In the 2025 novel drug mini-review, one can take a full measure of the ingenuity that underlies current drug design and development, despite the year's smaller harvest (46 novel drugs) compared to 2024 (53) and 2023 (70). 54% of the novel drugs are first-in-class (FIC). The emphasis on proteins/antibodies is maintained (~25% novel drugs in 2025), an industry trend that does not seem to abate. Fewer than half of the novel medicines address major or common disorders. Among the FIC drugs, it is worth mentioning the Nav1.8 channel inhibitor suzetrigine, the first non-opioid approved to palliate acute pain; the first positive allosteric modulator of transient receptor potential melastatin 8 (TRPM8), acoltremon, that increases basal tear production in dry eye disease, a globally common disorder; lerodalcibep, a 'third generation' adnectin inhibitor of the protease Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) to treat elevated LDL-c; and zoliflodacin and gepotidacin, both innovatively targeting bacterial topoisomerases to treat uncomplicated urinary tract infections. Most of the approved medicines target unmet medical need areas and/or orphan indications (the latter alone accounting for 41% of the 2025 novel drugs) by applying imaginative approaches. These approaches include: the combination of two FIC drugs, the RAF/MEK clamp avutometinib paired with the FAK/Pyk2 inhibitor defactinib, to block more efficiently the RAS-RAF-MEK-ERK/FAK oncogenic pathway in low-grade serous ovarian cancer; fitusiran, the first RNAi therapy for haemophilia, targeting for the first time the production of the natural anticoagulant anti-thrombin in the liver; and brensocatib, which attenuates the activation of downstream neutrophil proteases by inhibiting the protease DPP1, thereby preventing lung tissue destruction in bronchiectasis. The landscape of novel drugs approved in 2025 reveals that pharmaceutical innovation continues to advance through FIC mechanisms, sophisticated therapeutic approaches, and a strong focus on unmet medical need.

Reflecting the global expansion of research, the British Journal of Pharmacology (BJP) has observed a substantial increase in the number of studies focusing on natural products. However, disparities in publication requirements between studies of synthetic small molecules and natural products have led to variable acceptance rates. Building on the progress observed following the 2020 and 2024 BJP editorial on natural products, this updated editorial aims to harmonise expectations across different research domains and promote fair and unbiased assessment of natural product studies. By standardising these criteria, the BJP reaffirms its commitment to maintaining scientific rigour whilst ensuring that the guidelines are clear and practical, thereby contributing to high-quality research reporting that advances pharmacological science.

Previous studies have shown that altered AXL signaling is implicated in various diseases, with GAS6 recognized as its only relevant ligand to date. In this study, we show for the first-time a direct interaction between AXL and PROS1 using biochemical methods. Furthermore, we validate the biological significance of PROS1-AXL interaction through advanced quantitative and functional spatial imaging in both murine lung tissue, as well as human lung samples of idiopathic pulmonary fibrosis (IPF) patients. Our findings reveal the role of AXL-mediated biology in alveolar repair and the fibrotic response driven by GAS6 as well as PROS1. Notably, this effect involves PROS1 interacting with AXL to counteract GAS6 mediated effects. Together with the distinct temporal expression of profibrotic genes and the interplay between AXL and TGF-ß pathway, this emphasizes the potential of targeting AXL mediated biology for therapeutic intervention in IPF to allow alveolar restoration. ### Competing Interest Statement The authors have declared no competing interest.

Background: Gastric intestinal metaplasia (GIM) is a precancerous condition. Limited data exist on real-world clinical practice relative to guidelines. Aim: The aim of this study was to evaluate adherence to GIM risk stratification and identify factors associated with follow-up endoscopy. Materials and Methods: We conducted manual chart review of patients with histologically confirmed GIM at an urban, tertiary medical center were identified retrospectively and details of their demographics, Helicobacter pylori, biopsy protocol, endoscopic/histologic findings, and postendoscopy follow-up were recorded. Multivariable logistic regression was used to identify factors independently associated with follow-up endoscopy. Results: Among 253 patients, 59% were female, 37% non-Hispanic White (NHW), 26% Hispanic, 16% non-Hispanic Black (NHB). The median age at index endoscopy was 63.4 years (IQR: 55.9 to 70.0), with median follow-up of 65.1 months (IQR: 44.0 to 72.3). H. pylori was detected in 21.6% patients at index EGD. GIM extent and subtype data were frequently missing (22.9% and 32.8%, respectively). Based on available data, 26% had corpus-extended GIM and 28% had incomplete/mixed-type GIM. Compared with NHW, Hispanic patients had higher odds of follow-up EGD (OR=2.48, 95% CI: 1.23-5.01), while NHB patients had 59% lower odds of follow-up EGD (OR=0.41, 95% CI: 0.18-0.96). Corpus-extended GIM versus limited GIM (OR=2.27, 95% CI: 1.13-4.59) was associated with follow-up EGD, but GIM subtype and family history of gastric cancer were not. Conclusions: We observed suboptimal risk stratification among patients with GIM and notable race and ethnic disparities with respect to endoscopic surveillance. Targeted interventions are needed to improve practice patterns and mitigate observed disparities.

