Specific oncogene activation of the cell of origin in mucosal melanoma.

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we developed a zebrafish model in which all melanocytes experienced CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only developed from melanocytes lining internal organs, analogous to the location of patient MM. We found that zebrafish MMs had a unique chromatin landscape from cutaneous melanoma. Internal melanocytes could be labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes shared a gene expression signature with MMs. Patient and zebrafish MMs have increased migratory neural crest gene and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery.

SpatialCells: automated profiling of tumor microenvironments with spatially resolved multiplexed single-cell data.

Cancer is a complex cellular ecosystem where malignant cells coexist and interact with immune, stromal and other cells within the tumor microenvironment (TME). Recent technological advancements in spatially resolved multiplexed imaging at single-cell resolution have led to the generation of large-scale and high-dimensional datasets from biological specimens. This underscores the necessity for automated methodologies that can effectively characterize molecular, cellular and spatial properties of TMEs for various malignancies. This study introduces SpatialCells, an open-source software package designed for region-based exploratory analysis and comprehensive characterization of TMEs using multiplexed single-cell data. The source code and tutorials are available at https://semenovlab.github.io/SpatialCells. SpatialCells efficiently streamlines the automated extraction of features from multiplexed single-cell data and can process samples containing millions of cells. Thus, SpatialCells facilitates subsequent association analyses and machine learning predictions, making it an essential tool in advancing our understanding of tumor growth, invasion and metastasis.

Changes in management of head and neck malignancies during the COVID-19 pandemic.

Objective: Despite multiple studies from high-income countries, reports from low- and middle-income countries on the impact of COVID-19 on head and neck cancer care remain sparse. This study aimed to assess the effects of the COVID-19 pandemic on head and neck cancer patients at a tertiary reference centre in Bosnia and Herzegovina. Methods: We included 228 patients with malignant head and neck tumours evaluated and treated between January 1, 2019, and December 31, 2021. Patient demographics, histological characteristics, and treatment modalities were retrospectively obtained and compared between the pre-pandemic period (pre-COVID-19 group) and the period after the implementation of COVID-19 restrictive measures (COVID-19 group). Results: Patients were significantly older during the COVID-19 pandemic. In particular, 63 patients (44.7%) were under 65 and 78 (55.3%) were 65 or older, while in the pre-COVID-19 period, 53 patients (60.9%) were under 65 and 34 (39.1%) were 65 or older (p = 0.017). The pre-COVID-19 and COVID-19 groups did not significantly differ regarding other patient- and tumour characteristics, or primary treatment modalities. Conclusions: During the COVID-19 pandemic, significantly fewer patients were under 65 at the time of initial work-up, potentially reflecting the more enhanced disease-related anxiety of the younger population. Future studies are warranted to address this population's specific educational and psychological needs to ensure appropriate cancer care.

A Phase II study of ERK inhibition by ulixertinib (BVD-523) in Metastatic Uveal Melanoma.

PURPOSE: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases. PATIENTS AND METHODS: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts. RESULTS: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 years (34 -76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease in 4 pts, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months. CONCLUSIONS: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

Real-Life Study of Patient Preference for Dupilumab or Revision Surgery for Recurrent Chronic Rhinosinusitis with Nasal Polyps.

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high rate of recurrence in patients, despite therapy with local corticosteroids and functional endoscopic sinus surgery. Dupilumab, a recombinant monoclonal human IgG4 antibody directed against the IL-4 receptor α that inhibits both IL-4 and IL-13 signal transduction, is available for symptomatic therapy. Patient preference between repeated surgery and injection therapy with Dupilumab is not known. (2) Methods: Patients who had experienced at least one surgical intervention for nasal polyps and were treated with Dupilumab for at least 3 months completed a retrospective patient questionnaire. (3) Results: In a cohort of 75 previously operated CRSwNP patients, 91.5% preferred therapy with Dupilumab to repeated surgery for nasal polyps. Preference for Dupilumab in the subgroups of patients with concomitant Non-steroidal Anti-inflammatory Drugs Exacerbated Respiratory Disease (N-ERD) (n = 32), patients with concomitant asthma (n = 25), and patients without concomitant disease (n = 18) was 100%, 96%, and 72%, respectively. (4) Conclusions: Patient preference for Dupilumab over repeat surgery is strongest in previously operated CRSwNP patients with concomitant asthma or N-ERD, but remains very high in patients without concomitant disease.

