Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors and CAR-T Cell Therapy: A Comprehensive Imaging-Based Review.

Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers-including tumor progression, pseudoprogression, inflammation, and infection-to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events.

A pharmacist-led interprofessional medication adherence program improved adherence to oral anticancer therapies: The OpTAT randomized controlled trial.

BACKGROUND: Oral anticancer therapies such as protein kinase inhibitors (PKIs) are increasingly prescribed in cancer care. We aimed to evaluate the impact of a pharmacist-led interprofessional medication adherence program (IMAP) on patient implementation (dosing history), persistence (time until premature cessation of the treatment) and adherence to 27 PKIs prescribed for various solid cancers, as well as the impact on patients' beliefs about medicines (BAM) and quality of life (QoL). METHODS: Patients (n = 118) were randomized 1:1 into two arms. In the intervention arm, pharmacists supported patient adherence through monthly electronic and motivational feedback, including educational, behavioral and affective components, for 12 months. The control arm received standard care plus EM without intervention. All PKIs were delivered in electronic monitors (EMs). Medication implementation and adherence were compared between groups using generalized estimating equation models, in which relevant covariables were included; persistence was compared with Kaplan‒Meier curves. Information on all treatment interruptions was compiled for the analysis. Questionnaires to evaluate BAM and QoL were completed among patients who refused and those who accepted to participate at inclusion, 6 and 12 months post-inclusion or at study exit. RESULTS: Day-by-day PKI implementation was consistently higher and statistically significant in the intervention arm (n = 58) than in the control arm (n = 60), with 98.1% and 95.0% (Δ3.1%, 95% confidence interval (CI) of the difference 2.5%; 3.7%) implementation at 6 months, respectively. The probabilities of persistence and adherence were not different between groups, and no difference was found between groups for BAM and QoL scores. No difference in BAM or QoL was found among patients who refused versus those who participated. The intervention benefited mostly men (at 6 months, Δ4.7%, 95% CI 3.4%; 6.0%), those younger than 60 years (Δ4.0%, 95% CI 3.1%; 4.9%), those who had initiated PKI more than 60 days ago before inclusion (Δ4.5%, 95% CI 3.6%; 5.4%), patients without metastasis (Δ4.5%, 95% CI 3.4%; 5.7%), those who were diagnosed with metastasis more than 2 years ago (Δ5.3%, 95% CI 4.3%; 6.4%) and those who had never used any adherence tool before inclusion (Δ3.8%, 95% CI 3.1%; 4.5%). CONCLUSIONS: The IMAP, led by pharmacists in the context of an interprofessional collaborative practice, supported adherence, specifically implementation, to PKIs among patients with solid cancers. To manage adverse drug events, PKI transient interruptions are often mandated as part of a strategy for treatment and adherence optimization according to guidelines. Implementation of longer-term medication adherence interventions in the daily clinic may contribute to the improvement of progression-free survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484064.

Treatment of Metastatic Biliary Cancers With Irinotecan and 5-Fluorouracil Based Chemotherapy After Platinum/Gemcitabine Progression: A Systematic Review and Meta-Analysis.

BACKGROUND: Biliary tract carcinomas are cancers that, despite a lower prevalence compared with other gastrointestinal cancers, represent a significant public health burden due to their aggressiveness. The metastatic stage of the disease is highly lethal and difficult to treat. Options of systemic therapies, especially beyond the first line are few and less well established. METHODS: We performed a systematic review of literature databases to identify studies of the combination of irinotecan and 5-fluorouracil (5-FU) based chemotherapy as treatment of metastatic biliary tract carcinomas in second line, after first line treatment with platinum/gemcitabine chemotherapy. Both prospective and retrospective designs were admissible. A meta-analysis of identified studies to determine summary estimates for overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) was also performed. RESULTS: The search was performed in PubMed/Medline and in Embase databases and identified a total of 339 articles. Manual review resulted in 8 articles that were eligible for inclusion in the meta-analysis. Second line irinotecan/5-FU based combinations produced an ORR of 9.1% (95% CI, 5.5%-12.6%) and DCR of 43.3% (95% CI, 15.8%-70.8%). Summary PFS and OS were 2.7 months (95% CI, 2.3-3.1 months) and 6.8 months (95% CI, 5.6-8.0 months), respectively. Treatments appeared to be feasible with adverse effect profiles as expected from the combination. CONCLUSION: A moderate activity of second line irinotecan/5-FU based chemotherapy was observed in this meta-analysis. The combination is an option for patients progressing on platinum/gemcitabine chemotherapy, who maintain a sufficient general status to receive active therapy. This combination may also serve as the control arm of second line trials with new targeted agents.

