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Abstract This study focuses on refining growth-rate-based drug response metrics for patient-derived tumor organoid screening using brightfield live-cell imaging. Traditional metrics like Normalized Growth Rate Inhibition (GR) and Normalized Drug Response (NDR) have been used to assess organoid responses to anticancer treatments but face limitations in accurately quantifying cytostatic and cytotoxic effects across varying growth rates. Here, we introduce the Normalized Organoid Growth Rate (NOGR) metric, specifically developed for brightfield imaging-based assays. A label-free image analysis model was applied to segment organoids precisely, track their growth rates over time, and classify viable and dead organoids. Testing eleven phenotypically distinct pancreatic cancer organoid models with five chemotherapeutics demonstrates that the NOGR metric more effectively captures cytostatic and cytotoxic drug effects compared to existing methods. This approach enhances the biological relevance of drug sensitivity assessments on organoids and offers a valuable tool for advancing personalized cancer treatment strategies.

Summary: Background: Simlukafusp alfa (FAP-IL2v) is an immune cytokine engineered to selectively promote immune responses in the tumour microenvironment. We evaluated the antitumour activity and safety of FAP-IL2v plus atezolizumab in recurrent and/or metastatic cervical squamous cell carcinoma (SCC) in a phase 2 basket study (NCT03386721). Methods: Patients with confirmed metastatic, persistent or recurrent cervical SCC who had progressed on ≥1 anti-cancer therapy and had measurable disease were enrolled. FAP-IL2v 10 mg was administered once every 3 weeks (Q3W) or once weekly (QW) for 4 weeks then once every 2 weeks (Q2W) with the corresponding Q3W or Q2W atezolizumab regimens. The primary endpoint was objective response rate by investigator assessment. Findings: Forty-eight patients were enrolled (Q3W: n = 47; QW/Q2W: n = 1). Among 45 response evaluable patients, objective responses occurred in 12 patients (27%; CI 16.0–41.0), including 3 complete and 9 partial responses. Responses occurred in 6/19 PD-L1 positive patients (32%; 95% CI 15.4–54.0) and 5/24 PD-L1 negative patients (21%; 95% CI 9.2–35.6). Median duration of response was 13.3 months (95% CI 7.6–NE). Median progression-free survival was 3.7 months (95% CI 3.3–9.0). Adverse events (AEs) were consistent with the known safety profile of each drug. AEs leading to withdrawal of either agent occurred in 6 patients (13%). Pronounced expansion and activation of natural killer and CD8 T cells in peripheral blood and increased tumour infiltration and inflammation were observed. Interpretation: FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC. Funding: F. Hoffmann-La Roche Ltd.

PURPOSEMultiple disparities have been recognized in the area of location, gender, and funding for leadership in oncology clinical trials. Understanding their intersectionality is crucial to be able to formulate policies and actions, to ensure research is representative of the global oncology community. Here, data from phase III trials presented at the ASCO Annual Meeting of 2022 (ASCO22) were analyzed.METHODSThe location of institution, gender of lead and senior authors, and funding source for solid tumor phase III trial abstracts presented at the ASCO22 were analyzed. World Bank analytical grouping version 2021-2022 was used to describe regions and countries as high (HIC), upper-middle (UMIC), lower-middle (LoMIC), and low-income (LIC).RESULTSAcross 239 phase III abstracts, lead and senior authors respectively represented HIC institutions in 83% and 85%, UMIC in 13% and 12%, and LoMIC in 4% and 3%. No authors worked in LICs or sub-Saharan Africa. Women accounted for 29% of lead and 23% of senior authors. This distribution persisted across regions, with women as lead authors ranging from 19% (UMIC) to 31% (HIC), and as senior authors from 7% (UMIC) to 25% (HIC). Industry funded 62% of trials, academia 17%, and others 15%; 6% lacked funding. Industry funding was highest in HIC trials (66% for lead and senior authors), followed by UMICs (55% lead, 53% senior) and LoMICs (11% lead, 0% senior). Industry-sponsored trials were proportionally equally represented among female and male senior authors (63% each).CONCLUSIONThere is marked intersectionality in leadership of oncology clinical trials presented at the world's largest oncology conference.

