Daniel Birnbaum

By identifying somatic mutations, whole-exome sequencing (WES) has become a technology of choice for the diagnosis and guiding treatment decisions in many cancers. Despite advances in the field of somatic variant detection and the emergence of sophisticated tools incorporating machine learning, accurately identifying somatic variants remains challenging. Each new somatic variant caller is often accompanied by claims of superior performance compared to predecessors. Furthermore, most comparative studies focus on a limited set of tools and reference datasets, leading to inconsistent results and making it difficult for laboratories to select the optimal solution. Our study comprehensively evaluated 20 somatic variant callers across four reference WES datasets. We subsequently assessed the performance of ensemble approaches by exploring all possible combinations of these callers, generating 8178 and 1013 combinations for single-nucleotide variants (SNVs) and indels, respectively, with varying voting thresholds. Our analysis identified five high-performing individual somatic variant callers: Muse, Mutect2, Dragen, TNScope, and NeuSomatic. For somatic SNVs, an ensemble combining LoFreq, Muse, Mutect2, SomaticSniper, Strelka, and Lancet outperformed the top-performing caller (Dragen) by >3.6% (mean F1 score = 0.927). Similarly, for somatic indels, an ensemble of Mutect2, Strelka, Varscan2, and Pindel outperformed the best individual caller (Neusomatic) by >3.5% (mean F1 score = 0.867). By considering the computational costs of each combination, we were able to identify an optimal solution involving four somatic variant callers, Muse, Mutect2, and Strelka for the SNVs and Mutect2, Strelka, and Varscan2 for the indels, enabling accurate and cost-effective somatic variant detection in whole exome.

In solid cancer surgery, oxidative stress (OS) is of particular interest because both the malignancy itself and the surgical intervention are major contributors to the modulation of OS levels. This study aimed to investigate the effects of solid cancer surgery on OS levels. Because solid cancer is often accompanied by intense cell death, the study specifically focused on the pathway leading to uric acid formation, (i.e. adenosine deaminase (ADA) and xanthine oxidase (XO). Ische-mia-modified albumin (IMA), a recognized marker of oxidative stress, and plasma redox poten-tial (RP) were also measured. Thirty-six patients undergoing major solid cancer surgery (median age 68 years (58-76), 23 men and 13 women) and thirty controls (62 years (51-80)) were included. During the surgical procedure, serum ADA levels did not change significantly (10.4 International Units (IU) (6.9 – 13.7) vs. 8 IU (6 – 12); p = 0.47). In contrast, XO (IU), IMA (Arbitrary Units(AU)) and redox potential (mV) decreased significantly (22.5 IU (11 – 63) vs. 8.4 IU (5 – 27); p = 0.0041, 89 AU (69 – 105) vs. 74 AU (66 – 80); p = 0.01 and 98 mV (78 – 118) vs. 79 mV (65 – 101); p = 0.033). The correlation between XO and IMA or redox potential was positive (Spearman’s r = 0.32 ; p = 0.007, and r = 0.58; p < 0.001, respectively). XO was negatively correlated with ADA (r = -0.26; p = 0.03). Redox potential was positively correlated with IMA (r = 0.26; p = 0.04) and nega-tively correlated with ADA (r = -0.25 ;p = 0.04). We found that a major source of OS in solid cancer could be the result of an increase in xanthine oxidase activity and that the global effect of solid cancer surgery is a significant decrease in OS levels. We also found that ADA and XO were inversely correlate, suggesting the existence of a negative retrocontrol between the production of free radicals and the production of their sub-strate. Finally, our study highlights the potential value of XO inhibitors as adjuvant therapy in solid tumor surgery.

Purpose Gastric outlet obstruction (GOO) is mainly due to advanced malignant disease. GOO can be treated by surgical gastroenterostomy (SGE), endoscopic enteral stenting (EES), or endoscopic ultrasound-guided gastroenterostomy (EUS-GE) to improve the quality of life. Methods Between 2009 and 2022, patients undergoing SGE or EUS-GE for GOO were included at three centers. Technical and clinical success rates, post-procedure adverse events (AEs), length of hospital stay (LOS), 30-day all-cause mortality, and recurrence of GOO were retrospectively analyzed and compared between SGE and EUS-GE. Predictive factors for technical and clinical failure after SGE and EUS-GE were identified. Results Of the 97 patients included, 56 (57.7%) had an EUS-GE and 41 (42.3%) had an SGE for GOO, with 62 (63.9%) GOO due to malignancy and 35 (36.1%) to benign disease. The median follow-up time was 13,4 months (range 1 days-106 months), with no difference between the two groups (p = 0.962). Technical (p = 0.133) and clinical (p = 0.229) success rates, severe morbidity (p = 0.708), 30-day all-cause mortality (p = 0.277) and GOO recurrence (p = 1) were similar. EUS-GE had shorter median procedure duration (p < 0.001), lower post-procedure ileus rate (p < 0.001), and shorter median LOS (p < 0.001) than SGE. In univariate analysis, no risk factors for technical or clinical failure in SGE were identified and abdominal pain reported before the procedure was a risk factor for technical failure in the EUS-GE group. No risk factor for clinical failure was identified for EUS-GE. In the subgroup of GOO due to benign disease, SGE was associated with better technical success (p = 0.035) with no difference in clinical success rate compared to EUS-GE (p = 1). Conclusion EUS-GE provides similar long-lasting symptom relief as SGE for GOO whether for benign or malignant disease. SGE may still be indicated in centers with limited experience with EUS-GE or may be reserved for patients in whom endoscopic technique fails.

Cytogenetic normal AML with NPM1 mutations forms a distinct AML entity, associated with an intermediate prognosis and a heterogeneous response to treatment. We previously described an epigenetic biomarker, defined by the level of H3K27me3 on 70kb of the HIST1 cluster in patient blast DNA. This epigenetic mark separates cytogenetically normal NPM1 ^mut AML into two groups of patients differing in their survival rate following chemotherapy. To better characterize the influence of the biomarker on disease progression, we performed transcriptomic and histone mark profiling on patient blasts according to the level of H3K27me3 HIST1 . Our integrated analysis revealed that the two groups of patients display differences in terms of transcriptomic, chromatin landscape and cell surface markers, which could explain the clinical difference. Our profiling revealed novel targets and therefore constitutes an (epi)transcriptomic resource for NPM1 AML. It also highlights the power of epigenetic profiling to dissect the heterogeneity of a single AML genetic entity.

Cancer stem cell (CSC) has paved the way to many fundamental and translational studies. Recent studies have highlighted differentiated breast cancer cells (non-CSCs) switching phenotype to CSCs in response to various stimuli, depicting the existence of cancer stem cell plasticity. Although strategies to reduce the phenotypic plasticity of non-CSCs into CSCs are likely to prevent treatment-resilient cancer cells driving recurrence, most phenotypic plasticity mechanisms involve Notch, Wnt or MAPK signaling pathways. In this study, breast cancer cells were irradiated to identify soluble reprogramming factors. Using conditioned medias, protein arrays analyses, flow cytometry and in cellulo/in vivo functional assays, we demonstrated, for the first time, that radiation-induced chemokine expression, especially CXCL1 and CCL5 and their receptors CXCR2, CCR1 and CCR5, stimulates reprogramming of breast non-CSCs into CSCs. Treatment of non-CSCs with recombinant CXCL1 and CCL5 is sufficient to induce cell reprogramming, while their inhibition can be used to prevent reprogramming and sensitize tumor to radiation. Moreover, analysis of gene expression profiles from 38 public merged databases demonstrated that combined over-expression of CXCL1/CXCR2, CCL5/CCR1 or CCL5/CCR5 has a poorer prognosis in patients treated with radiotherapy, suggesting a promising way for patient stratification, where individuals with elevated cytokine levels could benefit from radiotherapy in conjunction with cytokine inhibitors. Taken together, our findings provide a rationale to consider these axes as potential targets and predictive biomarkers in breast cancer patients.

The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes.

Purpose Late post-pancreatectomy hemorrhage (PPH) represents the most severe complication after pancreatic surgery. We have measured the efficacy of major vessels “flooring” with falciform/round ligament to prevent life-threatening grade C late PPH after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). Methods All consecutive patients who underwent PD and DP between 2013 and 2021 were retrospectively reviewed on a prospectively maintained database. The cohort was divided in two groups: “flooring” vs. “no flooring” method group. The “no flooring” group had omental flap interposition. Patient characteristics and operative and postoperative data including clinically relevant postoperative pancreatic fistula (CR-POPF), late PPH (grade B and C), and 90-day mortality were compared between the two groups. Results Two hundred and forty patients underwent pancreatic resections, including 143 PD and 97 DP. The “flooring” method was performed in 61 patients (39 PD and 22 DP). No difference was found between the two groups concerning severe morbidity, CR-POPF, delayed PPH, and mortality rate. The rate of patients requiring postoperative intensive care unit was lower in the “flooring” than in the “no flooring” method group (11.5% vs. 25.1%, p = 0.030). Among patients with grade B/C late PPH (n = 30), the rate of life-threatening grade C late PPH was lower in the “flooring” than in the “no flooring” method group (28.6% (n = 2/7) vs. 82.6% (n = 19/24), p = 0.014). Risk factor analysis showed that the “flooring” method was the only protective factor against grade C late PPH occurrence (p = 0.013). Conclusion The “flooring” method using the falciform/round ligament should be considered during pancreatectomies to reduce the occurrence of life-threatening grade C late PPH.

Supplementary Table from Overcoming Resistance to Anti–Nectin-4 Antibody-Drug Conjugate