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We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions., (© 2024 Folkert et al.)

Background: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition., Patients and Methods: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns., Results: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044)., Conclusions: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients., Trial Registration: Clinicaltrials.gov, NCT02434354., Competing Interests: Disclosure GCK serves on an advisory board of Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed., Objective: To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM., Design, Setting, and Participants: This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022., Exposures: Pembrolizumab (200 mg or 2 mg/kg every 21 days)., Main Outcomes and Measures: Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test., Results: This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance., Conclusions and Relevance: The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.

High-risk resectable melanoma poses therapeutic challenges as this subgroup remains most vulnerable for disease recurrence. Immunotherapy has established its efficacy in cases of advanced melanoma, and now is actively being investigated in the multimodal management of resectable disease. Daromun, an intralesional immunocytokine, has emerged as a unique immunotherapy in its ability to preferentially target tumor cells, resulting in direct destruction, while generating a bystander effect that leads to a distant treatment effect. On the basis of its mechanism of action, there is growing interest in delivering immune-based therapies in a neoadjuvant setting. In this review, the neo-DREAM study, a Phase III trial comparing the safety and efficacy of neoadjuvant Daromun for resectable stage IIIB/C melanoma will be described. Clinical Trial Registration Number: NCT03567889.

Background: Gallbladder adenomyomatosis (GA) is a benign gallbladder entity discovered as an asymptomatic gallbladder mass. Since gallbladder cancer is in the differential diagnosis for gallbladder masses, the ability to differentiate benign disease avoids a more extensive oncologic resection. This study sought to review imaging modalities used to diagnose GA., Methods: PubMed and SciVerse Scopus were systematically searched using the terms: "gallbladder adenomyomatosis" and "gallbladder imaging" for articles published between January 2000 and January 2015., Results: A total of 14 articles were reviewed in this analysis. Contemporary series report the use of ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) in GA imaging. Ultrasound detection of Rokitansky-Aschoff sinuses, visualized as small cystic spaces with associated "comet-tail" or "twinkling" artifact, is pathognomonic for GA. A "Pearl-Necklace" sign of small connected sinuses on MRI or "Rosary" sign on CT are additional characteristics that may assist in establishing a diagnosis., Conclusion: Ultrasound is the most commonly used tool to investigate GA. If not diagnostic, CT or MRI are effective in attempting to differentiate a benign or malignant cholecystic mass. Characteristic signs should lead the surgeon to perform a laparoscopic cholecystectomy in symptomatic patients or manage non-operatively in asymptomatic patients., (Copyright © 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Chemotherapy regimens for intrahepatic cholangiocarcinoma (ICC) and gallbladder adenocarcinoma (GC) remain interchangeable; however, response rates are frequently suboptimal. Biomarkers from ICC and GC patients were interrogated to identify actionable differences with potential therapeutic implications., Methods: From 2009 to 2012, pathological specimens from 217 ICC and 28 GC patients referred to Caris Life Sciences were evaluated. Specific testing by immunohistochemical analysis for 17 different biomarkers was performed., Results: In the collective cohort (n = 245), actionable targets included: 95% low thymidylate synthase (TS), 82% low ribonucleotide reductase subunit M (RMM) 1 and 74% low excision repair cross complementation group (ERCC) 1, indicating potential susceptibility to fluoropyrimidines/capecitabine, gemcitabine and platinum agents, respectively. Additional targets included TOPO1 (53.3% high, Irinotecan), MGMT (50.3% low, temozolomide), TOP2A (33% high, anthracyclines) and PGP (30.1% low, taxanes). Subgroup analysis by tumour origin demonstrated a differential biomarker expression pattern with a higher frequency of ICC tumours showing low levels of TS (99% versus 72%, P < 0.01), and RRM1 (85% versus 64%, P = 0.02) when compared with GC. Conversely a greater frequency of GC demonstrated high levels of TOPO1 (76% versus 50%, P = 0.02) versus ICC, indicating a potential increased benefit from irinotecan., Discussion: Differences in the molecular profiles between ICC and GC provide evidence that the two are distinct diseases, requiring different treatment strategies to optimize a response., (© 2015 International Hepato-Pancreato-Biliary Association.)

Background: Ablation for ≤ 3-cm hepatocellular carcinoma (HCC) has been demonstrated to be an effective treatment strategy. The present study sought to examine the outcomes of patients with ≤3 cm HCC after ablation versus resection., Methods: Patients treated by ablation or surgical resection for ≤ 3 cm T1 HCC were identified from the National Cancer Database (2002-2011). Survival outcomes were analysed according to propensity score modelling., Results: A total of 2804 patients underwent ablation (n = 1984) or a resection (n = 820) for solitary HCC ≤ 3 cm. Patients treated with ablation as compared with a resection had a higher frequency in alpha-fetoprotein level (AFP) elevation (46.5% versus 39.1%, P < 0.01) and the presence of cirrhosis (22.2% versus 14.5%, P < 0.01). Unadjusted overall survival (OS) at 3 and 5 years was greater after a resection (67%, 55%) versus ablation (52%, 36%, P < 0.01). After propensity score matching, the improved overall survival (OS) was sustained among the resection cohort (5 year OS: 54% versus 37%, P < 0.001). In multivariable models, a resection was independently associated with an improved OS [hazard ratio (HR): 0.62, 95% confidence interval (CI): 0.48-0.81; P < 0.01]., Conclusion: Resection of HCC ≤ 3 cm results in better long-term survival as compared with ablation. Treatment strategies for small solitary HCC should emphasize a resection first approach, with ablation being reserved for patients precluded from surgery., (© 2015 International Hepato-Pancreato-Biliary Association.)

Background: Transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) is an important option as the majority of patients present with advanced disease. Data regarding treatment outcomes in patients who have undergone transjugular intrahepatic portosystemic shunts (TIPS) are limited. The present study seeks to evaluate the safety and efficacy of TACE in HCC patients with a TIPS., Methods: A retrospective review identifying patients with HCC and concomitant TIPS who were treated with TACE was performed., Results: From 1999 to 2014, 16 patients with HCC underwent a total of 27 TACE procedures; eight patients required multiple treatments. The median patient age at the time of the initial TACE was 60.5 years [interquartile range (IQR) : 52.5-67.5] with the majority being male (n = 12, 75%) and Childs-Pugh Class B (n = 12, 75%). At 6 weeks after TACE, 56.3% of patients achieved an objective response rate (complete and partial response) by mRECIST criteria. Clavien Grade 3 or higher complications occurred in 11.1% of TACE procedures. There were no peri-procedural deaths. The median progression-free (PFS) and overall survival (OS) were 9 and 22 months, respectively, when censored for liver transplantation (median follow-up: 11.5 months)., Conclusion: TACE is an effective treatment strategy for HCC in TIPS patients; albeit may be associated with higher complication rates., (© 2015 International Hepato-Pancreato-Biliary Association.)

Background: Concerns for morbidity after a pancreaticoduodenectomy (PD) has led to practitioners adopting endoscopic resection or ampullectomy in the treatment of T1 ampullary cancer (AC). It was hypothesized that survival for patients undergoing local resection of AC was inferior to those undergoing a PD., Methods: All the data of patients with AC reported in the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2010 were collected. Five-year survival rates according to nodal disease and histological type were compared., Results: There were 1916 cases of AC; 421 (22%) had T1 disease. Among those with T1 disease, 217 (51%) received endoscopic surveillance, 21 (5%) underwent local resection/ampullectomy, 20 (5%) underwent ampullectomy with regional lymphadenectomy and 163 (39%) underwent PD. For patients with complete nodal staging (PD, n = 163), 35 (22%) had metastatic disease in the nodes. Grade was significantly associated with node positivity (P = 0.007). In multivariate models, survival was improved with either an ampullectomy with regional lymphadenectomy [hazard ratio (HR) 0.19; 95% confidence interval (CI) 0.05-0.61, P < 0.005] or a PD (HR 0.23; 95% CI 0.15-0.36, P < 0.001)., Conclusion: Patients with T1 AC have a high risk for nodal metastases especially if they are higher-grade lesions. Nodal clearance with a lymphadenectomy or a PD is essential for long-term survival in these patients., (© 2014 International Hepato-Pancreato-Biliary Association.)

Background: NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications., Methods: 666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC)., Results: In the complete cohort (n = 1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2+ cohort (n = 88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (P < 0.05)., Conclusion: A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.

Background: The management of hepatic hemangiomas remains ill defined. This study sought to investigate the indications, surgical management and outcomes of patients who underwent a resection for hepatic hemangiomas., Methods: A retrospective review from six major liver centres in the United States identifying patients who underwent surgery for hepatic hemangiomas was performed. Clinico-pathological, treatment and peri-operative data were evaluated., Results: Of the 241patients who underwent a resection, the median age was 46 years [interquartile range (IQR): 39-53] and 85.5% were female. The median hemangioma size was 8.5 cm (IQR: 6-12.1). Surgery was performed for abdominal symptoms (85%), increasing hemangioma size (11.3%) and patient anxiety (3.7%). Life-threatening complications necessitating a hemangioma resection occurred in three patients (1.2%). Clavien Grade 3 or higher complications occurred in 14 patients (5.7%). The 30- and 90-day mortality was 0.8% (n = 2). Of patients with abdominal symptoms, 63.2% reported improvement of symptoms post-operatively., Conclusion: A hemangioma resection can be safely performed at high-volume institutions. The primary indication for surgery remains for intractable symptoms. The development of severe complications associated with non-operative management remains a rare event, ultimately challenging the necessity of additional surgical indications for a hemangioma resection., (© 2014 International Hepato-Pancreato-Biliary Association.)