Abstract Background This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF. Methods Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy. Results The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids. Conclusion Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, characterized by a treatment-resistant and invasive nature. In line with these inherent aggressive characteristics, only a subset of patients shows a clinical response to the standard of care therapies, thereby highlighting the need for a more personalized treatment approach. In this study, we comprehensively unraveled the intra-patient response heterogeneity and intrinsic aggressive nature of PDAC on bulk and single-organoid resolution. We leveraged a fully characterized PDAC organoid panel (N = 8) and matched our artificial intelligence-driven, live-cell organoid image analysis with retrospective clinical patient response. In line with the clinical outcomes, we identified patient-specific sensitivities to the standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX) using a growth rate-based and normalized drug response metric. Moreover, the single-organoid analysis was able to detect resistant as well as invasive PDAC organoid clones, which was orchestrates on a patient, therapy, drug, concentration and time-specific level. Furthermore, our in vitro organoid analysis indicated a correlation with the matched patient progression-free survival (PFS) compared to the current, conventional drug response readouts. This work not only provides valuable insights on the response complexity in PDAC, but it also highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and the emerging era of personalized medicine.

Background: There is an unmet medical need for the early detection of immune checkpoint inhibitor (ICI)-induced cardiovascular (CV) adverse events due to a lack of adequate biomarkers. This study aimed to provide insights on the incidence of troponin elevations and echocardiographic dynamics during ICI treatment in cancer patients and their role as potential biomarkers for submyocardial damage. In addition, it is the first study to compare hs-TnT and hs-TnI in ICI-treated patients and to evaluate their interchangeability in the context of screening. Results: Among 59 patients, the mean patient age was 68 years, and 76% were men. Overall, 25% of patients received combination therapy. Although 10.6% [95% CI: 5.0–22.5] of the patients developed troponin elevations, none experienced a CV event. No significant changes were found in 3D left ventricular (LV) ejection fraction nor in global longitudinal strain f (56 ± 6% vs. 56 ± 6%, p = 0.903 and −17.8% [−18.5; −14.2] vs. −17.0% [−18.8; −15.1], p = 0.663) at 3 months. There were also no significant changes in diastolic function and right ventricular function. In addition, there was poor agreement between hs-TnT and hs-TnI. Methods: Here, we present a preliminary analysis of the first 59 patients included in our ongoing prospective clinical trial (NCT05699915) during the first three months of treatment. All patients underwent electrocardiography and echocardiography along with blood sampling at standardized time intervals. This study aimed to investigate the incidence of elevated hs-TnT levels within the first three months of ICI treatment. Elevations were defined as hs-TnT above the upper limit of normal (ULN) if the baseline value was normal, or 1.5 ≥ times baseline if the baseline value was above the ULN. Conclusions: Hs-TnT elevations occurred in 10.6% of the patients. However, no significant changes were found on 3D echocardiography, nor did any of the patients develop a CV event. There were also no changes found in NT-proBNP. The study is still ongoing, but these preliminary findings do not show a promising role for cardiac troponins nor for echocardiographic dynamics in the prediction of CV events during the early stages of ICI treatment.

Abstract Cellular senescence is a state of stable cell-cycle arrest with secretory features in response to cellular stress. Historically, it has been considered as an endogenous evolutionary homeostatic mechanism to eliminate damaged cells, including damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, accumulation of senescent cells can cause long-term detrimental effects, mainly through the senescence-associated secretory phenotype, and paradoxically contribute to age-related diseases including cancer. Besides its role as tumor suppressor, cellular senescence is increasingly being recognized as an in vivo response in cancer patients to various anticancer therapies. Its role in cancer is ambiguous and even controversial, and senescence has recently been promoted as an emerging hallmark of cancer because of its hallmark-promoting capabilities. In addition, the prognostic implications of cellular senescence have been underappreciated due to the challenging detection and sparse in and ex vivo evidence of cellular senescence in cancer patients, which is only now catching up. In this review, we highlight the approaches and current challenges of in and ex vivo detection of cellular senescence in cancer patients, and we discuss the prognostic implications of cellular senescence based on in and ex vivo evidence in cancer patients.

