells are unsuitable for detailed mechanistic work due to the complexity of genetic manipulation required and their dedifferentiation when grown in monolayer culture . HeLa cemembrane . In addimembrane  which MIsupplementary figure S1c). GFP-SFTPC-WT migrated as a doublet of ∼50 kDa and a smaller band at ∼34 kDa (arrowhead). The doublet represents full-length proSFTPC±palmitoylation . St. Stvia tvesicles . As expea and b) . Remarkaper se.These data show that both SFTPC-WT and SFTPC-I73T traffic directly to the plasma membrane from the Golgi. Thus, the accumulation of SFTPC-I73T at the cell surface represents aberrant retention, rather than mistrafficking supplementary figure S5). The plateauing of the I73T signal may reflect recycling of labelled protein back to the plasma membrane during the course of the assay. The rapidity of initial SFTPC internalisation was consistent with clathrin-mediated endocytosis (CME). Prolonged bafilomycin treatment, which inhibits CME [We next studied the trafficking of SFTPC from the plasma membrane using antibody feeding: cell-surface SFTPC was labelled with primary antibody on ice, incubated at 37°C to allow internalisation, and then remaining cell surface protein detected using a fluorescently conjugated secondary antibody. Labelled GFP-SFTPC-WT was internalised more completely than GFP-SFTPC-I73T, although there was evidence of some early SFTPC-I73T internalisation . This wabits CME , caused Therefore, the I73T mutation partially impairs CME despite being topologically unable to interact with sorting factors such as AP2. Many membrane proteins undergo clustering to promote CME. Indeed, oligomerisation of SFTPC is known to occur during its trafficking . Howeversupplementary figure S6a). We generated GFP-SFTPC-K6R and confirmed this was not ubiquitinated (supplementary figure S6b). However, the rate of SFTPC-K6R internalisation was indistinguishable from that of SFTPC-WT indicating that ubiquitination is unnecessary for endocytosis and therefore cannot account for differing rates of endocytosis between SFTPC-WT and SFTPC-I73T (supplementary figure S5).We next considered the possibility that aberrant ubiquitination of SFTPC-I73T contributes to disrupted trafficking. SFTPC is ubiquitinated on residue K6, which has been reported to be involved in endosomal targeting , 14. Immsupplementary figure S6c). Since internalisation of proteins into intraluminal vesicles of MVBs involves recognition of ubiquitinated cargo by the endosomal-sorting complex required for transport (ESCRT) machinery [The observed accumulation of SFTPC-I73T in recycling endosomes suggests failure of sorting at endosomes towards MVBs. By microscopy, we observed that ubiquitination-deficient GFP-SFTPC-K6R localised to the plasma membrane and recycling endosomes . The majority of GFP-SFTPC-WT-HaloTag-containing puncta retained both tags, identifying them as compartments prior to C-terminal proteolysis  had shown less dramatic differences between SFTPC-WT and SFTPC-I73T than were observed by imaging the cytosolic GFP-tag . SimilarFull-length SFTPC is therefore first trafficked to the cell surface and then, following AP2-dependent endocytosis, C-terminal proteolysis occurs distal to the linker domain to yield SFTPC*. This is followed by a juxta-membrane cleavage to generate fully C-terminally cleaved SFTPC. While SFTPC-WT is then rapidly transported to the MVB for N-terminal proteolysis, the I73T mutation impairs juxta-membrane cleavage, leading to recycling of SFTPC* to the cell surface.supplementary figure S8). This disproportionately affected SFTPC-WT leading to accumulation of an SFTPC*-like product. Suspecting that juxta-membrane cleavage might be mediated by an endosomal membrane-bound sheddase, we treated cells with Z-VLL-CHO, an inhibitor of such proteases. Z-VLL-CHO dramatically increased levels of SFTPC-WT in lysates, predominantly as full-length protein and BRICHOS-cleaved intermediates  or Z-VLL-CHO  redistributed endogenous proSFTPC into AT2 apical membranes . These fTaken together, these experiments reveal that SFTPC undergoes proteolysis distal to the linker domain in endosomes followed by juxta-membrane cleavage, likely by a membrane-bound sheddase. Impaired juxta-membrane cleavage, either induced pharmacologically or by the I73T mutation, results in unproductive recycling of SFTPC between endosomes and the plasma membrane .via the plasma membrane. We observed that residue I73 of SFTPC, located within the extracellular linker region of the proprotein, is key to trafficking as its mutation results in impaired progression to MVBs and unproductive SFTPC recycling between the cell surface and early endosomes.We set out to understand the mechanisms by which SFTPC-I73T mistraffics to provide insight into its role in FPF. In doing so, we have defined the itinerary of wild-type SFTPC, which involves trafficking