BACKGROUND:Gastric intestinal metaplasia (GIM) is a precancerous condition. Limited data exist on real-world clinical practice relative to guidelines. AIM:The aim of this study was to evaluate adherence to GIM risk stratification and identify factors associated with follow-up endoscopy. MATERIALS AND METHODS:We conducted manual chart review of patients with histologically confirmed GIM at an urban, tertiary medical center were identified retrospectively and details of their demographics, Helicobacter pylori , biopsy protocol, endoscopic/histologic findings, and postendoscopy follow-up were recorded. Multivariable logistic regression was used to identify factors independently associated with follow-up endoscopy. RESULTS:Among 253 patients, 59% were female, 37% non-Hispanic White (NHW), 26% Hispanic, 16% non-Hispanic Black (NHB). The median age at index endoscopy was 63.4 years (IQR: 55.9 to 70.0), with median follow-up of 65.1 months (IQR: 44.0 to 72.3). H. pylori was detected in 21.6% patients at index EGD. GIM extent and subtype data were frequently missing (22.9% and 32.8%, respectively). Based on available data, 26% had corpus-extended GIM and 28% had incomplete/mixed-type GIM. Compared with NHW, Hispanic patients had higher odds of follow-up EGD (OR=2.48, 95% CI: 1.23-5.01), while NHB patients had 59% lower odds of follow-up EGD (OR=0.41, 95% CI: 0.18-0.96). Corpus-extended GIM versus limited GIM (OR=2.27, 95% CI: 1.13-4.59) was associated with follow-up EGD, but GIM subtype and family history of gastric cancer were not. CONCLUSIONS:We observed suboptimal risk stratification among patients with GIM and notable race and ethnic disparities with respect to endoscopic surveillance. Targeted interventions are needed to improve practice patterns and mitigate observed disparities.

633 Background: Immune checkpoint inhibitors (ICI) administered prior to liver resection (LR) lead to pathological responses in patients with hepatocellular carcinoma (HCC). However, the relative value of pathological versus radiological response in predicting relapse-free survival (RFS) remains unclear. Methods: We pooled patient-level data from 111 patients (pts) with HCC receiving ICI prior to LR as part of 5 phase I/II trials and observational clinical studies conducted in 12 centres in the United States, United Kingdom and Asia, as part of an academic consortium (NeoHCC). Pathological response was measured as the percentage of non-viable tumour in the resected specimen, with major (pMR) and complete pathological response (pCR) corresponding to ≥70% and 100% tumour regression. Radiological overall response rate (ORR) was assessed by RECIST v1.1 and modified RECIST (mRECIST) criteria. We correlated pathological response and ORR with RFS using Cox regression. Results: Pts received preoperative ICI between Oct 5, 2017, and Nov 15, 2023, mostly ICI combinations (69%, n=76). Most pts were male (78%, n=87) with viral chronic liver disease (66%, n=73), BCLC stage A HCC (55%, n=61). ORR was 28% per RECIST v1.1 and 32% per mRECIST criteria (available for n=81). Out of the 104 pathologically evaluable pts, pMR and pCR rates were 32% (n=33) and 18% (n=19). Radiological response by RECIST v1.1 showed a significant correlation with pathological response (R 2 = 0.43, p<0.001). When using RECIST v1.1, 74% of pts with ORR achieved pMR vs 14% of those without ORR (n=23/31 vs 10/73, p<0.001). However, 30% of pMR were not predicted by ORR (n=10/33). The discrepancy between pMR and ORR decreased using mRECIST. ORR per mRECIST was 83% in pMR pts (n=19/23), whereas it was 10% in non-pMR (n=5/51). After a median follow-up of 27.2 mos (95%CI 22.3-32.1), median RFS for the whole cohort was 43.6 mos (95%CI 28.3-NE). Achievement of pMR, pCR and ORR was associated with improved RFS (Table). However, reduction in the risk of relapse and/or death was higher in pts achieving pMR or pCR than ORR, regardless of the use of RECIST v1.1 or mRECIST. Conversely, pts without pMR had a lower mRFS than pts without ORR (28.3 mos [95%CI 12.8-43.8] and 32.8 mos [95%CI 13.7-51.9], respectively). Conclusions: Whilst radiological responses to neoadjuvant ICI are associated with improved RFS in pts with HCC, achievement of pMR is more accurate than RECIST and mRECIST-based responses in predicting for RFS, with lack of pMR identifying pts at a higher risk of relapse or mortality. Cox regression for RFS HR (95% CI) p value pCR 0.19 (0.05-0.78) 0.02 pMR 0.25 (0.10-0.66) 0.005 RECIST 1.1 0.34 (0.13-0.86) 0.02 mRECIST 0.38 (0.13-1.11) 0.08 RFS, relapse-free survival; HR, hazard ratio; CI, confidence interval; pCR, complete pathological response; pMR, major pathological response; mRECIST, modified RECIST.