Abstract Background Myocarditis in patients treated with immune checkpoint inhibitors has previously been reported to be rare, though it has most likely been underreported owing to misdiagnosis in the absence of overt clinical presentation. Early detection and characterization of this potentially life-threatening immune-related adverse event is of major importance. Herein we report a case of early-onset myocarditis in an asymptomatic patient treated with dual checkpoint inhibition for metastatic cholangiocarcinoma. Case presentation A 69-year-old male Caucasian patient with metastatic cholangiocarcinoma presented with mild epigastric pain and troponinemia prior to the third dose of dual checkpoint inhibition (ipilimumab 1 mg/kg body weight and nivolumab 3 mg/kg body weight). Initial workup showed no significant abnormalities (physical/neurological examination, electrocardiogram, 72-hour Holter monitoring, and a transthoracic echocardiogram). However, cardiac magnetic resonance imaging revealed a zone of contrast enhancement in the inferior segment of the left ventricular wall indicating a recent episode of myocarditis. Despite steroid initiation (0.5 mg/kg oral prednisolone per day), troponin levels kept increasing, in the absence of coronary disease, for which steroids were increased to 1.5 mg/kg/day. Fluorodeoxyglucose positron emission tomography/computed tomography, 28 days after detecting elevated troponin levels, depicted multiple zones of active myocardial inflammation (basal septal, mid-anterior, and apical inferior). The patient is currently stable, and troponinemia is slowly decreasing while steroids are steadily being tapered. Conclusion As the number of cancers treated with immune checkpoint inhibitors is expanding, the incidence of immune checkpoint inhibitor-induced myocarditis is likely to increase. Moreover, the emerging combination of immune checkpoint inhibitors with non-immune checkpoint inhibitor therapies with potential synergistic cardiotoxic side effects (for example, tyrosine kinase inhibitors) will further complicate the diagnosis of immune-related cardiotoxicity. This case highlights the urgent need for predictive biomarkers to stratify patients at risk and to develop a standardized and multidisciplinary management approach for early diagnosis and treatment of this severe immune-related adverse event.

Next-generation sequencing (NGS) can be used to detect tumor-specific genomic alterations. This retrospective single-center study aims to assess the application of an extensive NGS panel to identify actionable alterations and initiate matched targeted treatment for patients with advanced cancer. We analyzed genomic alterations in solid tumor biopsies from 464 patients with advanced cancer with the Foundation Medicine assay (FoundationOne®CDx). Therapeutic implications were determined using the Memorial Sloan Kettering Precision Oncology Knowledge Base (OncoKB) classification. The FoundationOne®CDx was successfully applied in 464/521 patients (89%). The most common altered genes were TP53 (61%), KRAS (20%), CDKN2A (20%), TERT (16%), and APC (16%). Among the 419 patients with successfully analyzed tumor mutational burden (TMB), 43 patients presented with a high TMB (≥10 mutations/megabase). Out of the 126 patients with an actionable target, 40 patients received matched treatment (32%) of which 17 were within a clinical trial. This study shows that the application of NGS is feasible in an academic center and increases the detection of actionable alterations and identification of patients eligible for targeted treatment or immunotherapy regardless of tumor histology. Strategies such as early referral for NGS, inclusion in clinical (basket) trials, and the development of new targeted drugs are necessary to improve the matched treatment rate.

Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based on anecdotal evidence and expert opinions, due to a lack of solid data and prospective studies. As many questions remain unanswered, cardiac monitoring, in patients receiving ICIs, is not always implemented by oncologists. Hence, an urgent need to investigate the possible short- and long-term CV effects of ICIs, as ICI approval is continuing to expand to the (neo)adjuvant setting. Methods: We have initiated a prospective, multicenter study, i.e., the CAVACI trial, in which a minimum of 276 patients with a solid tumor, eligible for ICI treatment, will be enrolled. The study consists of routine investigations of blood parameters (troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in particular) and a thorough CV follow-up (electrocardiograms, transthoracic echocardiograms, and coronary calcium scoring) at fixed time points for a total period of two years. The primary endpoint is the cumulative incidence of troponin elevation in the first three months of ICI treatment, compared to baseline levels. Furthermore, secondary endpoints include incidence above the upper limit of normal of both troponin and NT-proBNP levels, evolution in troponin and NT-proBNP levels, the incidence of CV abnormalities/major adverse cardiac events, evaluation of associations between patient characteristics/biochemical parameters and CV events, transthoracic echocardiography parameters, electrocardiography parameters, and progression of coronary atherosclerosis. Recruitment of patients started in January 2022. Enrolment is ongoing in AZ Maria Middelares, Antwerp University Hospital, AZ Sint-Vincentius Deinze, and AZ Sint-Elisabeth Zottegem. Trial registration: ClinicalTrials.gov Identifier: NCT05699915, registered 26 January 2023.