Aberrant retention of the linker region is associated with failure of SFTPC ubiquitination, which does not affect endocytosis, but impairs subsequent internalisation of SFTPC into MVBs. Our work delineates a mechanism that explains the previous observation that SFTPC-I73T localises to early endosomes while wild-type protein is found in MVBs . The preSFTPC is a highly hydrophobic protein thought to promote the spreading of pulmonary surfactant through interaction with phospholipid layers . How SFTvia the cell surface may have a role in normal AT2 cell function that is perturbed by the I73T mutant. Ongoing work will determine if surface accumulation of SFTPC in its multiple forms, retention in recycling endosomes and/or the released C-terminal cleavage products themselves affect signalling within the AT2 cell or with its neighbours. Understanding the intracellular interactome of SFTPC and its processing intermediates may shed fresh light on this. Alternatively, saturation of protein recycling pathways by SFTPC might have deleterious effects on surface expression of otherwise unrelated proteins.Here, we demonstrate that SFTPC-I73T accumulates at the plasma membrane through abnormal recycling from endosomes and from impaired internalisation. Recycled SFTPC-I73T includes the partially cleaved intermediate SFTPC*, consistent with previous plasma membrane profiling data . Interesvia the cell surface to MVBs, rather than directly from the Golgi. The accumulation of the SFTPC-I73T variant at the plasma membrane therefore reflects retardation along its normal route rather than mistrafficking per se. Whether SFTPC possesses additional functions that require it to transit via the cell surface remains to be established, and may prove crucial in understanding the role of SFTPC-I73T in alveolar dysfunction resulting in FPF. Such insight may also help to clarify the role of alveolar dysfunction in other, nonfamilial forms of IPF.In this work, by studying a naturally occurring pathogenic variant of SFTPC associated with FPF, we have discovered that all wild-type protein traffics 10.1183/13993003.00267-2021.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.ERJ-00267-2021.SupplementSupplementary materials and methods ERJ-00267-2021.Figure_S1Supplementary figure S1 ERJ-00267-2021.Figure_S2Supplementary figure S2 ERJ-00267-2021.Figure_S3Supplementary figure S3 ERJ-00267-2021.Figure_S4Supplementary figure S4 ERJ-00267-2021.Figure_S5Supplementary figure S5 ERJ-00267-2021.Figure_S6Supplementary figure S6 ERJ-00267-2021.Figure_S7Supplementary figure S7 ERJ-00267-2021.Figure_S8Supplementary figure S8 10.1183/13993003.00267-2021.Shareable1This one-page PDF can be shared freely online.ERJ-00267-2021.ShareableShareable PDF


Immunotherapies have revolutionized the field of cancer therapeutics, yet a substantial subset of patients fail to respond. Recent efforts have focused on identifying targets that could elicit or augment anti-tumor immune responses. One such novel target is STING or stimulator of interferon (IFN) genes, an endoplasmic protein that induces the production of pro-inflammatory cytokines such as type I IFNs. Since the discovery of STING, numerous natural and synthetic STING agonists have been tested in both pre-clinical and clinical settings in different tumors. However, the structural instability of first-generation agonists prompted the development of more stable and potent compounds. This review will highlight the latest pharmacologic classes of STING agonists, novel approaches for tumor-targeted drug delivery, and challenges in the clinical targeting of the STING pathway.The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches. Cancer immunotherapy based on immune-checkpoint blockade has modified cancer treatment paradigms across many tumor types. A major limitation on treatment response to immunotherapy is the inadequate pre-existence of anti-tumor immunity. A number of approaches to initiate de novo immune response have been proposed, with a majority centered on the generation of type I interferons. Of these, agonism of the cGAS/STING pathway is a high priority being pursued for drug development. Here, we discuss the rationale for targeting the STING pathway and comprehensively review the field of STING therapeutics from pre-clinical development through completed clinical trials.