Comparison of clinicopathological features and treatment outcomes for cutaneous melanomas of the head and neck and melanomas arising at other sites: implications for systemic therapy.

BACKGROUND: Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity. OBJECTIVE: Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS). METHODS: Patients with CHNM and CMOS diagnosed between 2000-2018 were included. Locoregional control (LRC), distant metastasis-free survival (DMFS), melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor (ICI) immunotherapy. RESULTS: Of 3007 CHNM and 10637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs. 58.5, p<0.001, median Breslow thickness 1.7mm vs. 1.2mm, p<0.001, ulceration 21.2% vs. 18.2%, p<0.001). CHNM had worse LRC (HR 1.17, p<0.001) and DMFS (HR 1.25, p<0.001) but there were no significant differences in MSS or OS. Amongst stage IV patients who received ICI, CHNM had better MSS (HR 0.56, p=0.001) and OS (HR 0.57, p<0.001) on multivariable analyses. LIMITATIONS: Retrospective study, offset by prospective data collection. CONCLUSION: CHNM is associated with a distinct clinicopathological and prognostic profile.

A Multicenter Phase II Clinical Trial of Low-Dose Subcutaneous Decitabine in Myelofibrosis.

Myelofibrosis (MF) in the chronic phase is a challenging disease entity to treat, and conventional treatment options are geared towards symptom palliation. In this prospective, multicenter, phase II trial, 21 patients with myelofibrosis (18 chronic-phase, 2 accelerated-phase, 1 blast-phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg/day. The overall response rate was 33% (95% CI, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high IPSS risk score, high baseline fetal hemoglobin level, and sustained decreases in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least one grade 3 or 4 cytopenia. Non-hematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in myelofibrosis with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. NCT00095784.

Approach Bias and Tobacco Craving as Mechanisms of the Effect of Approach Bias Retraining on Smoking Cessation.

INTRODUCTION: Approach bias, the automatic tendency to advance toward, rather than move away from appetitive cues, has been associated with greater tobacco cravings, dependence, and likelihood of smoking relapse. Approach bias retraining (ABR) has emerged as one way to reduce approach bias and promote avoidance toward smoking cues. Yet, additional research is needed to identify the mechanisms that may help explain the effect of ABR on smoking cessation. METHODS: The current study uses data collected as part of a randomized controlled trial to test two unique mechanisms of action ([1] approach bias and [2] tobacco craving) for the efficacy of standard smoking cessation treatment (ST) augmented by ABR on smoking abstinence. Participants were 96 adult daily smokers (Mage=43.1, SD=10.7) motivated to quit smoking. RESULTS: Results showed that lower approach bias and lower cravings at a treatment session were significantly related to next session smoking abstinence (p's<.018). Further, deviations in approach bias partially mediated the effect of ABR on smoking abstinence (ab=-12.17, 95%CI: [-29.67, -0.53]). However, deviations in tobacco craving did not mediate this relation (ab=.40, 95%CI: [-.27, 1.34]). CONCLUSIONS: The current findings add to extant literature by identifying approach bias as a mechanism of action of the effect of ABR on smoking abstinence during smoking cessation treatment. IMPLICATIONS: The current study adds to our knowledge on the effectiveness of approach bias retraining (ABR) as a part of smoking cessation treatment. Results indicate that reductions in approach bias partially mediate the effect of ABR on smoking abstinence. These findings are consistent with previous research on alcohol-dependent adults and underline the potential of ABR to reduce approach bias and promote smoking cessation among smokers. Such findings could inform the development of future research exploring more targeted and effective smoking cessation interventions, ultimately improving outcomes for individuals attempting to quit smoking.

Long-Term survival across breslow thickness categories: Findings from a Population-Based study of 210,042 Australian melanoma patients.

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the four AJCC 8th Edition T-categories by analyzing Australian registry data for 210,042 melanoma patients diagnosed from 1982-2014. The 30-year incidence rates of death due to melanoma and non-melanoma causes (with 95% confidence intervals) were 7.1% (CI 6.9-7.3%) and 32.8% (CI 32.3-33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (CI 21.0-22.3%) and 35.6% (CI 34.7-36.6%), for T3 melanomas 34.2% (CI 33.4-35.1%) and 39.6% (CI 38.5-40.8%), and for T4 melanomas 44.3% (CI 43.2-45.3%) and 39.6% (CI 38.3-41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years but there were ongoing melanoma-related deaths for the other T-categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T-categories.

Multifunctional gallium doped bioactive glasses: a targeted delivery for antineoplastic agents and tissue repair against osteosarcoma.

