Applications of single-cell multi-omics in liver cancer.

Primary liver cancer, more specifically hepatocellular carcinoma (HCC), remains a significant global health problem associated with increasing incidence and mortality. Clinical, biological, and molecular heterogeneity are well-known hallmarks of cancer and HCC is considered one of the most heterogeneous tumour types, displaying substantial inter-patient, intertumoural and intratumoural variability. This heterogeneity plays a pivotal role in hepatocarcinogenesis, metastasis, relapse and drug response or resistance. Unimodal single-cell sequencing techniques have already revolutionised our understanding of the different layers of molecular hierarchy in the tumour microenvironment of HCC. By highlighting the cellular heterogeneity and the intricate interactions among cancer, immune and stromal cells before and during treatment, these techniques have contributed to a deeper comprehension of tumour clonality, hematogenous spreading and the mechanisms of action of immune checkpoint inhibitors. However, major questions remain to be elucidated, with the identification of biomarkers predicting response or resistance to immunotherapy-based regimens representing an important unmet clinical need. Although the application of single-cell multi-omics in liver cancer research has been limited thus far, a revolution of individualised care for patients with HCC will only be possible by integrating various unimodal methods into multi-omics methodologies at the single-cell resolution. In this review, we will highlight the different established single-cell sequencing techniques and explore their biological and clinical impact on liver cancer research, while casting a glance at the future role of multi-omics in this dynamic and rapidly evolving field.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: A large real-life worldwide population.

BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

Clinical impact of using [18F]AlF-NOTA-octreotide PET/CT instead of [68Ga]Ga-DOTA-SSA PET/CT: Secondary endpoint analysis of a multicenter, prospective trial.

[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [68Ga]Ga-DOTA-SSA or [18F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [18F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [68Ga]Ga-DOTA-SSA, the use of [18F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [18F]AlF-OC. The use of [18F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.

Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.

PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma.

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell-cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.

Intra-individual qualitative and quantitative comparison of [68Ga]Ga-DOTATATE PET/CT and PET/MRI.

Background: Somatostatin receptor (SSTR) positron emission tomography (PET) is a cornerstone of neuroendocrine tumor (NET) management. Hybrid PET/magnetic resonance imaging (MRI) is now available for NET-imaging, next to PET/computed tomography (CT). Objectives: To determine whether CT or MRI is the best hybrid partner for [68Ga]Ga-DOTATATE PET. Design: Monocentric, prospective study. Methods: Patients received a same-day [68Ga]Ga-DOTATATE PET/CT and subsequent PET/MRI, for suspicion of NET, (re)staging or peptide receptor radionuclide therapy-selection. The union (PETunion) of malignant lesions detected on PETCT and PETMRI was the reference standard. Concordance of detection of malignant lesions in an organ was measured between PETunion and CT and PETunion and MRI. Seven bins were used to categorize the number of malignant lesions, containing following ordinal variables: 0, 1, 2-5, 6-10, 11-20, >20 countable and diffuse/uncountable. The difference in number of malignant lesions was obtained as the difference in bin level ('Δbin') between PETunion and CT and PETunion and MRI with a Δbin closer to zero implying a higher concordance rate. Results: Twenty-nine patients were included. Primary tumors included 17 gastroenteropancreatic-NETs, 1 colon neuroendocrine carcinoma, 7 lung-NETs and 2 meningiomas. Patient level concordance with PETunion was 96% for MRI and 67% for CT (p = 0.039). Organ level concordance with PETunion was 74% for MRI and 40% for CT (p < 0.0001). In bone, there was a higher concordance rate for MRI compared to CT, 92% and 33%, respectively (p = 0.016). Overall, a mean Δbin of 0.5 ± 1.1 for PETunion/MRI and 1.4 ± 1.2 for PETunion/CT (p < 0.0001) was noted. In liver, a mean Δbin of 0.0 ± 1.1 for PETunion/MRI and 1.7 ± 1.2 for PETunion/CT was observed (p = 0.0078). In bone, a mean Δbin closer to zero was observed for PETunion/MRI compared to PETunion/CT, 0.6 ± 1.4 and 2.0 ± 1.5, respectively (p = 0.0098). Conclusions: Compared to SSTR PET/CT, SSTR PET/MRI had a higher patient and organ level concordance for malignant tumoral involvement and number of malignant lesions, with a clear added value in bone and liver specifically.