+ dendritic cells [+ T cells. Increasing numbers of publications are suggesting that type I IFNs also inhibit the expression of vascular endothelial growth factor (VEGF) and therefore exert an inhibitory effect on tumor angiogenesis [Pattern recognition receptors (PRRs) are germline-encoded proteins that play a central role in immune responses against pathogens as well as recognizing danger molecules associated with endogenous injury . PRRs aric cells , and theic cells . Type I ogenesis ,13.STING is a transmembrane protein localized to the endoplasmic reticulum which functions as an adaptor protein in the cGAS (cyclic GMP-AMP synthase)-STING pathway . cGAS-STEarly evidence on the role of the STING pathway in immune homeostasis was derived from associations between constitutive STING activation and DNA-mediated inflammatory disorders. Gain-of-function mutations in TMEM173, the gene encoding STING protein, result in constitutive activation of the STING-IFN-β pathway, which is associated with the induction of IFN-response genes such as IP-10. Clinically, the chronic activation of the STING pathway has been linked with an autoinflammatory condition named STING-associated vasculopathy with onset in infancy (SAVI) . Symptom+ T cells in the tumor microenvironment have been correlated with favorable outcomes in different solid tumors. Studies using mixed bone marrow chimeras with selective IFN-α/β sensitivity in either innate or adaptive immune compartments have demonstrated that the effect of type I IFNs is most selectively targeted towards innate immune cells, particularly CD8α+ dendritic cells [+ T cell priming and fail to reject immunogenic tumors [+ T cell response.The type I IFN profile and presence of activated CD8ic cells . Furtherc tumors , contrar+ stromal cells, including dendritic cells and vascular endothelial cells [Tumors exhibit genetic instability owing to defects in the expression/functionality of DNA repair proteins ,22, leadal cells ,29,30. Sal cells ,31,32. Ial cells ,34.+ T cell transfer, high-dose DMXAA regimens failed to confer superior therapeutic benefits, owing to contraindicated impact on the recruitment and function of immune cells within the TME [However, local stimulation of vascular endothelial cells with prohibitively high concentrations of STING agonists results in cellular apoptosis and vascular necrosis/collapse ,36,37. I the TME .+ T cell infiltration of tumors driven primarily by STING activation in, and type I IFN produced by, tumor vascular endothelial cells [Pioneering work has since led to an appreciation that anti-angiogenic/anti-vascular agents may sponsor tumor vascular normalization when applied using low-dose regimens ,42. In cal cells ,32,45.+ vascular endothelial cells or their progenitors in peripheral tissues under pro-inflammatory conditions [+CD62L+ naïve and central memory T cells, CXCR5+ B cells and mature CCR7+ dendritic cells into TLS [As suggested by recent studies , the abinditions ,50. Notanditions ,52, and into TLS ,50,53. Winto TLS ,55. Consinto TLS ,59,60,61Given the reports supporting the ability of low-dose STING agonists to synergize with alternate anti-angiogenic and immune checkpoint strategies in treating established tumors in translational mouse tumor models, it may be anticipated that such combination and/or sustained (low-dose) delivery regimens will optimize tumor-associated vascular normalization, TLS formation within the TME and the evolution of durable protective anti-tumor immunity most capable of effectively controlling the progression of antigenically heterogeneous cancers ,53,62,63The substantial pre-clinical anti-tumor activity of STING agonists has led to the development of multiple pharmacologic classes of agents at various stages of being translated into the clinic .The most prominent tool compound STING agonist broadly used pre-clinically was DMXAA, a vascular disrupting agent known to possess anti-tumor activity. In a randomized phase II clinical trial, feasibility and safety of addition of DMXAA or ASA404 to standard therapy of paclitaxel and carboplatin was assessed in patients with previously untreated advanced non-small cell lung cancer . DMXAA wSynthetic cyclic dinucleotides (CDNs) were the first class of STING agonists that entered drug development .ADU-S100/MIW815 is a synthetic CDN that mimics natural ligands of STING and can activate all known alleles of human STING. Pre-clinical studies using a range of murine tumor models have shown that intratumoral injection of ADU-S100 leads to induction of tumor-specific CD8+ T cells [ T cells ,70, and  T cells ,72. ADU- T cells . In thisMK-1454 is synthetic CDN that has advanced into clinical development. The preliminary data of a phase I, open-label, multi-arm first-in-human study on MK-1454 was first publicly released at ESMO 2018 [SMO 2018 . In thisSB11285 is a small molecule CDN STING agonist which is being clinically evaluated for intravenous administration in patients with advanced solid tumors. Pre-clinical data using SB11285 in syngeneic mouse models showed significantly higher inhibition of tumor growth in mice injected with intratumoral SB11285 compared to the control group. Additionally, SB11285 in combination with cyclophosphamide resulted in a significant synergistic anti-tumor effect [To circumvent the limitations of intratumoral delivery, recent efforts have focused on developing STING agonists with stable