Completion pancreatectomy during pancreatoduodenectomy: A lifesaving solution in high-risk patients.

BACKGROUND: Postoperative pancreatic fistula (POPF) is responsible of most major complications and fatalities after PD. By avoiding POPF, TP may improve operative outcomes in high-risk patients. The aim was to compare total pancreatectomy (TP) and pancreatoduodenectomy (PD) in high-risk patients and evaluate results of implementing a risk-tailored strategy in clinical practice. METHODS: Between 2014 and 2023, 139 patients (76 men, median age 67 years) underwent resection of disease located in the head of the pancreas. Starting January 1, 2022, we offered TP to patients at high POPF risks (fistula risk score (FRS) ≥7) and to patients with intermediate POPF risks (FRS: 3-6) and high risks of failure to rescue (age> 75 years, ASA score ≥3). We compared outcomes of TP and PD and evaluated the results of the new strategy implementation on operative outcomes. Propensity score-based analysis was performed to limit bias of between-group comparison. RESULTS: Eventually, 26 (19%) patients underwent TP and 113 (81%) patients underwent PD. Severe complications occurred in 42 (30%) patients and 13 (9%) patients died. TP resulted in shorter lengths of hospital stay (median: 14 days [11; 18] vs. 17 days [13; 24], p = 0.016) and less risks of post-pancreatectomy hemorrhage (PPH) (0% vs. 20%, p < 0.001) compared to PD. Crude and propensity match analysis showed that the implementation of a risk-tailored strategy led to significant reduction of reoperation, POPF, PPH and mortality rates. CONCLUSION: The use of TP as part of a risk-tailored strategy in high-risk patients can be lifesaving.

Immunotherapy in hepatocellular carcinoma: How does underlying liver disease influence therapeutic strategy and outcomes?

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with up to 90% of HCC cases occurring in the setting of underlying cirrhosis. Therapeutic landscape for advanced HCC has dramatically changed in recent years with the advent of immunotherapy, including several combinations. Data suggest that the surrounding liver milieu may influence tumour response. In addition, different aetiologies of HCC and their effects on the host liver may impact response to immunotherapy. However, to date, guidelines do not take into account this parameter to guide therapeutic selection, and phase III trials are likewise performed in patients irrespective of HCC aetiology. Moreover, most clinical trial data are collected in highly selected patients with preserved liver function (defined as Child-Pugh class A) and controlled portal hypertension, which does not accurately reflect routine clinical practice. In this review, we discuss the influence of liver disease aetiology on the response to immunotherapy in patients with advanced HCC. We also discuss the safety and efficacy of various immunotherapeutic agents in Child-Pugh B patients to determine if these treatments are beneficial in this vulnerable patient population.

Discrepancies between dihydropyrimidine dehydrogenase phenotyping and genotyping: What are the explanatory factors?

AIM: Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil [U], with U ≥ 16 µg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors. METHODS: Data from patients who underwent both phenotyping and genotyping were retrospectively collected. Complementary genetic analyses (genotyping of the variant c.557A>G and DPYD sequencing) were performed for patients with U ≥ 16 µg/L without any common variants. The characteristics of patients classified according to the congruence of the phenotyping and genotyping approaches were compared (Kruskal-Wallis test), and determinants of U levels were studied in the whole cohort (linear model). RESULTS: Among the 712 included patients, phenotyping and genotyping were discordant for 12.5%, with 63 (8.8%) having U ≥ 16 µg/L in the absence of a common variant. Complementary genetic investigations marginally reduced the percentage of discrepancies to 12.1%: Among the nine additional identified variants, only the c.557A>G variant, carried by three patients, had been previously reported to be associated with DPD deficiency. Liver dysfunction could explain certain discordances, as ASAT, ALP, GGT and bilirubin levels were significantly elevated, with more frequent liver metastases in patients with U ≥ 16 µg/L and the absence of a DPYD variant. The impact of cytolysis was confirmed, as ASAT levels were independently associated with increased U (p < 0.001). CONCLUSION: The frequent discordances between DPD phenotyping and genotyping approaches highlight the need to perform these two approaches to screen for all DPD deficiencies.