EDITORIAL article Front. Immunol., 16 February 2023Sec. Mucosal Immunity Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1152140

Immunoglobulin (Ig)G4–related hepatic inflammatory pseudotumor (IgG4-HIPT) is a rare subset of IgG4-related disease characterized by IgG4-positive plasma cell infiltration and fibrosis.1 Only 28 cases have been reported, all occurring in native livers.1-3 We report herein the first case of IgG4-HIPT developing in a transplanted liver. All ethical approval and consent procedures were approved by the Medical Ethical Committee of Icahn School of Medicine at Mount Sinai. According to the institutional guidelines, the patient’s signed privacy consent is not necessary for a single case report with deidentified patient-specific information. Our patient, who is a 62-y-old women who underwent liver transplantation for primary biliary cholangitis 14 y prior, presented with bacteremia. Laboratory tests showed normal white blood cell count, elevated gamma-glutamyl transferase 101 U/L (normal, 8–35), normal alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin. Blood culture was positive for methicillin-resistant Staphylococcus aureus and Klebsiella oxytoca. Serological tests for hepatitis A, B, C, and E; cytomegalovirus; and Epstein-Barr virus were negative. Serum total IgG 1654 mg/dL (normal, 586–1602) and IgG4 171 mg/dL (normal, 2–96) were elevated. Computed tomography (Figure 1A) and magnetic resonance imaging (Figure 1C–E) of the abdomen revealed a 6-cm infiltrative mass in segment 8 of the liver. A biopsy of the lesion demonstrated parenchymal collapse replaced with fibrosis and sheets of plasma cells (Figure 1F). Immunohistochemical stains showed up to 150 IgG4-positive plasma cells per high power field and an IgG4:IgG ratio of 60% (Figure 1G and H). There was no evidence of malignancy, recurrent primary biliary cholangitis, acute cellular rejection, or chronic rejection, and a diagnosis of IgG4-HIPT was rendered. Given the patient’s bacteremia, she was started on intravenous daptomycin and ertapenem. Prednisone was deferred because she was asymptomatic from the lesion. The patient was restarted on mycophenolate mofetil 1 mo postdischarge. Repeat computed tomography of the abdomen 7 mo later demonstrated the decreased size of the lesion to 2.3 cm (Figure 1B).FIGURE 1.: Radiology features (A–E). A, Contrast-enhanced computed tomography images demonstrate an infiltrative enhancing mass in segment 8 measuring 6 cm (arrow). B, Follow-up postcontrast computed tomography after 7 mo demonstrates the decreased conspicuity and size of the lesion (measuring 2.3 cm, arrow). Contrast-enhanced MRI obtained during the (C) arterial, (D) portal venous, and (E) delayed venous phases demonstrates an ill-defined lobulated infiltrative progressively enhancing mass (arrow). Microscopic and immunohistochemical features (F–H). F, The inflammatory cells consist predominantly of lymphocytes and plasma cells (arrow) (hematoxylin and eosin stain ×200). The inflammatory cells demonstrated diffuse reactivity for (G) cluster of differentiation 138 and (H) immunoglobulin G4. MRI, magnetic resonance imaging.IgG4-related disease is generally described as an autoimmune disease because the oligoclonal expansions of both activated B cells and cytotoxic CD4+ T cells were considered central to the process.4 In our case, the IgG4-HIPT developed in a liver allograft in a patient on immunosuppression (tacrolimus target trough level 2–6 ng/dL, mycophenolate mofetil 500 mg twice daily). It may seem counterintuitive that an autoimmune process may develop in such a setting. On the other hand, infections such as Escherichia coli and Klebsiella may also incite an IgG4-predominant inflammatory response.3 In our case, the patient developed bacteremia with methicillin-resistant Staphylococcus aureus and Klebsiella at the time the liver mass was noted. Bacterial translocation from the gut to the portal circulation may have provoked an intrahepatic inflammatory response. This theory was further supported by partial or complete treatment response observed in the current and prior reported cases2 upon administration of antibiotics. Diagnosing IgG4-HIPT is challenging because of its rarity and overlapping clinical and radiological features with malignancy. Because IgG4-HIPT is clinically benign, the recognition of this entity is important to avoid unnecessary treatment.