Early Results With the New Active Bone-Conduction Hearing Implant: A Systematic Review and Meta-Analysis.

OBJECTIVE: The bone conduction implant (BCI) 602 is a new transcutaneous BCI with smaller dimensions. However, limited patient numbers restrict the statistical power and generalizability of the current studies. The present systematic review and meta-analysis summarize early audiological and medical outcomes of adult and pediatric patients implanted with the BCI 602 due to mixed or conductive hearing loss. DATA SOURCE: Following the Preferred Reporting items for Systematic Reviews and Meta-analyses guidelines, 108 studies were reviewed, and 6 (5.6%) were included in the meta-analysis. REVIEW METHOD: The data on study and patient characteristics, surgical outcomes, and audiological test results were extracted from each article. Meta-analysis employed the fixed-effect and random-effects models to analyze the mean differences (MDs) between pre- and postoperative performances. RESULTS: In total, 116 patients were evaluated, including 64 (55%) adult and 52 (45%) pediatric patients. No intraoperative adverse events were reported, while postoperative complications were reported in 2 (3.1%) adult and 2 (3.8%) pediatric patients. Studies consistently showed significant improvements in audiological outcomes, quality of life, and sound localization in the aided condition. In the meta-analysis, we observed a significant difference in the unaided compared to the aided condition in sound field thresholds (n = 112; MD, -27.05 dB; P < 0.01), signal-to-noise ratio (n = 96; MD, -6.35 dB; P < 0.01), and word recognition scores (n = 96; MD, 68.89%; P < 0.01). CONCLUSION: The implantation of the BCI 602 was associated with minimal surgical complications and excellent audiological outcomes for both the pediatric and the adult cohort. Therefore, our analysis indicates a high level of safety and reliability. Further research should focus on direct comparisons with other BCIs and long-term functional outcomes.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

High-throughput evaluation of genetic variants with prime editing sensor libraries.

Tumor genomes often harbor a complex spectrum of single nucleotide alterations and chromosomal rearrangements that can perturb protein function. Prime editing has been applied to install and evaluate genetic variants, but previous approaches have been limited by the variable efficiency of prime editing guide RNAs. Here we present a high-throughput prime editing sensor strategy that couples prime editing guide RNAs with synthetic versions of their cognate target sites to quantitatively assess the functional impact of endogenous genetic variants. We screen over 1,000 endogenous cancer-associated variants of TP53-the most frequently mutated gene in cancer-to identify alleles that impact p53 function in mechanistically diverse ways. We find that certain endogenous TP53 variants, particularly those in the p53 oligomerization domain, display opposite phenotypes in exogenous overexpression systems. Our results emphasize the physiological importance of gene dosage in shaping native protein stoichiometry and protein-protein interactions, and establish a framework for studying genetic variants in their endogenous sequence context at scale.

Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Gastric cancers commonly spread to the peritoneum. Its presence significantly alters patient prognosis and treatment-intent; however, current methods of peritoneal staging are inaccurate. Peritoneal tumor DNA (ptDNA) is tumor-derived DNA detectable in peritoneal lavage fluid. ptDNA positivity may indicate peritoneal micrometastasis and may be more sensitive than cytology in staging the peritoneum. In this meta-analysis, we evaluated the prognostic potential of ptDNA in gastric cancer. METHODS: PubMed, Embase, Scopus, and Web of Science databases were searched using PRISMA guidelines. Studies published between January 1, 1990, and April 30, 2023, containing quantitative data relating to ptDNA in gastric cancer were meta-analyzed. RESULTS: Six studies were analyzed. Of the total 757 patients with gastric adenocarcinoma, 318 (42.0%) were stage I, 311 (41.0%) were stage II/III, 116 (15.3%) were stage IV, and 22 (2.9%) were undetermined. Overall, ptDNA detected cytology-positive cases with a sensitivity and specificity of 85.2% (95% CI, 66.5 to 100.0) and 91.5% (95% CI, 86.5 to 96.6), respectively. Additionally, ptDNA was detected in 54 (8.5%) of 634 cytology-negative patients. The presence of ptDNA negatively correlated with pathological stage I (relative risk [RR], 0.29 [95% CI, 0.13 to 0.66]) and positively correlated with pathological stage IV (RR, 8.61 [95% CI, 1.86 to 39.89]) disease. Importantly, ptDNA positivity predicted an increased risk of peritoneal-specific metastasis (RR, 13.81 [95% CI, 8.11 to 23.53]) and reduced 3-year progression-free (RR, 5.37 [95% CI, 1.39 to 20.74]) and overall (hazard ratio, 4.13 [95% CI, 1.51 to 11.32]) survival. CONCLUSION: ptDNA carries valuable prognostic information and can detect peritoneal micrometastases in patients with gastric cancer. Its clinical utility in peritoneal staging for gastric cancer deserves further investigation.

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

Association between polyunsaturated fatty acids in adipose tissue and mortality of colorectal cancer patients.

INTRODUCTION: Nutritional intake and dysregulation of fatty acid metabolism play a role in the progression of various tumors, but the consumption of fatty acids is difficult to assess accurately with dietary questionnaires. Biomarkers can objectively assess intake, storage and bioavailability. OBJECTIVE: We studied the association between the polyunsaturated fatty acid (PUFA) composition of abdominal subcutaneous adipose tissue (good indicator of dietary intake over 2-3 years) and all-cause mortality. METHODS: In the multicenter AGARIC study, samples from 203 patients with colorectal cancer (CRC) undergoing curative surgery, were harvested from subcutaneous adipose tissue, which were then analyzed for PUFA composition. RESULTS: After a median follow-up of 45 months, 76 patients died. These patients were more often men (72.4% versus 57.5%, P = 0.04), diabetic (32.9% versus 13.4%, P = 0.001), old (median: 74.5 versus 66.6 years, P < 0.001) and with high alcohol consumption (47.4% versus 30.7%, P = 0.005). An increased risk of death was observed with higher levels of 20:2 ω-6 (hazard ratiotertile3 vstertile1 (HRT3vsT1) 2.12; 95% confidence interval (CI) 1.01-4.42; p-trend = 0.04), 22:4 ω-6 (HRT3vsT1 = 3.52; 95% CI = 1.51-8.17; p-trend = 0.005), and 22:5 ω-6 (HRT3vsT1 = 3.50; 95% CI = 1.56-7.87; p-trend = 0.002). Conversely, the risk of death seemed lower when higher concentrations of 18:3 ω-6 (HRT3vsT1 = 0.52; 95% CI = 0.27-0.99; p-trend = 0.04) and the essential fatty acid, α-linolenic acid 18:3 ω-3 (HRT3vsT1 = 0.47; 95% CI = 0.24-0.93; p-trend = 0.03) were observed. CONCLUSION: The risk of death was increased in CRC patients with higher concentrations of certain ω-6 PUFAs and lower concentrations of α-linolenic acid in their subcutaneous adipose tissue. These results reflect dietary habits and altered fatty acid metabolism. Our exploratory results warrant confirmation in larger studies with further exploration of the mechanisms involved.

Quantifying Perioperative Risks for Antireflux and Hiatus Hernia Surgery: A Multicenter Cohort Study of 4301 Patients.