Anatomical Quantitative Volumetric Evaluation of Liver Segments in Hepatocellular Carcinoma Patients Treated with Selective Internal Radiation Therapy: Key Parameters Influencing Untreated Liver Hypertrophy.

Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT using an anatomical volumetric approach in hepatocellular carcinoma (HCC) patients with different levels of treatment selectivity and evaluate the parameters affecting those changes. This retrospective, single-institution, IRB-approved study included 88 HCC patients. Whole liver, liver segments, tumor burden, and spleen volumes were quantified on MRI at baseline and 3/6/12 months post-SIRT using a segmentation-based 3D software relying on liver vascular anatomy. Treatment characteristics, longitudinal clinical/laboratory, and imaging data were analyzed. The Student's t-test and Wilcoxon test evaluated volumetric parameters evolution. Spearman correlation was used to assess the association between variables. Uni/multivariate analyses investigated factors influencing untreated liver volume (uLV) increase. Results: Most patients were cirrhotic (92%) men (86%) with Child-Pugh A (84%). Absolute and relative uLV kept increasing at 3/6/12 months post-SIRT vs. baseline (all, p ≤ 0.005) and was maximal during the first 6 months. Absolute uLV increase was greater in Child-Pugh A5/A6 vs. ≥B7 at 3 months (A5, p = 0.004; A6, p = 0.007) and 6 months (A5, p = 0.072; A6, p = 0.031) vs. baseline. When the Child-Pugh class worsened at 3 or 6 months post-SIRT, uLV did not change significantly, whereas it increased at 3/6/12 months vs. baseline (all p ≤ 0.015) when liver function remained stable. The Child-Pugh score was inversely correlated with absolute and relative uLV increase at 3 months (rho = -0.21, p = 0.047; rho = -0.229, p = 0.048). In multivariate analysis, uLV increase was influenced at 3 months by younger age (p = 0.013), administered 90Y activity (p = 0.003), and baseline spleen volume (p = 0.023). At 6 months, uLV increase was impacted by younger age (p = 0.006), whereas treatment with glass microspheres (vs. resin) demonstrated a clear trend towards better hypertrophy (f = 3.833, p = 0.058). The amount (percentage) of treated liver strongly impacted the relative uLV increase at 3/6/12 months (all f ≥ 8.407, p ≤ 0.01). Conclusion: Liver function (preserved baseline and stable post-SIRT) favored uLV hypertrophy. Younger patients, smaller baseline spleen volume, higher administered 90Y activity, and a larger amount of treated liver were associated with a higher degree of untreated liver hypertrophy. These factors should be considered in surgical candidates undergoing neoadjuvant SIRT.

CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas.

CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here, we generated a genome-wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild-type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation.

[Oncology: what's new in 2023]. / Oncologie: ce qui a changé en 2023.

The oncology field continues its remarkable evolution over the years, with promising advances leading to innovative and individualized treatments. The development of new molecules, the identification of new therapeutic targets and the search for new sequences or combinations promise to revolutionize cancer treatments and contribute to improving survival rates, patients' quality of life and to open new perspective in oncology research. In this article, the newest data released in 2023 are reviewed.

Le domaine de l'oncologie poursuit son évolution remarquable au fil des années, avec des avancées prometteuses ouvrant la voie à des traitements novateurs et individualisés. L'élaboration de nouvelles molécules, l'identification de nouvelles cibles thérapeutiques et la recherche de nouvelles séquences ou combinaisons de traitements promettent de révolutionner la prise en charge du cancer et de contribuer à améliorer les taux de survie, la qualité de vie des patients et à ouvrir de nouvelles perspectives dans la recherche en oncologie. Dans cet article, les nouveautés parues en 2023 sont passées en revue.

A Review of Ultrasound-Mediated Checkpoint Inhibitor Immunotherapy.

Over the past decade, immunotherapy has emerged as a major modality in cancer medicine. However, despite its unprecedented success, immunotherapy currently benefits only a subgroup of patients, may induce responses of limited duration and is associated with potentially treatment-limiting side effects. In addition, responses to immunotherapeutics are sometimes diminished by the emergence of a complex array of resistance mechanisms. The efficacy of immunotherapy depends on dynamic interactions between tumour cells and the immune landscape in the tumour microenvironment. Ultrasound, especially in conjunction with cavitation-promoting agents such as microbubbles, can assist in the uptake and/or local release of immunotherapeutic agents at specific target sites, thereby increasing treatment efficacy and reducing systemic toxicity. There is also increasing evidence that ultrasound and/or cavitation may themselves directly stimulate a beneficial immune response. In this review, we summarize the latest developments in the use of ultrasound and cavitation agents to promote checkpoint inhibitor immunotherapy.