physical properties that could be delivered systemically. Although multiple compounds are being developed for systemic delivery in preclinical murine models, only a few have entered clinical testing. r effect . The ongBMS-986301 in CT26 and MC38 murine tumor models yielded promising results, with >90% complete regression seen in injected and non-injected tumors as opposed to 13% with ADU-S100. In the CT26 model, a single dose of BMS-986301 combined with anti-PD1 resulted complete regression of 80% of injected and non-injected tumors when no regressions were seen with anti-PD1 alone [BI-STING, a CDN mimicking natural STING ligand, resulted in dose-dependent anti-tumor activity and inhibition of tumor development upon re-challenge [Pre-clinical evaluation of a novel STING agonist D1 alone . BMS-986hallenge . BI 1387MK-2118 is a STING agonist of unreported structure which is being tested as an intratumoral or subcutaneous injection alone or in combination with pembrolizumab in patients with advanced solid tumors or lymphomas (NCT03249792). In an early dosing phase 1 clinical trial, GSK3745417, a non-CDN small molecule with dimeric amidobenzimidazole (ABZI) scaffold, is being tested as an intravenous injection either alone or in combination with pembrolizumab in patients with refractory/relapsed solid tumors (NCT03843359). SNX281 is a novel small molecule therapeutic developed as a STING agonist, which is active against all isoforms of human STING and has stable drug properties thus permitting systemic delivery. In pre-clinical models, a single intravenous dose of SNX281 in mice bearing CT26 colorectal tumors resulted in complete regression of tumors. SNX281 also synergized with anti-PD1 agents in inhibiting tumor growth and improving the overall survival of tumor-bearing mice. In an ongoing phase 1 clinical trial, the safety, tolerability and maximum tolerated dose of systemic SNX281 will be assessed in patients with advanced solid tumors and lymphomas. This trial is comprised of two treatment arms, in which intravenous SNX281 is given either as monotherapy or in combination with pembrolizumab, in a dose escalation followed by dose expansion phase to determine the recommended dose for phase 2 studies (NCT04609579). TAK-676 is another small molecule STING agonist with an undisclosed structure that is now under clinical investigation in a phase I dose escalation study. This trial aims to determine the safety and tolerability of intravenous TAK-676 as monotherapy and in combination with pembrolizumab in patients with advanced or metastatic solid tumors (NCT04420884).E7766 belongs to the novel class of macrocycle-bridged STING agonists (MBSAs). MBSAs show superior in vitro activity against all major human STING genotypes. E7766 binds to both human and mouse STING protein and show activity against a broader range of human STING genotypes compared to reference CDNs. A single intratumoral injection of E7766 was shown to significantly reduce the growth of subcutaneous tumors in mice [ in mice . In mice in mice . Intrave in mice . The cliSYNB1891, a non-pathogenic E. Coli Nissle strain engineered to express cyclic di-AMP-producing enzymes in response to the hypoxic environment of tumor, while remaining localized to the tumor microenvironment. Pre-clinical studies show that intratumoral injection of SYNB1891 to B16.F10 melanoma tumor-bearing mice induces production of type I IFNs and leads to significant reduction in tumor growth eight days after treatment [STACT, an attenuated Salmonella Typhimurium strain that carries an inhibitory microRNA to TREX-1. TREX-1 exonuclease prevents activation of STING pathway by degrading cytosolic DNA. Pre-clinical studies show that intravenously delivered STACT-TREX-1 specifically colonizes to the myeloid compartment of the tumor microenvironment [Bacterial vectors have been used as a novel approach for delivering STING agonists to intratumoral antigen-presenting cells. One such vector is reatment . In an oironment . In CT26ironment . STACT-TThe chemical structure and stability of many clinically developed STING agonists have limited their use as systemic immunotherapeutics. In the past few years, novel cyclic CDN and non-CDN STING agonist compounds with improved structural properties, higher potency and affinity towards human STING, and with potential for systemic delivery have been identified and shown promising results in pre-clinical studies .JNJ-67544412 (JNJ-4412) is a recently developed CDN STING agonist, which is claimed to bind to all major alleles of human STING with a stronger affinity than other known CDNs. In syngeneic mouse tumor models, intratumoral injection of JNJ-4412 was shown to result in increased levels of pro-inflammatory cytokines in tumor and plasma, increased frequencies of CD8+ T cells, loss of vascularization, increased apoptosis and significant regression of