Osteosarcoma is the mostly commonly occurring primary bone cancer. Despite comprehensive treatment programs including neoadjuvant chemotherapy and tumour resection, survival rates have not improved significantly since the 1970s. Survival rates are dramatically reduced for patients who suffer a local recurrence. Furthermore, primary bone cancer patients are at increased risk of bone fractures. Consequently, there is an urgent need for alternative treatment options. In this paper we report the development of novel gallium doped bioactive glass that selectively kill bone cancer cells whilst simultaneously stimulating new bone growth. Here we show, using a combination of MTT, LIVE/DEAD assays and image analysis, that bioactive glasses containing gallium oxide are highly toxic and reduce both the proliferation and migration of bone cancer cells (Saos-2) in a dose dependant manner. Glasses containing 5 mol% gallium oxide reduced the viability of osteosarcoma cells by 99% without being cytotoxic to the non-cancerous normal human osteoblasts (NHOst) control cells. Furthermore, FTIR and Energy-dispersive X-ray spectroscopy results confirmed the formation of an amorphous calcium phosphate / hydroxy apatite layer on the surface of the bioactive glass particulates, after 7 days incubating in simulated body fluid, indicating the early stages of bone formation. These materials show significant potential for use in bone cancer applications as part of a multimodal treatment. .

Patient-derived Organoid Pharmacotyping As A Predictive Tool for Therapeutic Selection in Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: We integrate a new approach to chemosensitivity data for clinically-relevant regimen matching, and demonstrate the relationship with clinical outcomes in a large PDO biobank. SUMMARY BACKGROUND DATA: Pancreatic ductal adenocarcinoma (PDAC) usually recurs following potentially curative resection. Prior studies related patient-derived organoid (PDO) chemosensitivity with clinical responses. METHODS: PDOs were established from pre-treatment biopsies in a multi-institution clinical trial (n=21) and clinical specimens at a high-volume pancreatectomy center (n=74, of which 48 were pre-treated). PDO in vitro chemosensitivities to standard-of-care chemotherapeutics (pharmacotypes) were matched to potential clinically-relevant regimens by a weighted nearest-neighbors analysis. Clinical outcomes were then compared for patients who had well-matched versus poorly-matched treatment according to this metric. RESULTS: Our function matched 91% of PDOs to a standard-of-care regimen (9% pan-resistant). PDOs poorly-matched to the neoadjuvant regimen received would have matched to an alternative in 34% of cases. Patients receiving neoadjuvant chemotherapy well-matched to their pharmacotype experienced improved CA 19-9 response (60% decreased to normal when well-matched, 29% when poorly-matched, P<0.05) and lymph node down-staging (33% N0 after poorly-matched, 69% after well-matched, P<0.05). Patients receiving both well-matched neoadjuvant and adjuvant chemotherapy experienced improved recurrence-free- and overall survival (median RFS 8.5 mo poorly-matched, 15.9 mo well-matched, P<0.05; median OS 19.5 vs. 30.3 mo, P<0.05). CONCLUSION: In vitro PDO pharmacotyping can inform PDAC therapy selection. We demonstrate improved outcomes including survival for patients treated with regimens well-matched to their PDO chemosensitivities. A subsequent prospective study using PDO pharmacotype matching could improve oncologic outcomes and improve quality of life by avoiding therapies not expected to be effective.

Development of an Enhanced Recovery After Surgery Program in Ventral Hernia.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs have spread after initial success in colorectal surgery decreasing length of stay (LOS) and decreasing opioid consumption. Adoption of ERAS specifically for ventral hernia patients remains in evolution. This study presents the development and implementation of an ERAS pathway for ventral hernia. METHODS: A multidisciplinary team met weekly over 6 months to develop an ERAS pathway specific to ventral hernia patients. 75 process components and outcome measures were included, spanning multiple phases of care: Preoperative-Clinic, Preoperative Day of Surgery (DOS), Intraoperative, and Postoperative. Preoperative components included education and physiologic optimization. Pain control across phases of care focuses on nonopioid, multimodal analgesia. Postoperatively, the pathway emphasizes early diet advancement, early mobilization, and minimization of IV fluids. We compared compliance and outcome measures between a Pre Go-Live (PGL) period (9/1/2020-8/30/2021) and After Go-live (AGL) period (5/12/2022-5/19/2023). RESULTS: There were 125 patients in the PGL group and 169 patients in the AGL group. Overall, ERAS compliance increased from 73.9% to 82.9% after implementation. Length of stay decreased from an average of 2.27 days PGL to 1.92 days AGL. Finally, the average daily postoperative opioid usage decreased from 25.4 to 13.5 MME after the implementation. DISCUSSION: Enhanced Recovery After Surgery can be successfully applied to the care of hernia patients with improvements in LOS and decreased opioid consumption. Institutional support and multidisciplinary cooperation were key for the development of such a program.