Peutz-Jeghers polyps (PJPs) are hamartomatous polyps that may define patients with Peutz-Jeghers syndrome (PJS), a rare inherited polyposis syndrome with high cancer risk. However, the clinical significance of 1-2 sporadic PJPs (without other PJS stigmata) regarding malignant potential and identification of new PJS probands is still unclear. We identified 112 patients with 524 histologically confirmed PJPs and categorized them based on polyp number into syndromic (n = 38) if >= 3 PJPs or diagnosed PJS, solitary (1 PJP, n = 61), and intermediate (2 PJPs, n = 13). Clinicopathologic features, including presence of dysplasia in the polyp and development of neoplasia in the patient, were compared on a per-patient and per-polyp basis. Whereas patients with solitary and intermediate PJPs were not different from each other, patients with syndromic PJPs were, in multivariate analysis, younger (P = .001) and more likely to develop neoplasia (P = .02) over a 62.6-months median follow-up than patients with sporadic PJPs. On an individual polyp basis, syndromic PJPs were more likely, in multivariate analysis, to occur in the small intestine (P < .001), but less likely to harbor meta-plasia (P = .03) or dysplasia (P = .001), than sporadic PJPs. Dysplasia and metaplasia were more likely in larger PJPs, by multivariate analysis (P = .007 and P < .001, respectively). These data suggest that strict criteria for PJS (including >= 3 PJPs), as currently used, stratify patients into distinct groups with significant differences in clinicopathologic parameters, particularly regarding risk of neoplasia. However, sporadic PJPs exhibit characteristics such as dysplasia and are thus important to recognize and diagnose but perhaps as heralding only a forme fruste PJS.(c) 2023 Elsevier Inc. All rights reserved.

Background Although colorectal cancer (CRC) is traditionally considered to be immunologically inert, some subsets of colorectal cancer, particularly mismatch repair-deficient (MMRd) tumors, can be highly responsive to immune checkpoint blockade (ICB). Recent studies show -that even mismatch repair-proficient (MMRp) tumors can respond to combined PD-1/CTLA-4 ICB. Tumor-associated macrophages (TAMs) are an influential component of the tumor microenvironment (TME), although the exact role of these immune cells in tumor pathogenesis and progression remains enigmatic. TAMs are highly heterogenous and can be either pro-inflammatory or anti-inflammatory, and thus exhibit anti-tumorigenic or pro-tumorigenic effects respectively. Signal regulatory protein α (SIRPα) is a transmembrane protein expressed on TAMs that binds to CD47 on target cells, eliciting a 'don't-eat-me' signal that inhibits phagocytosis by macrophages. In preclinical studies, anti-SIRPα antibodies have been shown to induce macrophage-dependent anti-tumor activity and skew macrophages towards an anti-tumorigenic phenotype. Since colorectal cancer lesions are often dominated by both T cells and anti-inflammatory TAMs, combination therapy with an anti-SIRPα antibody and an anti-PD-1 antibody may result in synergistic killing of tumor cells by TAMs and T cells. Methods This phase I, open-label, parallel-cohort, single-center trial (NCT05446129) was designed to assess the safety, feasibility, clinical efficacy, and biological activity of BI-765063 (an anti-SIRPα antibody) in combination with either ezabenlimab (Cohort A) or pembrolizumab (Cohort B), both anti-PD-1 antibodies, in patients with early-stage, resectable CRC (figure 1). Each cohort will enroll 25 patients. Treatment will be given as a single-dose in the neoadjuvant setting. All patients will then be scheduled to undergo surgical resection 2 to 6 weeks after treatment administration. The primary endpoint is a composite safety and feasibility endpoint, defined as the proportion of patients exhibiting any grade-3 or higher treatment-related adverse event or any treatment-related adverse event delaying surgery more than 6 weeks after treatment administration. The secondary endpoints include pathological response, defined as 50% or greater tumor regression, time from treatment administration to surgery, and radiographic response. Tissue, blood, and stool will be collected prior to treatment administration and at the time of resection. Immune monitoring will be performed using multiplex and single-cell analysis platforms to define the immunodynamic effects of these therapies. Trial Registration ClinicalTrials.gov Identifier: NCT05446129 Ethics Approval On 9/23/2022 an Institutional Review Board of the Mount Sinai School of Medicine, in accordance with Mount Sinai's Federal Wide Assurances (FWA#00005656, FWA#00005651) to the Department of Health and Human Services approved the human subject research (ID 1502–0001; PRMC-22–037; STUDY-22–00928) from 9/23/2022 to 9/19/2023. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Supplementary Figures and Tables