both injected and contralateral tumors. Transient body weight loss was reported as an adverse event but was alleviated with less frequent dosing [3′3′-cyclic AIMP developed as a CDN STING agonist was tested in a murine model of hepatocellular carcinoma (HCC). Intraperitoneal injection of 3′3′-cyclic AIMP to STING-deficient mice with HCC resulted in a reduced tumor burden exemplified by smaller liver surface nodules, an increased number of CD8+ T cells and increased apoptotic cell death within the tumor. When 3’3’-cyclic AIMP was administered at a later stage after HCC development, tumor regression was observed in the majority of tumors; however, new tumors developed that were not responsive to CDN treatment, supporting the efficacy of this agent in reducing tumor burden but its inability to completely resolve all lesions in multi-focal disease models [GSK532, has shown improved stability with minimal degradation in human whole blood, and is able to induce cytokine responses in human cells with different STING haplotypes. In addition, intratumoral injection of GSK532 to mice harboring CT26 tumor cells was shown to induce anti-tumor responses in both injected and uninjected tumors [t dosing . In a ree models . Anotherd tumors . This coTTI-10001 is a non-CDN small molecule STING agonist which is able to bind to all five human STING alleles as well as to the murine STING protein. Intratumoral administration of TTI-10001 in murine models of syngeneic tumors was found to be safe and associated with increased levels of phospho-IRF3, pro-inflammatory cytokines, and anti-tumor activity [Selvita agonists are a group of recently developed small-molecule, non-nucleotide, non-macrocyclic STING agonists. These agonists selectively bind to both mouse and human STING proteins and have tunable properties with enhanced plasma stability and permeability, making them potential candidates for systemic delivery [Selvita agonists induce the expression of inflammatory cytokines and upregulate maturation markers on the surface of APCs. A group of selective non-CDN non-macrocylic small molecule compounds (Ryvu’s agonists) have shown promising results in pre-clinical animal models [activity . Selvitadelivery . In vitrl models . These al models .ALG-031048 is a novel STING agonist that has shown higher stability in in vitro studies compared to natural STING ligand and STING agonist ADU-S100. Intratumoral injection of ALG-031048 in mice bearing CT26 tumor cells resulted in tumor regression in 90% of mice (compared to 44% with ADU-S100). Treated mice were resistant to tumor development after re-challenge with the same tumor cell line [MSA-1 STING agonist compound has also shown robust anti-tumor efficacy when injected intratumorally to mice bearing MC38 syngeneic colon carcinomas. Complete responses were observed in 100% of tumors in mice receiving the highest tolerated dose of intratumoral MSA-1. Combination of MSA-1 with anti-PD1 antibody (mDX400) resulted in the restoration of T cell responses in anti-PD1 unresponsive tumors, further supporting the synergic anti-tumor activity of STING agonists with anti-PD1 therapy [CRD-5500, a next-generation small molecule STING agonist, has shown to be effective via intratumoral and systemic routes and also as an antibody-drug conjugate with Trastuzumab. The fact that CRD-5500 can be dosed via multiple routes makes it a favorable agent for future clinical development. Pre-clinical data show that both intravenous and intratumoral injections of CRD-5500 induce tumor regression in murine CT26 colon carcinoma models engineered to express human STING, and this anti-tumor effect is further amplified when CRD-5500 is combined with check point inhibitor therapy [ell line . In anotell line . MSA-1 S therapy . CRD-550 therapy .ENPP1 is a transmembrane phosphodiesterase known for its central role in purinergic signaling [MV-626 is a selective ENPP1 inhibitor with 100% bioavailability that has been studied in pre-clinical models. Intraperitoneal injection of MV-626 alone or in combination with radiation therapy in mice implanted with Panc02-SIY pancreatic adenocarcinoma tumors resulted in a durable anti-tumor immune response and improved overall survival [SR-8314 and SR-8291 are both highly selective ENPP1 inhibitors that have shown promising in vivo efficacy in syngeneic murine tumor models. Intraperitoneal injection of SR-8314 and SR-8291 led to increased frequencies of CD4+ and CD8+ T cells and a decrease in tumor-associated macrophages in tumor-bearing mice [SR8541A is another small molecule ENPP1 inhibitor which in recent in vitro studies has been shown to stimulate the migration and infiltration of peripheral blood myeloid cells into the tumor microenvironment [ignaling . Recent ignaling . This fiignaling . Orally ignaling . In one ignaling . MV-626 survival . SR-8314ing mice . SR8541Aironment . Though