[Diagnosis and management of tenosynovial giant cell tumor]. / Diagnostic et prise en charge de la tumeur à cellules géantes ténosynoviale.

Tenosynovial giant cell tumor is a benign condition that originates from synovial cells within joints, tendon sheaths, or bursae and may present either in localized (benign) or diffuse (locally aggressive) forms. Currently, the primary treatment approach is surgical, yielding satisfactory results with low recurrence rates in the localized forms, whereas the diffuse type displays high recurrence rates. In parallel, clinical trials are underway to explore pharmaceutical treatment options for the advanced diffuse type. This article aims at consolidating current knowledge about diagnosis and management of this rare tumor, additionally proposing a brief overview of novel therapeutic approaches.

La tumeur à cellules géantes ténosynoviale, bénigne, prend son origine dans les cellules synoviales des articulations, des gaines tendineuses ou des bourses et se présente dans une forme soit localisée (bénigne), soit diffuse (localement agressive). Le traitement principal est chirurgical, offrant des résultats satisfaisants à long terme, avec un faible risque de récidive dans la forme localisée, alors que le taux de récidives est élevé dans la forme diffuse. Parallèlement, des essais cliniques sont en cours pour explorer des options de traitement systémique pour les formes diffuses sévères. Cet article rappelle les connaissances actuelles pour le diagnostic et la prise en charge de cette tumeur rare. De plus, nous proposons un aperçu succinct des nouvelles approches thérapeutiques.

99mTc-macroaggregated albumin SPECT/CT predictive dosimetry and dose-response relationship in uveal melanoma liver metastases treated with first-line selective internal radiation therapy.

First-line selective internal radiation therapy (SIRT) showed promising outcomes in patients with uveal melanoma liver metastases (UMLM). Patient survival depends on liver's disease control. SIRT planning is essential and little is known about dosimetry. We investigated whether 99mTc-MAA-SPECT/CT dosimetry could predict absorbed doses (AD) evaluated on 90Y-PET/CT and assess the dose-response relationship in UMLM patients treated with first-line SIRT. This IRB-approved, single-center, retrospective analysis (prospectively collected cohort) included 12 patients (median age 63y, range 43-82). Patients underwent MRI/CT, 18F-FDG-PET/CT before and 3-6 months post-SIRT, and 90Y-PET/CT immediately post-SIRT. Thirty-two target lesions were included. AD estimates in tumor and non-tumor liver were obtained from 99mTc-MAA-SPECT/CT and post-SIRT 90Y-PET/CT, and assessed with Lin's concordance correlation coefficients (ρc and Cb), Pearson's coefficient correlation (ρ), and Bland-Altman analyses (mean difference ± standard deviation; 95% limits-of-agreement (LOA)). Influence of tumor characteristics and microsphere type on AD was analyzed. Tumor response was assessed according to size-based, enhancement-based and metabolic response criteria. Mean target lesion AD was 349 Gy (range 46-1586 Gy). Concordance between 99mTc-MAA-SPECT/CT and 90Y-PET/CT tumor dosimetry improved upon dose correction for the recovery coefficient (RC) (ρ = 0.725, ρc = 0.703, Cb = 0.969) with good agreement (mean difference: - 4.93 ± 218.3 Gy, 95%LOA: - 432.8-422.9). Without RC correction, concordance was better for resin microspheres (ρ = 0.85, ρc = 0.998, Cb = 0.849) and agreement was very good between predictive 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (mean difference: - 4.05 ± 55.9 Gy; 95%LOA: - 113.7-105.6). After RC correction, 99mTc-MAA-SPECT/CT dosimetry overestimated AD (- 70.9 ± 158.9 Gy; 95%LOA: - 382.3-240.6). For glass microspheres, concordance markedly improved with RC correction (ρ = 0.790, ρc = 0.713, Cb = 0.903 vs without correction: ρ = 0.395, ρc = 0.244, Cb = 0.617) and 99mTc-MAA-SPECT/CT dosimetry underestimated AD (148.9 ± 267.5 Gy; 95%LOA: - 375.4-673.2). For non-tumor liver, concordance was good between 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (ρ = 0.942, ρc = 0.852, Cb = 0.904). 99mTc-MAA-SPECT/CT slightly overestimated liver AD for resin (3.4 ± 3.4 Gy) and glass (11.5 ± 13.9 Gy) microspheres. Tumor AD was not correlated with baseline or post-SIRT lesion characteristics and no dose-response threshold could be identified. 99mTc-MAA-SPECT/CT dosimetry provides good estimates of AD to tumor and non-tumor liver in UMLM patients treated with first-line SIRT.