Purpose: We evaluated ctDNA as a pharmacodynamic and predictive biomarker in patients (pts) with resectable HCC treated with cemiplimab (anti-programmed cell death-1). Background: A biomarker-focused study of neoadjuvant cemiplimab in resectable HCC demonstrated acceptable safety and pathologic responses that were associated with immune signatures of intratumoral T-cell response (Marron TU et al. Lancet Gastroenterol. Hepatol. 2022). ctDNA is emerging as a tool to monitor therapy responses and predict RFS in perioperative HCC studies. Methods: We enrolled 21 pts who received 2 cycles of neoadjuvant cemiplimab (350 mg intravenous every 3 weeks), followed by surgical resection and 8 cycles of adjuvant cemiplimab (NCT03916627). The primary endpoint was significant tumor necrosis (STN; >70% necrosis). Secondary endpoints included safety, RFS, and overall survival. A post hoc analysis examined pathological response (≥50% necrosis). Pts underwent pretreatment biopsies and longitudinal blood collection for ctDNA analyses using bespoke multiplex PCR-next generation sequencing (Signatera). We evaluated correlatives of ctDNA changes and the prognostic value undetectable ctDNA after surgery on RFS. Results: Median pt age was 68 years; 52% were Asian, 43% white, and 5% Black; 19% were also Hispanic; 62% had a history of viral hepatitis. ctDNA measurements at baseline and after 1 dose of cemiplimab were available from 19 pts who completed neoadjuvant cemiplimab and underwent successful surgical resection. Pre-surgical absolute ctDNA levels decreased by >50% in 10 pts, including all with greater than 50% tumor necrosis. As of August 1, 2022; median follow-up for the adjuvant period was 23 months (interquartile range: 20-26 months). 8 pts of the 19 pts have relapsed. Pts with a >50% decrease in ctDNA had median RFS of 28 months (95% CI 10, 28), vs 17 months (95% CI 4, not evaluable [NE]) in those with ≤50% decrease in ctDNA. 17 pts had a baseline ctDNA measurement, surgical resection, and data following surgery. ctDNA detection following surgery was associated with disease relapse (Fischer’s exact test, p=0.015), shorter RFS (median 10 months, 95% CI: 4, 28) compared to ctDNA-negative pts (not reached, 95% CI 13 months, NE; hazard ratio 0.14, p=0.006), and identified molecular relapse based on ctDNA with a median lead time of 5 months before imaging relapse. 20 pts (95%) were alive at last follow-up. Interpretation: Changes in ctDNA identify early response to immunotherapy more accurately than standard modalities such as imaging, correlating closely with pathological responses and RFS. ctDNA monitoring during neoadjuvant treatment and following surgery may identify pts with early antitumor responses, improve the prediction of disease relapse or RFS, and inform additional early treatment decisions. Citation Format: Thomas U. Marron, Laura Brennan, Pauline Hamon, Maria Isabel Fiel, Stephen C. Ward, Yuan O. Zhu, Edward Kim, Alice O. Kamphorst, Pradeep Thanigaimani, Thomas S. Uldrick, Natalie Lucas, Kathy Wu, Olivia Hapanowicz, Paula King, Siyu Li, Elizabeth Miller, Nina Bhardwaj, Gavin Thurston, Israel Lowy, Sacha Gnjatic, Myron E. Schwartz, Vladimir Jankovic, Miriam Merad. Circulating tumor DNA (ctDNA) correlates closely with tumor necrosis and relapse-free survival (RFS) in hepatocellular carcinoma (HCC) patients treated with perioperative cemiplimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2178.

Purpose: To describe the longitudinal response in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) and who underwent liver transplant (LT) using gadoxetate-enhanced MRI.Methods: Five men (median age 61y, range 57-64y) with 6 HCCs treated with SBRT (median dose 50 Gy) who subsequently underwent LT were included in this retrospective study. Patients underwent gadoxetate-enhanced MRI before and after SBRT over a period of 3-18 months. Response was assessed using RECIST1.1, mRECIST, LIRADS and image subtraction, by 2 observers in consensus. Percentage of pathologic tumor necrosis was evaluated.Results: LT was performed 278 days (IQR, 148-418d) after completion of SBRT and 48d after the last MRI. Histopathology demonstrated tumor necrosis of 48 +/- 42% (range, 10-100%). Mean tumor size at baseline and last post-treatment MRIs pre-LT were 2.6 +/- 0.8 cm and 2.4 +/- 0.9 cm. Enhancing tumor component size at baseline MRI and last post-treatment MRI pre-LT were 1.6 +/- 0.8 cm and 0.9 +/- 1.0 cm. Responses assessed at the last LRI pre-LT were: partial response (PR, n = 3), stable disease (SD, n = 3) using RECIST1.1; complete response (CR, n = 2), partial response (PR, n = 2), stable disease (SD, n = 2) using mRECIST; and LR-TR viable (n = 4), LRTR non-viable (n = 2) using LI-RADS. At the last MRI pre-LT, per-lesion features of arterial phase hyperenhancement (APHE, 4/6), portal venous washout (3/6) and capsule (3/6) were observed. 5/6 lesions displayed a hypointense perilesional halo on hepatobiliary phase with a mean delay of 3.1 months post-SBRT.Conclusions: This case-series showed decreased size, persistent APHE, and incomplete pathologic necrosis in most HCCs treated with SBRT undergoing transplant.

Lesion scores on procurement donor biopsies are commonly used to guide organ utilization for deceased-donor kidneys. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. Therefore, we constructed deep-learning based models to recognize kidney tissue compartments in hematoxylin & eosin-stained sections from procurement needle biopsies performed nationwide in years 2011-2020. To do this, we extracted whole-slide abnormality features from 2431 kidneys and correlated with pathologists’ scores and transplant outcomes. A Kidney Donor Quality Score (KDQS) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. The performance on wedge biopsies was additionally evaluated. Our model identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis; 90% of tubules. Whole-slide features of Sclerotic Glomeruli (GS)%, Arterial Intimal Fibrosis (AIF)%, and Interstitial Space Abnormality (ISA)% demonstrated strong correlations with corresponding pathologists’ scores of all 2431 kidneys, but had superior associations with post-transplant estimated glomerular filtration rates in 2033 and graft loss in 1560 kidneys. The combination of KDQS and other factors predicted one- and four-year graft loss in a discovery set of 520 kidneys and a validation set of 1040 kidneys. By using the composite KDQS of 398 discarded kidneys due to “biopsy findings”, we suggest that if transplanted, 110 discarded kidneys could have had similar survival to that of other transplanted kidneys. Thus, our composite KDQS and survival prediction models may facilitate risk stratification and organ utilization while potentially reducing unnecessary organ discard.

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13 + CH25H + IL-21 + PD-1 + CD4 + T helper cells (“CXCL13 + T H ”) and Granzyme K + PD-1 + effector-like CD8 + T cells, whereas terminally exhausted CD39 hi TOX hi PD-1 hi CD8 + T cells dominated in nonresponders. CD4 + and CD8 + T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1 + TCF-1 + (Progenitor-exhausted) CD8 + T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8 + T cell differentiation occurs upon ICB. We found that these Progenitor CD8 + T cells interact with CXCL13 + T H within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13 + T H control the differentiation of tumor-specific Progenitor exhasuted CD8 + T cells following ICB.