amidobenzimidazole (ABZI)-based compounds. One such compound, called Compound 3, was shown to activate STING and induce IFN-β production approximately 400-fold stronger than natural cGAMP. Intravenous administration of Compound 3, an ABZI-based compound, in the CT26 mouse model of colorectal cancer led to significant inhibition in tumor growth and improved overall survival, effects that were dependent on CD8+ T cell-mediated immune responses [Most CDN-based STING agonists in clinical development are delivered intratumorally due to their poor stability, which makes their utility limited to accessible tumors. To circumvent this, recent efforts have focused on the development of compounds that are capable of activating STING and are structurally stable for systemic delivery. A class of novel small molecule non-cyclic dinucleotides intended for systemic delivery are esponses .SR-717 was identified as a novel non-nucleotide cGAMP mimetic with potential for systemic delivery. Daily intraperitoneal injections of SR-717 to mice bearing established B16.F10 melanomas for one week resulted in a significant reduction in tumor growth and the increased survival of tumor-bearing mice [MSA-2 is another novel and orally available STING agonist with distinct structural properties that makes it stable for systemic delivery [In a recent study, ing mice . Additiodelivery . In vitrdelivery .JNJ-‘6196 has been developed as a next-generation STING agonist, which binds to STING protein with weaker affinity and a faster off rate, but is able to activate dendritic cells and induce cytokine expression with a higher potency compared to other CDNs. JNJ-‘6196 can be administered systemically via the intravenous route, where it has been shown to effectively eliminate bilateral tumors, promote immune-mediated resistance to tumor re-challenge, and to improve the efficacy of checkpoint inhibitors in PD-1 non-responsive tumor models in mice [ in mice . Further in mice . The funXMT-2056 is the first STING ADC developed through the Immunosynthen platform that is expected to enter phase I clinical testing in 2022.Antibody drug conjugates (ADCs) represent a novel approach for systemic yet targeted STING agonist delivery. STING antibody-drug conjugates have shown promising pre-clinical results . In in vPC7A NP is a synthetic nanoparticle which is shown to improve the delivery and cross-presentation of antigens by APCs, activate type I IFN genes, and stimulate specific CTL responses in mice [ONM-500 nanovaccine was shown to effectively accumulate in lymph nodes after subcutaneous injection in mice [Nanoparticle (NP) vaccines or nanovaccines are a novel delivery platform that optimizes the spatiotemporal coordination of antigen presentation to APCs with innate immune responses in order to amplify the cytotoxic T cell responses . PC7A NP in mice . Of note in mice . A study in mice . ONM-500 in mice . Adminis in mice . Subcuta in mice .Antigen-presenting cell (APC)-targeted tumor vaccines are another recent development in the field of cancer therapeutics. One such formulation combining granulocyte macrophage colony stimulating factor (GCSF)-secreting pancreatic tumor cells with attenuated Listeria-expressing mesothelin has shown promising results in patients with pancreatic carcinoma . A novelExosomes are cell-derived nanovesicles that transmit signals and molecules between cells. In recent years, there has been an emerging interest in exosome-based therapies as a platform for delivering anti-tumor agents. In animal models, vaccination with tumor-asociated exosome-loaded dendritic cells or T cells has been shown to enhance immune responses against tumors ,119. MulSince the initial discovery of STING and the potency of agonizing the pathway in the pre-clinical setting, there have been accelerated attempts to develop STING agonists as effective immunotherapeutic agents. The presence of a human autoimmune phenotype (SAVI) and an ever-expanding number of pre-clinical and clinical studies support the potential for numerous STING agonist compounds in boosting anti-tumor immunity and enhancing the effects of existing immunotherapies. Despite this, there remain substantial barriers for the clinical targeting of the cGAS-STING pathway. The first-generation CDN STING agonists to enter clinical testing were administered intratumorally. This presents challenges as the approach limits the use of STING agonists to only accessible tumors. Numerous efforts are under investigation towards the development of compounds with improved properties enabling their stability for systemic delivery, with promising results obtained in pre-clinical studies implementing these compounds. Advances in imaging-guided drug delivery methods are also expected to enhance the applicability of intratumorally administered STING agonists to a wider range of tumor types. A concern raised over the systemic administration of STING agonists is whether these agents induce a state of pathologic inflammation, as the overactivation of STING has been implicated in a broad range of autoimmune conditions. The off-target effect of STING activation on other immune cells such as effector T cells could be another area of concern. In in vitro studies, STING activation was associated with the induction of stress and apoptosis in T cells . Whether