Abstract Background Neoadjuvant treatment followed by esophagectomy is standard practice in locally advanced esophageal cancer. However, not all patients who started neoadjuvant treatment will undergo esophageal resection. The purpose of our study was to investigate the group of patients, scheduled for neoadjuvant treatment followed by esophagectomy, who never made it to esophageal resection. Methods We retrospectively analyzed patients treated between 2002 and 2015 for locally advanced esophageal cancer, who did not undergo esophagectomy after neoadjuvant treatment. Subanalysis was performed according to time period (2002–2010 versus 2011–2015) and histology (adenocarcinoma versus squamous cell carcinoma). Results In 114 of 679 patients (16.8%), surgery was not performed after neoadjuvant treatment. Reasons for cancelation were disease progression (50 patients, 43.9%), poor general condition (26 patients, 22.8%), irresectability (14 patients, 12.3%), patients’ own decision (15 patients, 13.2%), and death during neoadjuvant treatment (9 patients, 7.9%). In the second time period, there were less irresectable tumors (17.7% versus 5.8%; p = 0.044). Median overall survival was not different over time (9.2 versus 12.5 months; p = 0.937). Irresectability (p = 0.032), patients’ refusal (p = 0.012), and poor general condition (p = 0.002) were more frequent as reasons for cancelation in squamous cell carcinoma patients. Median overall survival was, respectively, 12.5 and 9.9 months for adenocarcinoma and squamous cell carcinoma patients (p = 0.441). The majority of patients refusing surgery had a clinical complete response (73.3%). They had a median overall survival of 33.2 months. Conclusions One in six patients starting neoadjuvant treatment for locally advanced esophageal cancer never made it to esophagectomy, more than half of them for oncological reasons, but also 1.3% because of death during treatment. Over time, irresectability as reason decreased. As a result, the relative weight of medical inoperability increased, indicating the importance of upfront testing of medical operability. Cancelation of surgery was significantly more common in patients with a squamous cell carcinoma, and this histology seems to represent a more complex oncological and functional entity. Refusal of esophagectomy based on clinical complete response showed a significant survival benefit compared to those who did not undergo esophagectomy because of other reasons.

Abstract Background Correct staging of patients with colorectal cancer is of utmost importance for the prediction of operability. Although computed tomography (CT) has a good overall performance, estimation of peritoneal cancer spread is a known weakness, a problem that cannot always be overcome by Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT); especially in infiltrative and miliary disease spread. Due to its high spatial and contrast resolution magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) might have a better performance. Our aim was to evaluate the added value of whole-body diffusion-weighted MRI (WB-DWI/MRI) to CT for prediction of peritoneal cancer spread and operability assessment in colorectal cancer patients with clinically suspected peritoneal carcinomatosis (PC). Methods This institutional review board approved retrospective study included sixty colorectal cancer patients who underwent WB-DWI/MRI in addition to CT for clinically suspected peritoneal metastases. WB-DWI/MRI and CT were assessed for detecting PC following the peritoneal cancer index (PCI), determination of PCI-score categorized as PC 15, detection of nodal and distant metastases and estimation of overall operability. Histopathology after surgery and biopsy and/or 6 months follow-up were used as reference standard. Results For detection of PC, CT had 43.2% sensitivity, 95.6% specificity, 84.5% positive predictive value (PPV) and 75.2% negative predictive value (NPV). WB-DWI/MRI had 97.8% sensitivity, 93.2% specificity, 88.9% PPV and 98.7% NPV. WB-DWI/MRI enabled better detection of inoperable distant metastases (all 12 patients) than CT (2/12 patients) and significantly improved prediction of PCI category [WB-DWI/MRI PCI 15: 16/17 patients (94.1%) versus CT PCI 15: 2/17 patients (11.8%); p

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling pathways simultaneously and quantitatively with high resolution in tissue samples and circulating tumor cells, specifically with very small specimen quantities. The approach uses mRNA levels of a pathway’s direct target genes, selected based on literature for multiple proof points, and used as evidence that a pathway is functionally activated. Using these validated target genes, a Bayesian network model has been built and calibrated on mRNA measurements of samples with known pathway status, which is used next to calculate a pathway activity score on individual test samples. Translation to RT-qPCR assays enables broad clinical diagnostic applications, including small analytes. A large number of cancer samples have been analyzed across a variety of cancer histologies and benchmarked across normal controls. Assays have been used to characterize cell types in the cancer cell microenvironment, including immune cells in which activated and immunotolerant states can be distinguished. Results support the expectation that the assays provide information on cancer driving signaling pathways which is difficult to derive from next generation DNA sequencing analysis. Current clinical oncology applications have been complementary to genomic mutation analysis to improve precision medicine: (1) prediction of response and resistance to various therapies, especially targeted therapy and immunotherapy; (2) assessment and monitoring of therapy efficacy; (3) prediction of invasive cancer cell behavior and prognosis; (4) measurement of circulating tumor cells. Preclinical oncology applications lie in a better understanding of cancer behavior across cancer types, and in development of a pathophysiology-based cancer classification for development of novel therapies and precision medicine.