Prospective comparison of [18F]AlF-NOTA-octreotide PET/MRI to [68Ga]Ga-DOTATATE PET/CT in neuroendocrine tumor patients.

BACKGROUND: Fluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [18F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [18F]AlF-OC PET/CT outperforms [68Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [18F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [18F]AlF-OC ("incremental lesions"). METHODS: Ten patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [68Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [18F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient. RESULTS: In total, 195 unique lesions were detected: 167 with [68Ga]Ga-DOTATATE and 193 with [18F]AlF-OC. The DR for [18F]AlF-OC was 99.1% versus 91.4% for [68Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [18F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [18F]AlF-OC, of which 91% were confirmed by MRI and considered true positives. CONCLUSION: The DR of [18F]AlF-OC was numerically higher and non-inferior to the DR of [68Ga]Ga-DOTATATE. [18F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [18F]AlF-OC as a new alternative for SSTR PET in clinical practice. Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta. CLINICALTRIALS: gov/study/NCT04552847.

18F-Labeled Somatostatin Analogs as PET Tracers for the Somatostatin Receptor: Ready for Clinical Use.

Molecular imaging of the somatostatin receptor plays a key role in the clinical management of neuroendocrine tumors. PET imaging with somatostatin analogs (SSAs) labeled with 68Ga or 64Cu is currently the gold standard in clinical practice. However, widespread implementation of 68Ga imaging is often hampered by practical and economic issues related to 68Ge/68Ga generators. 18F offers several advantages to tackle these issues. Recent developments in radiochemistry have allowed a shift from 68Ga toward 18F labeling, leading to promising clinical translations of 18F-labeled SSAs, such as Gluc-Lys-[18F]FP-TOCA, [18F]F-FET-ßAG-TOCA, [18F]AlF-NOTA-octreotide, [18F]SiTATE, and [18F]AlF-NOTA-JR11. This review gives an update of currently available clinical data regarding 18F-labeled SSA tracers and provides justification for the clinical application of this class of tracers.

Therapeutic yield of extensive molecular profiling in cholangiocarcinoma: a retrospective single-center study.

INTRODUCTION: Current available systemic therapies for advanced cholangiocarcinoma (CCA) are of limited effectiveness and prognosis is poor. Recently, introduction of next-generation sequencing (NGS) technologies led to a better understanding of the genetic pathophysiology and, consequently, identification of molecular alterations for targeted treatment. AIM: To determine the proportion of actionable alterations using extensive molecular profiling in a routine diagnostic setting and to study the effect of targeted treatment on disease control. METHODS: Results of extensive molecular testing by either FoundationOne NGS or an in-house developed 96 cancer gene panel were retrospectively collected from patients with locally advanced or metastatic CCA diagnosed between 01/12/2018 and 01/08/2021 in a single center. Gene variants were classified according to ESCAT and correlated with efficacy endpoints. RESULTS: Of 125 patients included, 65 patients had an intrahepatic CCA (iCCA). FGFR2 fusions and IDH1/BAP1 mutations were more frequent in iCCA, while KRAS and SMAD4 mutations were predominant in extrahepatic CCA (eCCA). Targetable alterations (ESCAT tiers I-IV) were identified in 73,6% of patients. Overall survival was significantly better for higher tiers regardless of treatment. Thirteen patients (10.4%) received targeted treatment based on molecular profiling, with a median progression-free survival (PFS) of 7.3 months. CONCLUSIONS: Extensive molecular characterization led to the identification of targetable and potentially targetable alterations in a significant proportion of patients with locally advanced or metastatic CCA. We confirmed the association between higher ESCAT tier and benefit of a targeted treatment. Molecular analysis should therefore be considered in all patients fit enough for systemic treatment.