OBJECTIVE: Using a comprehensive Australian cohort, we quantified the incidence and determined the independent predictors of intraoperative and postoperative complications associated with antireflux and hiatus hernia surgeries. In addition, we performed an in-depth analysis to understand the complication profiles associated with each independent risk factor. BACKGROUND: Predicting perioperative risks for fundoplication and hiatus hernia repair will inform treatment decision-making, hospital resource allocation, and benchmarking. However, available risk calculators do not account for hernia anatomy or technical aspects of surgery in estimating perioperative risk. METHODS: Retrospective analysis of all elective antireflux and hiatus hernia surgeries in 36 Australian hospitals over 10 years. Hierarchical multivariate logistic regression analyses were performed to determine the independent predictors of intraoperative and postoperative complications accounting for patient, surgical, anatomic, and perioperative factors. RESULTS: A total of 4301 surgeries were analyzed. Of these, 1569 (36.5%) were large/giant hernias and 292 (6.8%) were revisional procedures. The incidence rates of intraoperative and postoperative complications were 12.6% and 13.3%, respectively. The Charlson Comorbidity Index, hernia size, revisional surgery, and baseline anticoagulant usage independently predicted both intraoperative and postoperative complications. These risk factors were associated with their own complication profiles. Finally, using risk matrices, we visualized the cumulative impact of these 4 risk factors on the development of intraoperative, overall postoperative, and major postoperative complications. CONCLUSIONS: This study has improved our understanding of perioperative morbidity associated with antireflux and hiatus hernia surgery. Our findings group patients along a spectrum of perioperative risks that inform care at an individual and institutional level.

A scoping review of Rasch analysis and item response theory in otolaryngology: Implications and future possibilities.

Objective: Item response theory (IRT) is a methodological approach to studying the psychometric performance of outcome measures. This study aims to determine and summarize the use of IRT in otolaryngological scientific literature. Methods: A systematic search of the Medline, Embase, and the Cochrane Library databases was performed for original English-language published studies indexed up to January 28, 2023, per the following search strategy: ("item response theory" OR "irt" OR "rasch" OR "latent trait theory" OR "modern mental test theory") AND ("ent" OR "otorhinolaryngology" OR "ear" OR "nose" OR "throat" OR "otology" OR "audiology" OR "rhinology" OR "laryngology" OR "neurotology" OR "facial plastic surgery"). Results: Fifty-five studies were included in this review. IRT was used across all subspecialties in otolaryngology, and most studies utilizing IRT methodology were published within the last decade. Most studies analyzed polytomous response data, and the most commonly used IRT models were the partial credit and the rating scale model. There was considerable heterogeneity in reporting the main assumptions and results of IRT. Conclusion: IRT is increasingly being used in the otolaryngological scientific literature. In the otolaryngology literature, IRT is most frequently used in the study of patient-reported outcome measures and many different IRT-based methods have been used. Future IRT-based outcome studies, using standardized reporting guidelines, might improve otolaryngology-outcome research sustainably by improving response rates and reducing patient response burden. Level of evidence: 2.

Risk Factors for Rescue Opioid Prescription After Cubital Tunnel Surgery.