Immune checkpoint inhibitors (ICI) are a class of immunotherapy drugs used increasingly in the treatment of multiple types of cancer. Major side effects include immune-related adverse effects, potentially resulting in damage to normal tissue across multiple different organ systems.A 74-year-old woman with a history of triple negative metastatic breast cancer treated with the ICI atezolizumab presented with new-onset autoimmune diabetes in diabetic ketoacidosis. She required fluid resuscitation, insulin infusion, vasopressors, and initial hospitalization in the intensive care unit. The patient was subsequently discharged on bolus dose insulin and remained an insulin-dependent diabetic at three-month follow-up.Autoimmune diabetes is a rare, but life-threatening, adverse event associated with ICIs such as atezolizumab. To our knowledge this is the only case report of atezolizumab causing autoimmune diabetes in the setting of metastatic breast cancer. As ICIs become more common in the treatment of cancer, emergency physicians should remain vigilant for the various immune-mediated complications associated with this class of immunotherapy drugs. Immune checkpoint inhibitors (ICI) are a class of immunotherapy drugs used increasingly in the treatment of multiple types of cancer. Immune checkpoint inhibitors function by removing inhibitory signals for T-cells and facilitating antitumor activity; however, this can also result in autoimmune-mediated damage to normal tissue. Known as immune-related adverse effects (irAE), these side effects most often affect the skin and gastrointestinal, and endocrine systems. Hypophysitis and thyroid dysfunction are the most common endocrine abnormalities.2Atezolizumab is a monoclonal ICI, first approved by the US Food and Drug Administration (FDA) in 2016 for the treatment of metastatic urothelial cancer. It is currently used in multiple other malignancies, including urothelial carcinoma and triple negative breast cancer.A 74-year-old woman presented to the emergency department with two days of nausea, vomiting, dyspnea, lightheadedness, and malaise. The patient had been diagnosed with invasive ductal carcinoma of the right breast 12 months prior to presentation. The malignancy was estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negative with known metastasis to the bone. After initial treatment with doxorubicin hydrochloride, cyclophosphamide and paclitaxel, the patient was transitioned to atezolizumab and paclitaxel combination therapy. She had completed 14 cycles over the preceding 52 weeks, and oncology reported her disease to be well controlled and stable. She carried a prior diagnosis of paroxysmal atrial fibrillation managed with diltiazem, metoprolol and warfarin.The patient had no history of diabetes or insulin resistance and had previously demonstrated consistently normal serum glucose levels. There was no preceding starvation, insulin use, thromboembolic event, or ischemic process. She had been started on low-dose steroid of prednisone 5 milligrams (mg) daily three months prior for autoimmune-mediated arthritis and chemotherapy-induced neuropathy of her left lower extremity. Her non-fasting blood glucose level two months prior to presentation on routine blood work was 135 mg/deciliter (dL) (reference range 70 – 139 mg/dL).2) (18.5 – 24.9 kg/m2).On initial assessment, her vital signs were temperature 36.3º C, blood pressure 126/78 millimeters of mercury (mm Hg), heart rate 123 beats per minute, respiratory rate 24 breaths per minute, and oxygen saturation 96% on room air. She had atrial fibrillation with rapid ventricular response. Physical exam was significant for Kussmaul respirations, bibasilar rales, and mild subcostal retractions. Her body mass index was 39.4 kilograms per meter squared  for management of DKA and septic shock. Her urine culture later revealed greater than 100,000 colony-forming units/mL During hospital admission, her C-peptide level was 0.10 nanograms/mL (ng/mL) (reference range 0.80–3.85 ng/mL). Glutamic acid decarboxylase antibodies were less than 5 international units per milliliter (IU/mL (<5 IU/mL). The diagnosis of new-onset diabetes was deemed autoimmune in nature and attributed to her use of atezolizumab over the prior year. She was discharged on hospital day eight on insulin lispro and insulin detemir and remained an insulin-dependent diabetic at three-month follow-up.What do we already know about this clinical entity?Immune checkpoint inhibitors are associated with rare yet potentially fatal immune-related adverse effects and can damage almost any organ system.What makes this presentation of disease reportable?To our knowledge this is the only case report of atezolizumab causing autoimmune diabetes in the setting of triple negative metastatic breast cancer.What is the major learning point?When treating cancer patients in the ED, it is crucial to determine the cancer diagnosis and treatment history including past and present types of therapeutics.How might this improve emergency medicine practice?Early recognition and diagnosis of immune-related adverse effects by emergency physicians can help provide timely acute management and improve patient outcomes.We present a rare case of atezolizumab-induced autoimmune diabetes mellitus in a patient treated for metastatic breast cancer. While cases of ICI-induced autoimmune DKA have been previously reported related to the treatment of urothelial, skin, lung, and renal cancer, no prior case has been described in the setting of metastatic breast cancer treatment.1Atezolizumab is a humanized monoclonal antibody to programmed death-ligand 1 (PD-L1) and is classified as an ICI. Atezolizumab is FDA approved for the treatment of various types of cancer, including metastatic non-small cell lung cancer, locally advanced or metastatic urothelial carcinoma, and triple-negative breast cancer in patients who experience disease progression after platinum-based chemotherapy. The recommended dose is 840 mg administered as an intravenous infusion every three weeks until disease progression or unacceptable toxicity is noted.4Atezolizumab functions by inhibiting the binding of programmed cell death 1 (PD-1), which is expressed on T cells, to PD-L1, which is expressed on antigen-presenting cells and tumor cells . This inThe onset of ICI-mediated autoimmune diabetes has been shown to range from a single dose in the first week to 228 weeks, with a median onset of 20 weeks, after drug initiation.3In the majority of cases involving irAE secondary to ICI therapy, the emergency physician should discuss with oncology whether urgent initiation of glucocorticoids is indicated. Most patients can continue taking the ICI after stabilization of glucose levels because the majority of insulin-producing pancreatic cells have already been eliminated.5In addition to diabetes, there are a multitude of other immune-mediated complications associated with ICIs. A meta-analysis of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies found the overall incidence of adverse events to be 72% with 24% involving high-grade complications.10Autoimmune diabetes is a rare but significant potential side effect of immune checkpoint inhibitor therapy. Emergency physicians should be aware of this and other immune-mediated complications in patients receiving ICI immunotherapy. Emergency physicians are likely to encounter more patients on ICIs and should routinely consider diabetes, diabetic ketoacidosis, and other acute conditions related to underlying immune-related adverse effects.


Imaging revealed a small osteolytic, somatostatin receptor (SSTR) positive lesion containing calcifications in the alveolar process of the maxilla. No other SSTR-positive focus was found. A biopsy was performed by an oral and maxillofacial surgeon that revealed a calcifying epithelial odontogenic tumor (Pindborg tumor). This case shows that epithelial odontogenic tumors as an uncommon benign tumor entity can also be SSTR-positive.A 62-year-old-woman with a suspected Tumor-induced-osteomalacia (TIO), a rare neoplastic syndrome that results in renal phosphate wasting with hypophosphatemia, underwent  Although rare, in most cases the underlying cause of TIO is a small mesenchymal neoplasm that is difficult to detect without hybrid imaging [68Ga-DotaTOC PET/CT revealed a focally increased tracer uptake maxillary left  because of biochemical evidence of Fibroblast growth factor 23 (FGF23) after several fractures caused by low bone density underwent somatostatin receptor imaging PET/CT (SSTR-PET/CT) using  imaging  because ary left D. A biopPhotomicrographs including hematoxylin and eosin-stained sections , Image EA Pindborg tumor is an uncommon, benign epithelial odontogenic tumor which was first described by Pindborg in 1955 . It is lThis case shows that epithelial odontogenic tumors as an uncommon benign tumor entity can also be SSTR-positive. To the best of our knowledge, there are no known cases of Pindborg tumors being SSTR positive or detected with other radioligands.Although we thought that our case was just a rare SSTR-positive pitfall, amazingly, after partial resection, the level of FGF-23 in blood decreased and normalized after total resection. Therefore, it might be possible that besides mesenchymal tumors known for producing FGF-23 , epithel