Position statement on the management of the immune checkpoint inhibitor-induced colitis via multidisciplinary modified Delphi consensus.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) in cancer immunotherapy has shown increased overall survival in a wide range of cancer types with the associated risk of developing severe immune-mediated adverse events, commonly involving the gastrointestinal tract. AIM: The aim of this position statement is to provide an updated practice advice to the gastroenterologists and oncologists on the diagnosis and management of ICI-induced gastrointestinal toxicity. METHODOLOGY: The evidence reviewed in this paper includes a comprehensive search strategy of English language publications. Consensus was reached using a three-round modified Delphi methodology and approved by the members of the Belgian Inflammatory Bowel Disease Research and Development Group (BIRD), Belgian Society of Medical Oncology (BSMO), Belgian group of Digestive Oncology (BGDO), and Belgian Respiratory Society (BeRS). CONCLUSIONS: The management of ICI-induced colitis requires an early multidisciplinary approach. A broad initial assessment is necessary (clinical presentation, laboratory markers, endoscopic and histologic examination) to confirm the diagnosis. Criteria for hospitalisation, management of ICIs, and initial endoscopic assessment are proposed. Even if corticosteroids are still considered the first-line therapy, biologics are recommended as an escalation therapy and as early treatment in patients with high-risk endoscopic findings.

Considerations for individualized first-line systemic treatment in advanced hepatocellular carcinoma.

Primary liver cancer is the third most common cause of cancer-related death worldwide and hepatocellular carcinoma (HCC) accounts for approximately 80%-90% of all primary liver malignancies. Until 2007, there was no effective treatment option available for patients diagnosed with advanced HCC, whereas today, both multireceptor tyrosine kinase inhibitors as well as immunotherapy combinations have entered clinical practice. The choice between the different options is a tailor-made decision to match the efficacy and safety data of the clinical trials with the specific patient and disease profile. This review provides clinical stepstones to make an individualized decision for every patient with its specific tumor and liver characteristics in mind.

Development of a Patient Decision Aid for Rectal Cancer Patients with Clinical Complete Response after Neo-Adjuvant Treatment.

Surgery is the primary component of curative treatment for patients with rectal cancer. However, patients with a clinical complete response (cCR) after neo-adjuvant treatment may avoid the morbidity and mortality of radical surgery. An organ-sparing strategy could be an oncological equivalent alternative. Therefore, shared decision making between the patient and the healthcare professional (HCP) should take place. This can be facilitated by a patient decision aid (PtDA). In this study, we developed a PtDA based on a literature review and the key elements of the Ottawa Decision Support Framework. Additionally, a qualitative study was performed to review and evaluate the PtDA by both HCPs and former rectal cancer patients by a Delphi procedure and semi-structured interviews, respectively. A strong consensus was reached after the first round (I-CVI 0.85-1). Eleven patients were interviewed and most of them indicated that using a PtDA in clinical practice would be of added value in the decision making. Patients indicated that their decisional needs are centered on the impact of side effects on their quality of life and the outcome of the different options. The PtDA was modified taking into account the remarks of patients and HCPs and a second Delphi round was held. The second round again showed a strong consensus (I-CVI 0.87-1).

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAFV600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAFV600E-mutated mCRC. METHODS: In this multicenter, open-label, single-arm study, patients with BRAFV600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m2 once on day 1 of cycle 1, then 250 mg/m2 once weekly for the first seven cycles, and 500 mg/m2 once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAFV600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421).

Unraveling the Synergy between Atezolizumab and Bevacizumab for the Treatment of Hepatocellular Carcinoma.

Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome.

18F-AlF-NOTA-Octreotide Outperforms 68Ga-DOTATATE/NOC PET in Neuroendocrine Tumor Patients: Results from a Prospective, Multicenter Study.

18F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18F-AlF-NOTA-octreotide (18F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18F-AlF-OC compared with 68Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68Ga-DOTATATE (n = 56) or 68Ga-DOTANOC (n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18F-AlF-OC and 68Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10-5). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUVmax were observed (P = 0.067), but mean tumor-to-background ratio was significantly higher with 18F-AlF-OC than with 68Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.

[68Ga]Ga-DOTATATE-avid tumor volume, uptake and inflammation-based index correlate with survival in neuroendocrine tumor patients treated with [177Lu]Lu-DOTATATE PRRT.