BACKGROUND: Concerns regarding the ongoing opioid epidemic have led to heightened scrutiny of postoperative opioid prescribing patterns for common orthopedic surgical procedures. This study investigated patient- and procedure-specific risk factors for additional postoperative opioid rescue prescriptions following ambulatory cubital tunnel surgery. METHODS: A retrospective review was performed of patients who underwent cubital tunnel surgery at 2 academic medical centers between June 1, 2015 and March 1, 2020. Patient demographics, comorbidities, prior opioid history, and surgical variables were recorded. The primary outcome was postoperative rescue opioid prescription. Univariate and bivariate statistical analyses were performed. RESULTS: Two hundred seventy-four patients were included, of whom 171 (62%) underwent in situ ulnar nerve decompression and 103 (38%) underwent ulnar nerve decompression with anterior transposition. The median postoperative opioid prescription amount was 90 morphine equivalent units (MEU) for the total cohort, 77.5 MEU for in situ ulnar nerve decompression, and 112.5 MEU for ulnar nerve decompression with transposition. Twenty-two patients (8%) required additional rescue opioid prescriptions postoperatively. Female sex, fibromyalgia, chronic opioid use, chronic pain diagnosis, and recent opioid were associated with the need for additional postoperative rescue opioid prescriptions. CONCLUSIONS: While most patients do not require additional rescue opioid prescriptions after cubital tunnel surgery, chronic pain patients and patients with pain sensitivity syndromes are at risk for requiring additional rescue opioid prescriptions. For these high-risk patients, preoperative collaboration of a multidisciplinary team may be beneficial for developing a perioperative pain management plan that is both safe and effective.

Vagal sparing gastrectomy: A systematic review and meta-analysis.

Radical gastrectomy is associated with significant functional complications. In appropriate patients may be amenable to less invasive resection aimed at preserving the vagal trunks. The aim of this systematic review and meta-analysis is to assess the functional consequences and oncological safety of vagal sparing gastrectomy (VSG) compared to conventional non-vagal sparing gastrectomy (CG). A systematic review of four databases was undertaken for studies published between 1/11990 and 15/122021, comparing patients who underwent VSG to CG. We meta-analysed the following outcomes: operative time, blood loss, nodal yield, days to flatus, body weight changes, as well as the incidence of post-operative cholelithiasis, diarrhoea, delayed gastric emptying, and dumping syndrome. Thirty studies were included in the meta-analysis with a selection of studies qualitatively analysed. VSG was associated with a lower rate of cholelithiasis (OR 0.25, 95% CI 0.15-0.41, p<0.010) and early dumping syndrome (OR 0.42, 95% CI 0.21 - 0.86; p=0.02), less blood loss (MD -51 ml, 95% CI -89.11 to -12.81 ml, p=0.009), less long term weight loss (MD 2.03%, 95% CI 0.31-3.76%, p=0.02) and a faster time to flatus (MD -0.42 days, 95% CI -0.48 - 0.36, p<0.001). There was no significant difference in nodal harvest, overall survival, and all other endpoints. VSG significantly reduces the incidence of post-operative cholelithiasis and dumping syndrome, decreases weight loss and facilitates an earlier return of gut motility. Although technically more challenging, VSG should be considered for prophylactic surgery.

A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers.

BACKGROUND: There is accumulating evidence supporting the clinical use of circulating tumor DNA (ctDNA) in solid tumors, especially in different types of gastrointestinal cancer. As such, appraisal of the current and potential clinical utility of ctDNA is needed to guide clinicians in decision-making to facilitate its general applicability. CONTENT: In this review, we firstly discuss considerations surrounding specimen collection, processing, storage, and analysis, which affect reporting and interpretation of results. Secondly, we evaluate a selection of studies on colorectal, esophago-gastric, and pancreatic cancer to determine the level of evidence for the use of ctDNA in disease screening, detection of molecular residual disease (MRD) and disease recurrence during surveillance, assessment of therapy response, and guiding targeted therapy. Lastly, we highlight current limitations in the clinical utility of ctDNA and future directions. SUMMARY: Current evidence of ctDNA in gastrointestinal cancer is promising but varies depending on its specific clinical role and cancer type. Larger prospective trials are needed to validate different aspects of ctDNA clinical utility, and standardization of collection protocols, analytical assays, and reporting guidelines should be considered to facilitate its wider applicability.

Systematic Review of Prophylactic Plastic Surgery Closure to Prevent Postoperative Wound Complications Following Spine Surgery.