Endovascular Lymphatic Decompression via Thoracic Duct Stent Placement for Refractory Ascites in Patients with Cirrhosis: A Pilot Study.

PURPOSE: To evaluate the technical and clinical success of endovascular lymphatic decompression via thoracic duct (TD) stent placement in patients with cirrhosis with refractory ascites. MATERIALS AND METHODS: Nine patients (6 men and 3 women; median age, 66 [interquartile range {IQR}, 65-68] years; range, 62-78 years) who underwent TD stent placement for refractory ascites with contraindications for liver transplantation and transjugular intrahepatic portosystemic shunt creation were included in this retrospective study. TD stent placement was performed under local anesthesia using retrograde access from the venous system. Self-expanding stents from 5 to 8 mm in diameter were used and extended into the subclavian vein by approximately 1 cm. Technical (correct positioning of the stent) and clinical success (no more requirement of paracentesis) were evaluated. In addition, the safety of the procedure and TD pressure evolution were evaluated. RESULTS: The technical success rate was 100%, and 3 (33%) patients reported clinical success. Five (56%) patients reported 7 minor adverse events (Grade I), among which 2 TD perforations were induced by stent angioplasty, with no clinical manifestation or treatment required. The median TD pressure decreased from 19 mm Hg (IQR, 11-24 mm Hg) at the beginning of the procedure to 6 mm Hg (IQR, 5-11 mm Hg) after TD stent placement. The median survival time after the procedure was 7.1 months. CONCLUSIONS: Endovascular lymphatic decompression via TD stent placement is feasible and safe and was effective on ascites in some patients with cirrhosis with refractory ascites.

Optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma-a retrospective, international, multicentric AGEO study.

BACKGROUND: The optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma (OGA) remains challenging. METHODS: Patients treated with trastuzumab (T) plus platinum salts and fluoropyrimidine (F) as first-line chemotherapy between 2010 and 2020 for HER2-positive advanced OGA at 17 academic care centers in France, Italy, and Austria were included. The primary objective was the comparison of F + T vs T alone as maintenance regimen in terms of progression-free survival (PFS) and overall survival (OS) after a platinum-based chemotherapy induction + T. As secondary objective, PFS and OS between patients treated with reintroduction of initial chemotherapy or standard second-line chemotherapy at progression were assessed. RESULTS: Among the 157 patients included, 86 (55%) received F + T and 71 (45%) T alone as a maintenance regimen after a median of 4 months of induction chemotherapy. Median PFS from start of maintenance therapy was 5.1 months in both groups (95% CI 4.2-7.7 for F + T and 95% CI 3.7-7.5 for T alone; p = 0.60) and median OS was 15.2 (95% CI 10.9-19.1) and 17.0 months (95% CI 15.5-21.6) for F + T and T alone, respectively (p = 0.40). Of 112/157 patients (71%) receiving systemic therapy after progression under maintenance, 26/112 (23%) were treated with a reintroduction of initial chemotherapy + T and 86/112 (77%) with a standard second-line regimen. Here, median OS was significantly longer with the reintroduction (13.8 (95% CI 12.1-19.9) vs 9.0 months (95% CI 7.1-11.9); p = 0.007) as confirmed by multivariate analysis (HR 0.49; 95% CI 0.28-0.85; p = 0.01). CONCLUSION: No additional benefit of adding F to T monotherapy as a maintenance treatment could be observed. Reintroduction of initial therapy at first progression may be a feasible approach to preserve later treatment lines.

FOLFIRI plus BEvacizumab or aFLIbercept after FOLFOX-bevacizumab failure for COlorectal cancer (BEFLICO): An AGEO multicenter study.

After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3-14.7) and 10.4 months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4-6.5) and 5.1 months (95% CI: 4.3-5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P = .0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab.

Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC.

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

Percutaneous Ablation-Induced Immunomodulation in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.

Lysine methylation signaling in pancreatic cancer.

PURPOSE OF REVIEW: Despite better knowledge of its genetic basis, pancreatic cancer is still highly lethal with very few therapeutic options. In this review, we discuss the potential impact of epigenetic therapies, focusing on lysine methylation signaling and its implication in pancreatic cancer. RECENT FINDINGS: Protein lysine methylation, a key mechanism of posttranslational modifications of histone proteins, has emerged as a major cell signaling mechanism regulating physiologic and pathologic processes including cancer. This finely tuned and dynamic signaling mechanism is regulated by lysine methyltransferases (KMT), lysine demethylases (KDM) and signal transducers harboring methyl-binding domains. Recent evidence demonstrates that overexpression of cytoplasmic KMT and resulting enhanced lysine methylation is a reversible event that enhances oncogenic signaling through the Ras and Mitogen-Activated Protein Kinases pathway in pancreatic cancer, opening perspectives for new anticancer chemotherapeutics aimed at controlling these activities. SUMMARY: The development of potent and specific inhibitors of lysine methylation signaling may represent a hitherto largely unexplored avenue for new forms of targeted therapy in cancer, with great potential for yet hard-to-treat cancers such as pancreatic cancer.

Radiological diagnosis of hepatocellular carcinoma does not preclude biopsy before treatment.

Background & Aims: The diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis relies on non-invasive criteria based on international guidelines. The advent of systemic therapies warrants reconsideration of the role of biopsy specimens in the diagnosis of HCC. Accordingly, we investigated the diagnostic performance of the LI-RADS 2018 and the AASLD 2011 criteria. Methods: Consecutive patients with cirrhosis who underwent a biopsy for suspected HCC between 2015 and 2020 were included. The available imaging studies (computed tomography and/or magnetic resonance imaging) were blindly reviewed by two independent radiologists. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for LI-RADS, AASLD, and biopsies. Results: In total, 167 patients underwent both available biopsy and imaging. Of the 137 relevant biopsies, 114 patients had HCC (83.2%), 12 (9%) had non-HCC malignant lesions, and 11 (8%) had benign nodules. The PPV and NPV of the biopsies were 100% and 62%, respectively; 30 biopsies were non-contributive. The PPV and NPV of the LI-RADS categories were 89% and 32.8% for LR-5 and 85.5% and 54.5% for LR-4 + 5 + TIV, respectively. The PPV and NPV of the 2011 AASLD criteria were 93.2% and 35.6%, respectively. The interobserver kappa (k = 0.380) for the LR-5 categories was reasonable. Of 100 LR-5 nodules, 11 were misclassified, in particular one case was a colorectal metastasis, and two cases were cholangiocarcinomas, of which nine were identified through biopsy, whereas six were correctly classified according to LI-RADS (LR-M or LR-TIV). Fifty percent of macrotrabecular HCC and 48.4% of poorly differentiated HCC (Edmonson 3 and 4) were not classified as LR-5. Conclusions: LI-RADS 2018 did not outperform the AASLD 2011 score as a non-invasive diagnosis of HCC. Tumor biopsy allowed restoration of an accurate diagnosis in 11% of LR-5 cases. A combined radiological and histological diagnosis should be considered mandatory for good treatment assessment. Impact and Implications: Although biopsy is not required for hepatocellular carcinoma diagnosis when the LI-RADS criteria are met according to current guidelines, our study underscores the limits of radiology and the need for biopsy when hepatocellular carcinoma is suspected. Histological findings could change therapeutics of liver tumors even if only for a small proportion of patients. Histological proof of the type of cancer is a standard in oncology.

Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8+ Lymphocyte Repopulation in Hepatocellular Carcinoma.

BACKGROUND: Palmitoyl-protein thioesterase-1 (PPT1) is a clinical stage druggable target for inhibiting autophagy in cancer. OBJECTIVE: We aimed to determine the cellular and molecular activity of targeting PPT1 using ezurpimtrostat, in combination with an anti-PD-1 antibody. METHODS: In this study we used a transgenic immunocompetent mouse model of hepatocellular carcinoma. RESULTS: Herein, we revealed that inhibition of PPT1 using ezurpimtrostat decreased the liver tumor burden in a mouse model of hepatocellular carcinoma by inducing the penetration of lymphocytes into tumors when combined with anti-programmed death-1 (PD-1). Inhibition of PPT1 potentiates the effects of anti-PD-1 immunotherapy by increasing the expression of major histocompatibility complex (MHC)-I at the surface of liver cancer cells and modulates immunity through recolonization and activation of cytotoxic CD8+ lymphocytes. CONCLUSIONS: Ezurpimtrostat turns cold tumors into hot tumors and, thus, could improve T cell-mediated immunotherapies in liver cancer.

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study.

PURPOSE: GEMPAX was an open-label, randomized phase III clinical trial designed to assess the efficacy and tolerability of gemcitabine plus paclitaxel versus gemcitabine alone as second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received 5-fluorouracil, oxaliplatin, and irinotecan. METHODS: Patients with histologically or cytologically confirmed mPDAC were randomly assigned (2:1) to receive GEMPAX (paclitaxel 80 mg/m2 + gemcitabine 1,000 mg/m2; IV; once at day (D) 1, D8, and D15/arm A) or gemcitabine (arm B) alone once at D1, D8, and D15 every 28 days until progression, toxicity, or patient's decision. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), quality of life, and safety. RESULTS: Overall, 211 patients (median age, 64 [30-86] years; 62% male) were included. After a median study follow-up for alive patients of 13.4 versus 13.8 months in arm A versus arm B, the median OS (95% CI) was 6.4 (5.2 to 7.4) versus 5.9 months (4.6 to 6.9; hazard ratio [HR], 0.87 [0.63 to 1.20]; P = 0.4095), the median PFS was 3.1 (2.2 to 4.3) versus 2.0 months (1.9 to 2.3; HR, 0.64 [0.47 to 0.89]; P = 0.0067), and the ORR was 17.1% (11.3 to 24.4) versus 4.2% (0.9 to 11.9; P = 0.008) in arm A versus arm B, respectively. Overall, 16.7% of patients in arm A and 2.9% in arm B discontinued their treatment because of adverse events (AEs). One grade 5 AE associated with both gemcitabine and paclitaxel was reported in arm A (acute respiratory distress), and 58.0% versus 27.1% of patients experienced grade ≥3 treatment-related AEs in arm A versus arm B, among which 15.2% versus 4.3% had anemia, 15.9% versus 15.7% had neutropenia, 19.6% versus 4.3% had thrombocytopenia, 10.1% versus 2.9% had asthenia and 12.3% versus 0.0% had neuropathy. CONCLUSION: While GEMPAX did not meet the primary end point of OS versus gemcitabine alone in patients with mPDAC in the second-line setting, both PFS and ORR were significantly improved.

Biliary tract cancers: French national clinical practice guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, AFEF, SFRO, SFP, SFR, ACABi, ACHBPT).

INTRODUCTION: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023. RESULTS: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date. CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

Pemigatinib for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements: A joint analysis of the French PEMI-BIL and Italian PEMI-REAL cohort studies.

BACKGROUND: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting. MATERIAL AND METHODS: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included. RESULTS: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs. CONCLUSIONS: These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

Cholangiocarcinoma: what are the options in all comers and how has the advent of molecular profiling opened the way to personalised medicine ?

Cholangiocarcinoma is a deadly cancer comprising very heterogenous subtypes with a limited therapeutic arsenal in all comers. However, recent significant advances were made with immunotherapy in the first-line treatment of advanced cholangiocarcinoma, with the addition of durvalumab to cisplatin-gemcitabine chemotherapy showing a survival benefit. In the second line setting, only FOLFOX (5FU/folinic acid-oxaliplatin) is validated by a phase 3 trial, yet with a very modest benefit on survival; new options using 5FU with nanoliposomal-irinotecan may emerge in the next few years. The advent of molecular profiling in advanced cholangiocarcinoma in the last decade revealed frequent targetable alterations such as IDH1 mutations, FGFR2 fusions or rearrangements, HER2 amplification, BRAF V600E mutation and others. This strategy opened the way to personalised medicine for patients which are still fit after first-line treatment and the use of targeted inhibitors in first line constitutes a huge challenge with many ongoing trials to improve patients' care. This review exposes the recent clinical trial findings in non-molecularly selected advanced cholangiocarcinoma, offers a focus on how systematic molecular screening should be structured to allow patients to access to personalised medicine, and details which are the therapeutic options accessible in case of actionable alteration.

Quality of life of patients with solid malignancies at 3 months after unplanned admission in the intensive care unit: A prospective case-control study.

BACKGROUND: Although short- and long-term survival in critically ill patients with cancer has been described, data on their quality of life (QoL) after an intensive care unit (ICU) stay are scarce. This study aimed to determine the impact of an ICU stay on QoL assessed at 3 months in patients with solid malignancies. METHODS: A prospective case-control study was conducted in three French ICUs between February 2020 and February 2021. Adult patients with lung, colorectal, or head and neck cancer who were admitted in the ICU were matched in a 1:2 ratio with patients who were not admitted in the ICU regarding their type of cancer, curative or palliative anticancer treatment, and treatment line. The primary endpoint was the QoL assessed at 3 months from inclusion using the mental and physical components of the Short Form 36 (SF-36) Health Survey. The use of anticancer therapies at 3 months was also evaluated. RESULTS: In total, 23 surviving ICU cancer patients were matched with 46 non-ICU cancer patients. Four patients in the ICU group did not respond to the questionnaire. The mental component score of the SF-36 was higher in ICU patients than in non-ICU patients: median of 54 (interquartile range: 42-57) vs. 47 (37-52), respectively (p = 0.01). The physical component score of the SF-36 did not differ between groups: 35 (31-47) vs. 42 (34-47) (p = 0.24). In multivariate analysis, no association was found between patient QoL and an ICU stay. A good performance status and a non-metastatic cancer at baseline were independently associated with a higher physical component score. The use of anticancer therapies at 3 months was comparable between the two groups. CONCLUSION: In patients with solid malignancies, an ICU stay had no negative impact on QoL at 3 months after discharge when compared with matched non-ICU patients.

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cells dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cells ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulates lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation loose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo . Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

Biliary cytology: A diagnostic tree for adenocarcinoma based on a cohort of 135 patients with endoscopic retrograde cholangiopancreatography for stenosis of the extrahepatic bile duct.

BACKGROUND: The diagnosis of well-differentiated adenocarcinoma on bile aspiration is a well-known challenge. This study was aimed at improving the diagnostic performance and providing a biliary cytology learning atlas. METHODS: This single-center, retrospective study included 135 cases of informative biliary samples collected between 2009 and 2018 that were classified as benign, atypical, or malignant. A double assessment was performed by a novice and a cytopathologist experienced in biliary cytology to establish the specificities, sensitivities, and inter- and intraobserver κ index agreements of 24 cytological criteria, which were illustrated in a learning atlas. RESULTS: A multivariate logistic regression was used to assess whether the most specific and reproducible criteria were associated with malignancy. A scoring system was statistically determined: 6 points were attributed in the presence of a 3-dimensional (3D) cluster, anisonucleosis, and a nuclear to cytoplasmic (N:C) ratio > 0.5, whereas 4 points were given in the presence of an enhanced nuclear membrane. A score higher than 10 points resulted in a malignancy diagnosis with 96% sensitivity and 97% specificity. CONCLUSIONS: A diagnostic tree of malignancy based on 4 criteria, together with a multidisciplinary approach, allows the diagnosis of adenocarcinoma with a specificity of 100% and a sensitivity of 88% or 72% depending on the presence of a single malignant cell or the presence of 3 combined criteria (a 3D cluster, anisonucleosis, and an N:C ratio > 0.5). It comes with a learning atlas useful for cytopathologist training and accuracy in this uncommon cytology.