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti–PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC. Materials and methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle. Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months. Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing. Clinical trial registration number: NCT03000257Statement on originality of the workThe manuscript represents original work and has not been submitted for publication elsewhere nor previously published.Statement of prior presentationData from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.

Objectives: To compare the diagnostic performance of intra-arterial dual phase cone-beam computed tomography (DP-CBCT) with contrast-enhanced computed tomography (CE-CT) when characterizing tumor burden in patients with metastatic liver cancer. Materials and Methods: This retrospective study included 29 patients with colorectal (n =10), breast (n = 9) and neuroendocrine (n = 10) liver metastases, referred for catheter-directed treatment. Tumor type, number, maximum size, and appearance were assessed. Paired-sample t-tests compared image quality, tumor numbers, and diameters between imaging modalities. Results: Image quality was not different between DP-CBCT and CE-CT (p = 0.9). In 18 patients (62%) DP-CBCT and CE-CT showed diffuse, uncountable metastases in the liver. Of the remaining 11 patients, DP-CBCT identified two patients with diffuse tumors that appeared as a sum of 17 distinct metastases on CE-CT. In the remaining nine patients a total of 102 metastases were found using both DP-CBCT and CE-CT. Tumor detection accuracy was 98% in DP-CBCT and 67% in CE-CT (p = 0.025). Metastases were larger in diameter on DP-CBCT: colorectal: 57 +/– 9.5 mm versus 43 +/– 8.3 mm (p = 0.02); breast: 57 +/– 10 mm versus 43 +/– 8.5 mm (p = 0.03) and neuroendocrine: 56 +/– 6.3 mm versus 51 +/– 5.8 mm (p = 0.01). Rim enhancement appeared in 100% of patients with colorectal and 89% of patients with breast metastases on DP-CBCT, but was variable on CE-CT. Neuroendocrine tumors had variable rim enhancement within the same patient and across imaging modalities. Conclusions: DP-CBCT of the liver may demonstrate larger metastatic tumor burden and lesion size with a variable contrast enhancement compared to CE-CT.

The last decade has seen important developments in the treatment of metastatic colorectal cancer (mCRC). In this scenario, interventional locoregional treatments could play an expanding role offering safe and effective integrated options in the continuum-of-care offering curative as well as palliative approaches.Based on ESMO guidelines, the toolbox of ablative treatments also includes intra-arterial palliative options, like chemoembolization, that can be offered as an alternative option in patients failing the available chemotherapeutic regimens.However, to date, there is still a limited use of chemoembolization in clinical practice.Based on this background, a comprehensive review of the methodologic and technical considerations as well as clinical indications and future perspectives seems to be useful with the aim to demonstrate the field’s value of the procedure, highlight their advantages, and ensure an increased role in treatment management of patients with colorectal liver metastases.

Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.

Abstract Background Cytoreductive surgery (CRS) plus hyperthermic intra-operative peritoneal chemotherapy (HIPC) for gastric peritoneal carcinomatosis (PC) is controversial, and selection criteria for this treatment modality are lacking. Methods Thirty-two patients (F/M ratio 12/20; median (range) age 58 (32-75) years) underwent CRS + HIPC with cisplatin for PC from gastric adenocarcinoma in 2010-2014. This monocentric phase-2 nonrandomized prospective study with a power of 90% aimed to improve the 1-year overall survival (OS) rate with 40% (historical reference of 52% to 72%). Median PCI score was 8 (range 1-20), number of regions involved was 6 (range 1-11). The impact of 16 prognostic factors on survival was evaluated using univariable and multivariable Cox regression models. Follow-up was complete in all patients, and closed 2 years after patient inclusion. Results All patients had complete cytoreduction (CCR-0) and histopathological R0 resection. PCI

Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.

Abstract Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy.

This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m(2) followed by weekly 250 mg/m(2)) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients.Clinicaltrials.gov NCT01032291.