Spinal surgeries are increasingly performed in the United States, but complication rates can be unacceptably high at up to 26%. Consequently, plastic surgeons (PS) are sometimes recruited by spine surgeons (SS) for intraoperative assistance with soft tissue closures. An electronic multidatabase literature search was systematically conducted to determine whether spinal wound closure performed by PS minimizes postoperative wound healing complications when compared to closure by SS (neurosurgical or orthopedic), with the hypothesis that closures by PS minimizes incidence of complications. All published studies involving patients who underwent posterior spinal surgery with closure by PS or SS at index spine surgery were identified. Filtering by exclusion criteria identified 10 studies, 4 of which were comparative in nature and included both closures by PS and SS. Of these 4, none reported significant differences in postoperative outcomes between the groups. Across all studies, PS were involved in cases with higher baseline risk for wound complications and greater comorbidity burden. Closures by PS were significantly more likely to have had prior chemotherapy in 2 of the 4 (50%) studies (P = 0.014, P < 0.001) and radiation in 3 of the 4 (75%) studies (P < 0.001, P < 0.01, P < 0.001). In conclusion, closures by PS are frequently performed in higher risk cases, and use of PS in these closures may normalize the risk of wound complications to that of the normal risk cohort, though the overall level of evidence of the published literature is low.

TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.

A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING-IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell-derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING-IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies. SIGNIFICANCE: STING-IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell-mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance. This article is featured in Selected Articles from This Issue, p. 695.

Preoperative 18F-FDG PET/CT in Patients with Presumed Localized Colon Cancer: A Prospective Study with Long-Term Follow-Up.

We analyzed whether preoperative 18F-FDG PET/CT adds to conventional primary staging in patients with presumed non-metastatic colonic cancer (CC). The prognostic role of 18F-FDG uptake in the primary tumor was evaluated after a mean follow-up of 15 years. Patients with a new diagnosis of presumed localized CC were prospectively enrolled and underwent presurgical 18F-FDG PET/CT. For each colon lesion, SUVmax, SUVpeak, TLG, and MTV were assessed and tested as prognostic factors. Forty-eight patients were included. Post-surgery pathology identified a total of 103 colon lesions, including 58 invasive adenocarcinomas, 4 in situ adenocarcinomas, 3 adenomas with high-grade dysplasia, and 38 adenomas with low-grade dysplasia. Per lesion sensitivity, specificity, positive (PPVs) and negative predictive values (NPVs) for colonic primary tumor detection were 78%, 97%, 98%, and 73% for conventional workup, and 94%, 87%, 92%, and 89% for 18F-FDG PET/CT. Only sensitivity was significantly different between 18F-FDG PET/CT and conventional workup. PET detected an additional ten pathological colonic lesions in seven patients. SUVmax, SUVpeak, and TLG showed significant differences between invasive adenocarcinomas, in situ adenocarcinomas, and high-grade dysplasia compared to low-grade dysplasia. There was a statistically significant difference between pT1-pT2 and pT3-pT4 adenocarcinomas. On patient-based analysis, sensitivity, specificity, PPV, and NPV for nodal staging were 22%, 84%, 44%, and 65% for CECT, and 33%, 90%, 67%, and 70% for 18F-FDG PET/CT, without a statistically significant difference. PET/CT also identified unknown metastatic spread and one synchronous lung cancer in four patients. Overall, 18F-FDG PETCT had an additional diagnostic value in 11 out of 48 patients (23%). 18F-FDG uptake of the primary tumor did not predict nodal or distant metastases. The difference in disease-free survival categorized by median SUVmax, SUVpeak, TLG, and MTV was not significant. Finally, preoperative 18F-FDG PET/CT is valuable in detecting potential colon lesions not visualized by conventional workups, especially in cases of incomplete colonoscopy. It effectively highlights distant metastases but exhibits limitations for N staging. Mainly due to the relatively small sample size, the quantitative analysis of 18F-FDG uptake in the primary tumor did not reveal any association with recurrence or disease-free survival, adding no significant prognostic information.

Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.