Optimal Delivery of Follow-Up Care Following Treatment for Adults Treated for Ewing Sarcoma.

Ewing sarcoma (ES) is a rare, highly malignant sarcoma. It usually presents in the second decade of life; however, patients can be diagnosed as early as newborns and as late as in their seventies. ES is most frequently found in the long bones of the extremities and the pelvis. In older patients, ES can also arise in the soft tissues. Currently, there is no standard schedule for surveillance of adult patients with ES after their initial treatment for localised disease, not only for the early detection of recurrence but also for long-term side effects. Follow-up is based on group recommendations using extrapolated data obtained primarily from studies with paediatric patients. The main objective of this review is to summarise the data available on treatment-associated complications in long-term survivors. Furthermore, we provide a set of recommendations for optimising the follow-up of adults ES survivors, as well as for managing the sequelae that result from intensive multimodal treatment.

Imaging assessment of toxicity related to immune checkpoint inhibitors.

In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management. 18F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.

The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer.

Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for cancer progression by providing background for adaptation to adverse environments and attack by the immune system. Mutations in BRCA1 and BRCA2 genes have been known for decades to predispose to familial breast and ovarian cancers, and, more recently, prostate and pancreatic cancers have been added to the constellation of cancers that show increased prevalence in these families. Cancers associated with these genetic syndromes are currently treated with PARP inhibitors based on the exquisite sensitivity of cells lacking BRCA1 or BRCA2 function to inhibition of the PARP enzyme. In contrast, the sensitivity of pancreatic cancers with somatic BRCA1 and BRCA2 mutations and with mutations in other homologous recombination (HR) repair genes to PARP inhibitors is less established and the subject of ongoing investigations. This paper reviews the prevalence of pancreatic cancers with HR gene defects and treatment of pancreatic cancer patients with defects in HR with PARP inhibitors and other drugs in development that target these molecular defects.

Pancreatic adenocarcinomas without KRAS, TP53, CDKN2A and SMAD4 mutations and CDKN2A/CDKN2B copy number alterations: a review of the genomic landscape to unveil therapeutic avenues.

BACKGROUND: Pancreatic adenocarcinoma is one of the cancers with the worst prognosis. The current treatment paradigm based on combination chemotherapy has improved survival over the last decade, but the disease is still fatal in most cases. New therapies exploiting the increasing understanding of the molecular pathology of the disease are needed. Although the disease presents with few recurrent molecular alterations, these represent opportunities for targeted treatments to be developed. However, a minority of cases are devoid of these common alterations. A description of the molecular landscape of this sub-set of pancreatic adenocarcinoma could uncover other molecular lesions present in them that could serve as therapeutic targets. METHODS: The sub-set of pancreatic cancers without the common alterations in KRAS, TP53, CDKN2A and SMAD4 has been examined from published and publicly available pancreatic cancer cohorts for determination of their clinical and molecular characteristics. The cBioportal platform was used for this evaluation and the OncoKB knowledgebase was used for determination of the functional significance of discovered mutations. RESULTS: About 5% to 10% of pancreatic adenocarcinomas present without the usual molecular alterations that characterize the disease. These cases tend to be genomically stable and have low prevalence of microsatellite or chromosome instability. Molecular alterations that are observed in pancreatic cancers in lower frequencies than the four most prevalent alterations, such as DNA Damage Response and epigenetic modifier mutations, are still observed in the sub-set without the common alterations and may be pathogenically relevant. CONCLUSIONS: Despite the absence of most frequent pancreatic cancer alterations in a sub-set of pancreatic adenocarcinomas, this sub-set possesses other alterations in frequencies similar to the rest of pancreatic cancers. Putative targeting of alterations present is discussed and can serve as the basis for targeted therapies development.

Clear cell sarcoma: state-of-the art and perspectives.