To meet the increasing demand for PRRT in the treatment of patients with inoperable/disseminated well-differentiated neuroendocrine tumors (NETs) and to guide optimization strategies, adequate and accessible predictive tools that allow to stratify patients who will benefit from treatment from those who will not are becoming indispensable. Previously, we have investigated the role of baseline [68Ga]Ga-DOTATOC PET tumor uptake and volumetric parameters and a blood-derived inflammatory biomarker, the inflammation-based index (IBI), for outcome prediction in NET patients treated with [90Y]Y-DOTATOC. In this retrospective study in 83 NET patients treated with [177Lu]Lu-DOTATATE in a routine clinical setting, we aimed to evaluate the generalizability of our previous findings to [177Lu]Lu-DOTATATE treatment combined with a pre-therapeutic [68Ga]Ga-DOTATATE PET. A semi-automatic customized SUV threshold-based approach was used for tumor delineation. The previously identified SUVmean cut-off of 13.7 for better survival could not be applied to this patient cohort. Instead, a more optimal cut-off could be identified: an SUVmean lower or equal than 11.2 was associated with worse overall survival (OS) (hazard ratio (HR) 2.28; P = 0.008). Also in line with our previous study, a [68Ga]Ga-DOTATATE-avid tumor volume (TV) higher than 672 mL and an elevated baseline IBI were correlated with worse OS (HR 3.13 (P = 0.0001) and HR 2.00 (P = 0.034), respectively). Multivariate analysis confirmed independent associations between OS and baseline IBI (P = 0.032), SUVmean (P = 0.027) and [68Ga]Ga-DOTATATE-avid TV (P = 0.001). Taking baseline IBI, [68Ga]Ga-DOTATATE-avid TV and [68Ga]Ga-DOTATATE uptake into account may help guide PRRT treatment decisions.

Pleural decortication and hyperthermic intrathoracic chemotherapy for pseudomyxoma.

Aim: Pleural dissemination of pseudomyxoma peritonei (PMP) is an extremely rare diagnosis, for which no standard therapy is available.Methods: We describe the successful treatment of a 67-year-old male diagnosed with left-sided intrapleural dissemination of PMP (low-grade appendiceal mucinous neoplasm), 2 years after treatment of abdominal PMP with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy. Treatment consisted of extended pleural decortication (ePD) and oxaliplatin-based hyperthermic intrathoracic chemotherapy (HITHOC). The patient is doing well without complications or signs of recurrence, 26 months after thoracic surgery.Conclusion: ePD in combination with HITHOC is a valuable treatment for thoracic PMP.

Nonoperative versus operative approach according to the response to neoadjuvant chemoradiotherapy for rectal cancer: A prospective cohort study.

Purpose: To report on organ preservation following chemoradiotherapy (CRT) in a prospective cohort of locally advanced rectal cancer patients. Methods and materials: Fifty-two patients received CRT. MRI and 18F-FDG-PET/CT were performed prior to CRT. Response assessment was done 6 and 12 weeks after CRT using digital rectal examination, MRI, 18F-FDG-PET/CT and endoscopy. For clinical complete response or minimal residual disease, a watch-and-wait (W&W) protocol was started.Regrowth-free survival (ReFS), Total Mesorectal Excision-free disease-free survival, distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier method. Functional outcome was compared with the Wilcoxon signed-rank test using EORTC QLQ-C30, MSKCC BFI, LARS and IIEF-5/FSFI-5 questionnaires. A previously developed prediction model performance was tested using receiver operating characteristic analysis. Results: 29/52 patients entered a W&W protocol. There was no difference in two-year DMFS (81.1 % vs 78.8 %, p = 0.82), two-year OS (96.4 % vs 100 %, p = 0.38) and two-year DFS (77.5 % vs 78.8 %, p = 0.87) between W&W patients and those who underwent surgery at 12 weeks after CRT. Two-year DMFS differed between W&W with local regrowth, W&W with sustained response and patients who had surgery (66.7 % vs 88.0 % vs 78.8 %; p = 0.04). At 6 and 12 months, W&W patients reported good QoL and bowel function. The model validation reached an AUC of 0.627. Conclusion: Good functional outcome in patients with rectal cancer allocated to surveillance after CRT needs to be balanced against potentially worse DMFS in a subset of patients without sustained clinical complete response. Reliable prediction of patients eligible for surveillance programs needs further investigation.