IgE glycosylation and impact on structure and function: A systematic review.

The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non-allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE-mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE-FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues.

Revisiting the Posterior Approach for Cervical Radiculopathy Utilizing Endoscopic Techniques: A Favorable Short-Term Outcome and Cost Comparison With Anterior Cervical Discectomy and Fusion.

BACKGROUND: Cervical radiculopathy is a spine ailment frequently requiring surgical decompression via anterior cervical discectomy and fusion (ACDF) or posterior foraminotomy/discectomy. While endoscopic posterior foraminotomy/discectomy is gaining popularity, its financial impact remains understudied despite equivalent randomized long-term outcomes to ACDF. In a cohort of patients undergoing ACDF vs endoscopic posterior cervical foraminotomy/discectomy, we sought to compare the total cost of the surgical episode while confirming an equivalent safety profile and perioperative outcomes. METHODS: A single-center retrospective cohort study of patients with unilateral cervical radiculopathy undergoing ACDF or endoscopic cervical foraminotomy between 2018 and 2023 was undertaken. Primary outcomes included the total cost of care for the initial surgical episode (not charges or reimbursement). Perioperative variables and neurological recovery were recorded. Multivariable analysis tested age, body mass index, race, gender, insurance type, operative time, and length of stay. RESULTS: A total of 38 ACDF and 17 endoscopic foraminotomy/discectomy operations were performed. All patients underwent single-level surgery except for 2 two-level endoscopic decompressions. No differences were found in baseline characteristics and symptom length except for younger age (46.8 ± 9.4 vs 57.6 ± 10.3, P = 0.002) and more smokers (18.4% vs 11.8%, P = 0.043) in the ACDF group. Actual hospital costs for the episode of surgical care were markedly higher in the ACDF cohort (mean ±95% CI; $27,782 ± $2011 vs $10,103 ± $720, P < 0.001) driven by the ACDF approach (ß = $17,723, P < 0.001) on multivariable analysis. On sensitivity analysis, ACDF was never cost-efficient compared with endoscopic foraminotomy, and endoscopic failure rates of 64% were required for break-even cost. ACDF was associated with significantly longer operative time (167.7 ± 22.0 vs 142.7 ± 27.4 minutes, P < 0.001) and length of stay (1.1 ± 0.5 vs 0.1 ± 0.2 days, P < 0.001). No significant difference was found regarding 90-day neurological improvement, readmission, reoperation, or complications. CONCLUSION: Compared with patients treated with a single-level ACDF for unilateral cervical radiculopathy, endoscopic posterior cervical foraminotomy/discectomy can achieve a similar safety profile, pain relief, and neurological recovery at considerably less cost. These findings may help patients and surgeons revisit offering the posterior cervical foraminotomy/discectomy utilizing endoscopic techniques. CLINICAL RELEVANCE: Endoscopic posterior cervical foraminotomy/discectomy offers comparable safety, pain relief, and neurological recovery to traditional methods but at a significantly lower cost.

Distinct conformational states enable transglutaminase 2 to promote cancer cell survival versus cell death.

Transglutaminase 2 (TG2) is a GTP-binding, protein-crosslinking enzyme that has been investigated as a therapeutic target for Celiac disease, neurological disorders, and aggressive cancers. TG2 has been suggested to adopt two conformational states that regulate its functions: a GTP-bound, closed conformation, and a calcium-bound, crosslinking-active open conformation. TG2 mutants that constitutively adopt an open conformation are cytotoxic to cancer cells. Thus, small molecules that bind and stabilize the open conformation of TG2 could offer a new therapeutic strategy. Here, we investigate TG2, using static and time-resolved small-angle X-ray scattering (SAXS) and single-particle cryoelectron microscopy (cryo-EM), to determine the conformational states responsible for conferring its biological effects. We also describe a newly developed TG2 inhibitor, LM11, that potently kills glioblastoma cells and use SAXS to investigate how LM11 affects the conformational states of TG2. Using SAXS and cryo-EM, we show that guanine nucleotides bind and stabilize a monomeric closed conformation while calcium binds to an open state that can form higher order oligomers. SAXS analysis suggests how a TG2 mutant that constitutively adopts the open state binds nucleotides through an alternative mechanism to wildtype TG2. Furthermore, we use time resolved SAXS to show that LM11 increases the ability of calcium to bind and stabilize an open conformation, which is not reversible by guanine nucleotides and is cytotoxic to cancer cells. Taken together, our findings demonstrate that the conformational dynamics of TG2 are more complex than previously suggested and highlight how conformational stabilization of TG2 by LM11 maintains TG2 in a cytotoxic conformational state.

PRAP study-partial versus radical adrenalectomy in hereditary pheochromocytomas.

OBJECTIVE: Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC. METHODS: Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality. RESULTS: The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09). CONCLUSION: In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.

Apixaban vs Aspirin in Patients With Cancer and Cryptogenic Stroke: A Post Hoc Analysis of the ARCADIA Randomized Clinical Trial.

Importance: Approximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke. Objective: To compare apixaban vs aspirin for the prevention of adverse clinical outcomes in patients with history of cancer and cryptogenic stroke. Design, Setting, and Participants: Post hoc analysis of data from 1015 patients with a recent cryptogenic stroke and biomarker evidence of atrial cardiopathy in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, a multicenter, randomized, double-blind clinical trial conducted from 2018 to 2023 at 185 stroke centers in North America. Data analysis was performed from October 15, 2023, to May 23, 2024. Exposures: Oral apixaban, 5 mg (or 2.5 mg if criteria met), twice daily vs oral aspirin, 81 mg, once daily. Subgroups of patients with and without cancer at baseline were examined. Main Outcomes and Measures: The primary outcome for this post hoc analysis was a composite of major ischemic or major hemorrhagic events. Major ischemic events were recurrent ischemic stroke, myocardial infarction, systemic embolism, and symptomatic deep vein thrombosis or pulmonary embolism. Major hemorrhagic events included symptomatic intracranial hemorrhage and any major extracranial hemorrhage. Results: Among 1015 participants (median [IQR] age, 68 [60-76] years; 551 [54.3%] female), 137 (13.5%) had a history of cancer. The median (IQR) follow-up was 1.5 (0.6-2.5) years for patients with history of cancer and 1.5 (0.6-3.0) years for those without history of cancer. Participants with history of cancer, compared with those without history of cancer, had a higher risk of major ischemic or major hemorrhagic events (hazard ratio [HR], 1.73; 95% CI, 1.10-2.71). Among those with history of cancer, 8 of 61 participants (13.1%) randomized to apixaban and 16 of 76 participants (21.1%) randomized to aspirin had a major ischemic or major hemorrhagic event; however, the risk was not significantly different between groups (HR, 0.61; 95% CI, 0.26-1.43). Comparing participants randomized to apixaban vs aspirin among those with cancer, events included recurrent stroke (5 [8.2%] vs 9 [11.8%]), major ischemic events (7 [11.5%] vs 14 [18.4%]), and major hemorrhagic events (1 [1.6%] vs 2 [2.6%]). Conclusions and Relevance: Among participants in the ARCADIA trial with history of cancer, the risk of major ischemic and hemorrhagic events did not differ significantly with apixaban compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Acetabular posterior column screws via an anterior approach.

Screw fixation of acetabular column fractures is a well-established alternative option to plate fixation providing comparable biomechanical strength and requiring less surgical exposure. For displaced acetabular fractures involving both columns open reduction and plate fixation of one column in combination with a column-crossing screw fixation of the opposite column via a single approach is a viable treatment option. Preoperative planning of posterior column screws (PCS) via an anterior approach is mandatory to assess the eligibility of the fracture for this technique and to plan the entry point and the screw trajectory. The intraoperative application requires fluoroscopic guidance using several views. A single view showing an extraarticular screw position is adequate to rule out hip joint penetration. The fluoroscopic assessment of cortical perforation of the posterior column requires several oblique views such as lateral oblique views, obturator oblique views and axial views of the posterior column or alternatively intraoperative CT scans. The application of PCS via an anterior approach is a technically demanding procedure, that allows for a relevant reduction of approach-related morbidity, surgical time and blood loss by using a single approach.

Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations.

The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.

Frontal and occipital brain glutathione levels are unchanged in autistic adults.

BACKGROUND: The neurobiological underpinnings of Autism Spectrum Disorder (ASD) are diverse and likely multifactorial. One possible mechanism is increased oxidative stress leading to altered neurodevelopment and brain function. However, this hypothesis has mostly been tested in post-mortem studies. So far, available in vivo studies in autistic individuals have reported no differences in glutathione (GSH) levels in frontal, occipital, and subcortical regions. However, these studies were limited by the technically challenging quantification of GSH, the main brain antioxidant molecule. This study aimed to overcome previous studies' limitations by using a GSH-tailored spectroscopy sequence and optimised quantification methodology to provide clarity on GSH levels in autistic adults. METHODS: We used spectral editing proton-magnetic resonance spectroscopy (1H-MRS) combined with linear combination model fitting to quantify GSH in the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) of autistic and non-autistic adults (male and female). We compared GSH levels between groups. We also examined correlations between GSH and current autism symptoms, measured using the Autism Quotient (AQ). RESULTS: Data were available from 31 adult autistic participants (24 males, 7 females) and 40 non-autistic participants (21 males, 16 females); the largest sample to date. The GSH levels did not differ between groups in either region. No correlations with AQ were observed. CONCLUSION: GSH levels as measured using 1H-MRS are unaltered in the DMPFC and mOCC regions of autistic adults, suggesting that oxidative stress in these cortical regions is not a marked neurobiological signature of ASD.

Rapid postradiation malignant transformation of a pilocytic astrocytoma in an adult with neurofibromatosis type 1: illustrative case.

BACKGROUND: Juvenile pilocytic astrocytoma (JPA) is the most common primary brain tumor of childhood and is rarely seen in adults. Neurofibromatosis type 1 (NF1), a common tumor predisposition syndrome, demonstrates a strong association with low-grade gliomas, most notably pilocytic astrocytoma, which are relatively indolent. Unlike its juvenile counterpart, reports of adult pilocytic astrocytoma (APA) vary widely in terms of disease progression from benign to much more malignant courses. Moreover, current studies discussing APA report different treatment approaches and outcomes (e.g., malignant transformation of JPA and APA with or without radiation), as little is known regarding the management of recurrent tumors and how adjuvant therapies may alter disease progression. OBSERVATIONS: The authors report the unique case of an adult male with NF1 and APA who underwent rapid malignant conversion after intensity-modulated radiation therapy. LESSONS: The authors demonstrate that caution should be taken in utilizing radiotherapy instead of resection in cases of APA and NF1, with close monitoring for posttreatment recurrence. https://thejns.org/doi/10.3171/CASE24241.

Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway.

Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product "sperminal" is reduced to "sperminol." Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

Weakly supervised deep learning image analysis can differentiate melanoma from naevi on haematoxylin and eosin-stained histopathology slides.

BACKGROUND: The broad histomorphological spectrum of melanocytic pathologies requires large data sets to develop accurate and generalisable deep learning (DL)-based diagnostic pathology classifiers. Weakly supervised DL promotes utilisation of larger training data sets compared to fully supervised (patch annotation) approaches. OBJECTIVES: To evaluate weakly supervised DL image classifiers for discriminating melanomas from naevi on haematoxylin and eosin (H&E)-stained pathology slides. METHODS: A representative H&E slide for 260 naevi and 260 melanomas from mucocutaneous sites at one tertiary institution was digitized. Clinicopathological features were recorded for each case including thickness and histological subtype. Whole-slide or whole-tissue section labels were applied. The ground truth was established by consensus diagnosis from two pathologists. Multiple-instance learning models, Trans-MIL, CLAM and DTFD-MIL were evaluated at 10×, 20× and 40× magnifications using stratified fivefold Monte Carlo cross-validation, with 80/10/10 splits for training/validation/test groups, to predict melanoma from naevus. Heatmaps were generated to understand model performance. RESULTS: Naevi cases were younger (median age: 51 years; melanoma median age: 71.5 years), with more balanced sex distribution (males: 48.8%, melanoma male subgroup: 64.2%). The most frequent histological subtypes of naevi and melanomas were dysplastic compound (n = 99, 38.1%) and superficial spreading (n = 124, 47.7%), respectively. Average AUC (±1 SD) for Trans-MIL, CLAM and DTFD-MIL across test groups were 0.9952 ± 0.006, 0.9925 ± 0.0052 and 0.9708 ± 0.0328, at 20× magnification, respectively. Performance of the models varied according to the magnification used. Heatmaps from the two best performing models, Trans-MIL and CLAM, generally indicated attention on appropriate tissue regions for interpretation. CONCLUSIONS: Weakly supervised DL on pathological slides of common mucocutaneous melanocytic tumours provides highly accurate diagnostic value for discrimination of melanomas and naevi. External validation and further assessment on less frequently occurring histologic subtypes and borderline cases using this method is required.