INTRODUCTION: Clear cell sarcoma (CCS) is an ultrarare soft tissue sarcoma (STS) with a poor prognosis due to its propensity to metastasize and its low chemosensitivity. The standard treatment of localized CCS consists of wide surgical excision with or without additive radiotherapy. However, unresectable CCS is generally treated with conventional systemic therapies available for treatment of STS despite the weak scientific evidence to support its use. AREAS COVERED: In this review, we discuss the clinicopathologic characteristics of CSS, as well as the current treatment landscape and future therapeutic approaches. EXPERT OPINION: The current treatment strategy of advanced CCSs, based on STSs regimens, shows a lack of effective options. Combination therapiesin particular, the association of immunotherapy and TKIs, represent a promising approach. Translational studies are needed in order to decipher the regulatory mechanisms involved in the oncogenesis of this ultrarare sarcoma and identify potential molecular targets.

[Oncology: what's new in 2022]. / Oncologie : ce qui a changé en 2022.

The past year has brought several innovations in medical oncology, opening up promising new options for many solid tumors, both localized and metastatic. Immunotherapy, a real spearhead of emerging therapies in metastatic diseases, is seeing its use extend to adjuvant and neoadjuvant modalities, particularly in colon and lung cancers. 2022 also sees a great deal of focus on targeted therapies, as well as on antibody-drug conjugates, which creates new standards in both breast and lung cancers. Here we present the major advances in solid tumors.

L'année écoulée a apporté son lot d'innovations en oncologie médicale, ouvrant de nouvelles options prometteuses pour bon nombre de tumeurs solides, qu'elles soient localisées ou métastatiques. L'immunothérapie, véritable fer de lance des thérapies émergentes dans les maladies métastatiques, voit son usage s'étendre à des modalités adjuvantes et néoadjuvantes, notamment dans les cancers du côlon et du poumon. 2022 donne également la part belle aux thérapies ciblées mais aussi aux conjuguées anticorps-médicaments qui apportent de nouveaux standards tant pour les cancers du sein que du poumon. Nous vous présentons ici les avancées majeures concernant les tumeurs solides.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

A differential process mining analysis of COVID-19 management for cancer patients.

During the acute phase of the COVID-19 pandemic, hospitals faced a challenge to manage patients, especially those with other comorbidities and medical needs, such as cancer patients. Here, we use Process Mining to analyze real-world therapeutic pathways in a cohort of 1182 cancer patients of the Lausanne University Hospital following COVID-19 infection. The algorithm builds trees representing sequences of coarse-grained events such as Home, Hospitalization, Intensive Care and Death. The same trees can also show probability of death or time-to-event statistics in each node. We introduce a new tool, called Differential Process Mining, which enables comparison of two patient strata in each node of the tree, in terms of hits and death rate, together with a statistical significance test. We thus compare management of COVID-19 patients with an active cancer in the first vs. second COVID-19 waves to quantify hospital adaptation to the pandemic. We also compare patients having undergone systemic therapy within 1 year to the rest of the cohort to understand the impact of an active cancer and/or its treatment on COVID-19 outcome. This study demonstrates the value of Process Mining to analyze complex event-based real-world data and generate hypotheses on hospital resource management or on clinical patient care.

First communication on the efficacy of combined 177Lutetium-PSMA with immunotherapy outside prostate cancer.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is a validated treatment option for patients with advanced prostate cancer. Although PSMA expression is not limited to prostate tissue, little is known about its relevance to other types of cancer. Here, we present a case report of a patient with uterine leiomyosarcoma that is progressing while on immunotherapy and treated with 177Lu-PSMA radionuclide therapy. We report for the first time that 177Lu-PSMA radionuclide therapy combined with immunotherapy outside of prostate cancer. We did observe post-treatment reduction of tumor growth rate, although we did not notice disease response based on RECIST criteria. We suggest that 177Lu-PSMA treatment especially combined with immunotherapy may be an option for patients with cancer without other therapeutic options. Insights: 177Lu-PSMA radionuclide therapy should be considered for any tumor stained positive for PSMA.

Organoids: A New Chapter in Sarcoma Diagnosis and Treatment.

Sarcomas are malignant tumors of mesenchymal origin that can occur at any age. The rarity of these tumors in combination with the vast number of histological subtypes render the study of sarcomas challenging. Organoids represent complex three-dimensional cell culture systems, deriving from stem cells and preserving the capacity to differentiate into the cell types of their tissue of origin. The aim of the present review is to study the current status of patient-derived organoids, as well as their potential to model tumorigenesis and perform drug screenings for sarcomas. In order to identify relevant studies, a literature review was conducted and we were able to identify 16 studies published between 2019 and 2022. The current manuscript represents the first comprehensive review of the literature focusing on the use of organoids for disease modelling and drug sensitivity testing in diverse sarcoma subtypes.

Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin.

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients.