Publications by authors named "Olivier Michielin"

192 Publications

Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis.

J Immunother Cancer 2021 Oct;9(10)

Immunology and allergy division, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland

Background: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare but potentially fatal adverse event that can occur following ICI exposure. Early diagnosis and treatment are key to improve patient outcomes. Somatostatin receptor-based positron emission tomography-CT (PET/CT) showed promising results for the assessment of myocardial inflammation, yet information regarding its value for the diagnosis of ICI-related myocarditis, especially at the early stage, is limited. Thus, we investigated the value of Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (Ga-DOTATOC) PET/CT for the early detection and diagnosis of ICI-related myocarditis.

Methods: Consecutive patients with clinically suspected ICI-related myocarditis from July 2018 to February 2021 were retrospectively evaluated in this single-center study. All patients underwent imaging for the detection of ICI-related myocarditis using either cardiac magnetic resonance (CMR) imaging or Ga-DOTATOC PET/CT. PET/CT images were acquired 90 min after the injection of 2 MBq/kg Ga-DOTATOC with pathological myocardial uptake in the left ventricle (LV) suggestive of myocarditis defined using a myocardium-to-background ratio of peak standard uptake value to mean intracavitary LV standard uptake (MBR) value above 1.6. Patients had a full cardiological work-up including ECG, echocardiography, serum cardiac troponin I (cTnI), cardiac troponin T and creatine kinase (CK), CK-MB. Endomyocardial biopsy and inflammatory cytokine markers were also analyzed. The detection rate of ICI-related myocarditis using Ga-DOTATOC PET/CT and CMR was assessed.

Results: A total of 11 patients had clinically suspected ICI-related myocarditis; 9 underwent Ga -DOTATOC PET/CT. All nine (100%) patients with Ga-DOTATOC PET/CT presented with pathological myocardial uptake in the LV that was suggestive of myocarditis (MBR of 3.2±0.8, range 2.2-4.4). Eight patients had CMR imaging and 3/8 (38%) patients had lesions evocative of myocarditis. All PET-positive patients were previously treated with a high dose of steroids and intravenous immunoglobulin prior to PET/CT had elevated serum cTnI except for one patient for whom PET/CT was delayed several days. Interestingly, in 5/6 (83%) patients who presented with concomitant myositis, pathological uptake was seen on whole-body Ga-DOTATOC PET/CT images in the skeletal muscles, suggesting an additional advantage of this method to assess the full extent of the disease. In contrast, four patients with CMR imaging had negative findings despite having elevated serum cTnI levels (range 20.5-5896.1 ng/mL), thus defining possible myocarditis. Newly identified immune correlates could provide specific biomarkers for the diagnosis of ICI-related myocarditis. Most tested patients (six of seven patients) had serum increases in the inflammatory cytokine interleukin (IL)-6 and in the chemokines CXCL9, CXCL10, and CXCL13, and the mass cytometry phenotypes of immune cell populations in the blood also showed correlations with myocardial inflammation. Four of five patients with myocarditis exhibited a Th1/Th2 imbalance favoring a pronounced inflammatory Th1, Th1/Th17, and Th17 CD4 memory T-cell response. The high proportion of non-classical monocytes and significantly reduced levels of CD31 in four to five patients was also consistent with an inflammatory disease.

Conclusion: The use of Ga-DOTATOC PET/CT along with immune correlates is a highly sensitive method to detect ICI-related myocarditis especially in the early stage of myocardial inflammation, as patients with elevated cTnI may present normal CMR imaging results. Ga-DOTATOC PET/CT is also useful for detecting concomitant myositis. These results need to be confirmed in a larger population of patients and validated against a histological gold standard if available.
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http://dx.doi.org/10.1136/jitc-2021-003594DOI Listing
October 2021

Patient-reported outcomes for monitoring symptomatic toxicities in cancer patients treated with immune-checkpoint inhibitors: A Delphi study.

Eur J Cancer 2021 Sep 15;157:225-237. Epub 2021 Sep 15.

Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Institute of Higher Education and Research in Healthcare, Faculty of Biology and Medicine, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland. Electronic address:

Background: Immune-related adverse events (IrAEs) associated with the use of immune checkpoint inhibitors (ICIs) may not be fully covered by existing measures like the PRO-CTCAE™. Selecting PRO-CTCAE™ items for monitoring symptomatic adverse events is hindered by the heterogeneity and complexity of IrAEs, and no standardised selection process exists. We aimed to reach expert consensus on the PRO-CTCAE™ symptom terms relevant for cancer patients receiving ICIs and to gather preliminary expert opinions about additional symptom terms reflecting ICI symptomatic toxicities. Additionally, we gathered expert consensus about a core set of priority symptom terms for prospective surveillance and monitoring.

Design: This Delphi study involved an international panel of experts (n = 6 physicians; n = 3 nurses, n = 1 psychiatrist and n = 1 patient advocates). Experts prioritised the relevance and importance of symptom terms to monitor in patients treated with ICIs.

Results: Experts reached a consensus on the relevance of all (n = 80) PRO-CTCAE™ Symptom Terms. Consensus on the importance of these symptom terms for prospective monitoring in patients receiving ICIs was reached for 81% (n = 65) of these terms. Additional symptoms terms (n = 56) were identified, with a consensus that 84% (47/56) of these additional symptom terms should also be considered when monitoring symptomatic IrAEs.

Conclusion: This study identified a prioritised list of symptom terms for prospective surveillance for symptomatic IrAEs in patients receiving ICI treatment. Our results indicate the need to strengthen the validity of PRO measures used to monitor patients receiving ICIs. While these results provided some support for the content validity of the PRO CTCAE™ and resulted in a preliminary set of salient symptomatic adverse events related to the use of ICIs, broader international agreement and patient involvement are needed to further validate our initial findings.
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http://dx.doi.org/10.1016/j.ejca.2021.08.026DOI Listing
September 2021

Real-life data for first-line combination immune-checkpoint inhibition and targeted therapy in patients with melanoma brain metastases.

Eur J Cancer 2021 Oct 25;156:149-163. Epub 2021 Aug 25.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Melanoma brain metastases (MBM) have a poor prognosis. Systemic treatments that have improved outcomes in advanced melanoma have been shown to have an intracranial (IC) effect. We studied the efficacy and outcomes of combined immune checkpoint inhibitor ipilimumab/nivolumab (Combi-ICI) or targeted therapy (Combi-TT) as first-line treatment in MBM.

Methods: MBM patients treated with Combi-ICI or Combi-TT within 3 months after MBM diagnosis. Endpoints were progression-free survival (PFS) and overall survival (OS).

Results: 53 patients received Combi-ICI, 32% had symptomatic MBM and 33.9% elevated LDH. 71.7% required local treatment. The disease control rate was 60.3%. IC response rate (RR) was 43.8% at 3-months with durable responses at 6- (46.5%) and 12-months (53.1%). Extracranial (EC) RR was 44.7% at 3-months and 50% at 12-months. Median PFS was 9.6 months (95% CI 3.6-NR) and median overall survival (mOS) 44.8 months (95% CI; 26.2-NR). 63 patients received Combi-TT, 55.6% of patients had symptomatic MBM, 57.2% of patients had elevated LDH and 68.3% of patients required local treatment. The disease control rate was 60.4%. ICRR was 50% at 3-months, but dropped at 6-months (20.9%). ECRR was 69.2% at 3-months and 17.6% at 12-months. Median PFS was 5.8 months (95% CI 4.2-7.6) and mOS 14.2 months (95% CI 8.99-26.8). In BRAFV600 patients, 26.7% of patients received Combi-ICI and 73.3% Combi-TT with OS (p = 0.0053) and mPFS (p = 0.03) in favour to Combi-ICI.

Conclusion: Combi-ICI showed prolonged mOS with sustainable IC and EC responses. Despite the initially increased efficacy, Combi-TT responses at 12 months were low. Combi-ICI appeared superior to Combi-TT for OS and PFS in BRAFV600 patients. Other clinical factors are determinants for first-line treatment choice.
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http://dx.doi.org/10.1016/j.ejca.2021.07.028DOI Listing
October 2021

Pathophysiology, diagnosis and management of cardiac toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors.

Cancer Treat Rev 2021 Nov 18;100:102282. Epub 2021 Aug 18.

Department of Oncology, Bern University Hospital (Inselspital), University of Bern, Switzerland; International Cancer Prevention Institute, Epalinges, Switzerland. Electronic address:

Immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors (BRAFi/MEKi) have drastically improved the outcome of melanoma patients. ICIs can induce myocarditis, a rare immune related adverse event (irAE) with an estimated lethality of 50%. BRAFi/MEKi may induce left ventricular ejection fraction decrease, hypertension or QT interval prolongation. While the BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation and symptomatic therapy is often sufficient to restore cardiac function, the treatment of ICI-induced myocarditis mainly relies on high dose corticosteroids. There is no established therapy for steroid resistant myocarditis, yet various drugs have been reported to improve outcome. Shared epitopes between melanoma cells and cardiac tissue are thought to underlie the development of ICIs induced myocarditis. The mechanism of BRAFi/MEKi induced cardiotoxicity appears to be related to the Ras-Raf-MEK-ERK pathway in cardiomyocyte repair, survival and proliferation. With the emerging application of ICI-BRAFi/MEKi combinations, so called triplet therapies, differentiating between these two types of cardiotoxicity will become important for appropriate patient management. In this article we provide a summary of the existing literature on the pathophysiology, diagnosis and management of cardiotoxicity of melanoma therapies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102282DOI Listing
November 2021

Acute cardiac manifestations under immune checkpoint inhibitors-beware of the obvious: a case report.

Eur Heart J Case Rep 2021 Aug 12;5(8):ytab262. Epub 2021 Aug 12.

Department of Cardiology, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the management of many cancer types by drastically improving the median survival rate of patients. However, this efficiency comes at the cost of a high rate of immune-related adverse events, including lethal cardiac manifestations. Rapidly fatal cases of ICI-induced myocarditis have been reported and drawn considerable attention over the past years. However, it is essential to bear in mind that not all cardiac events occurring under ICI therapy are necessarily myocarditis.

Case Summary: A 61-year-old female treated with pembrolizumab for a stage IV melanoma was admitted for chest pain leading to the diagnosis of ICI-related myocarditis based on the description of a discrete left ventricular subepicardial late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. ICI were suspended and intravenous methylprednisolone initiated. A second line anti-MEK therapy was initiated. After a month of treatment, similar chest pain occurred. CMR revealed a midventricular stress cardiomyopathy and no LGE was detected. interrogation revealed emotional stressors preceding both episodes. Review of the first CMR, performed 2 weeks after symptom onset, indicated a pattern compatible with the recovery phase of a stress cardiomyopathy and the presence of LGE was questioned. ICI were reintroduced without recurrence of cardiac events.

Discussion: Not all cardiac manifestations occurring under ICI therapy are drug-related adverse events, therefore differential diagnoses must systematically be considered as the contraindication of ICI may have a major impact on patient prognosis. Cardiac imaging should be performed early and plays a key role in the management strategy.
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http://dx.doi.org/10.1093/ehjcr/ytab262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374985PMC
August 2021

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Sci Immunol 2021 Jul;6(61)

Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
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http://dx.doi.org/10.1126/sciimmunol.abi7083DOI Listing
July 2021

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

Eur J Cancer 2021 Aug 29;153:213-222. Epub 2021 Jun 29.

Melanoma Institute Australia, The University of Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospitals, NSW, Australia. Electronic address:

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.04.021DOI Listing
August 2021

Machine learning analyses of antibody somatic mutations predict immunoglobulin light chain toxicity.

Nat Commun 2021 06 10;12(1):3532. Epub 2021 Jun 10.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

In systemic light chain amyloidosis (AL), pathogenic monoclonal immunoglobulin light chains (LC) form toxic aggregates and amyloid fibrils in target organs. Prompt diagnosis is crucial to avoid permanent organ damage, but delayed diagnosis is common because symptoms usually appear only after strong organ involvement. Here we present LICTOR, a machine learning approach predicting LC toxicity in AL, based on the distribution of somatic mutations acquired during clonal selection. LICTOR achieves a specificity and a sensitivity of 0.82 and 0.76, respectively, with an area under the receiver operating characteristic curve (AUC) of 0.87. Tested on an independent set of 12 LCs sequences with known clinical phenotypes, LICTOR achieves a prediction accuracy of 83%. Furthermore, we are able to abolish the toxic phenotype of an LC by in silico reverting two germline-specific somatic mutations identified by LICTOR, and by experimentally assessing the loss of in vivo toxicity in a Caenorhabditis elegans model. Therefore, LICTOR represents a promising strategy for AL diagnosis and reducing high mortality rates in AL.
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http://dx.doi.org/10.1038/s41467-021-23880-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192768PMC
June 2021

Ovarian cancer with high-level focal amplification responds to trastuzumab and pertuzumab.

Gynecol Oncol Rep 2021 Aug 19;37:100787. Epub 2021 May 19.

Department of Oncology, University Hospitals of Geneva (HUG), Geneva, Switzerland.

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and significantly contributes to cancer mortality in women. Despite multimodal treatment associating chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. In EOC, the efficacy of anti-HER2 agents is minimal even after selecting patients for HER2 expression. gene amplification is observed in 3-10% of patients, depending on the specific method of detection and cutoffs. We report the case of a young woman with a FIGO stage IV high-grade serous ovarian cancer with an amplification of . She was treated with the association of trastuzumab - pertuzumab after two lines of standard treatment and presented an excellent long-lasting partial response after 36 months of treatment. The association of trastuzumab and pertuzumab, without chemotherapy, has not been previously tested in this context and could be more efficacious than monotherapy with either agent. In addition, the significant benefit observed in this case could be attributed to the presence of a high-level focal amplification that is relatively rare and probably more specific than an increase in HER2 expression. In conclusion, prospective trials of the trastuzumab and pertuzumab combination should be considered in an appropriately selected EOC patient population.
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http://dx.doi.org/10.1016/j.gore.2021.100787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165411PMC
August 2021

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

Lancet Oncol 2021 06 11;22(6):836-847. Epub 2021 May 11.

Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Mater Hospital, Sydney, NSW, Australia. Electronic address:

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(21)00097-8DOI Listing
June 2021

[Telephone follow-up of SARS-CoV-2 positive patients at the Oncology Department of Lausanne University Hospital].

Rev Med Suisse 2021 Apr;17(733):703-707

Institut universitaire de formation et recherche en soins (IUFRS), Faculté de biologie et médecine, UNIL-CHUV, 1010 Lausanne.

Compared with the general population, oncology patients face a higher morbidity and mortality caused by the COVID-19 pandemic. As a result, health systems had to quickly adapt cancer care in order to maintain the best quality and patient safety. From March to May and from October to December 2020, 254 patients diagnosed with cancer and tested positive for SARS-CoV-2 benefited from a tele-health monitoring at the Oncology Department at CHUV. This article describes the key points of the development, implementation and operation of this tele-health monitoring, enabled by an interdisciplinary and inter-professional collaboration between different units and healthcare professionals.
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April 2021

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.

Eur J Cancer 2021 05 3;149:37-48. Epub 2021 Apr 3.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.
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http://dx.doi.org/10.1016/j.ejca.2021.02.037DOI Listing
May 2021

[Impact of COVID pandemic on the detection of skin cancer].

Rev Med Suisse 2021 Mar;17(732):635-639

Service de dermatologie et vénéréologie, CHUV, 1011 Lausanne.

In 2020, we have seen patients with neglected skin cancer in the context of the COVID pandemic. But what is the global health impact of the pandemic on skin cancer patients ? Is it as high as the delayed care of a heart infarct ? To answer this question, we have confronted a theoretic, a probabilistic and a scientific approach. These analyses allow us to conclude that the impact overall was moderate. It allows to draw general guidelines on the diagnosis and treatment of skin cancer for future pandemics.
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March 2021

Swiss-PO: a new tool to analyze the impact of mutations on protein three-dimensional structures for precision oncology.

NPJ Precis Oncol 2021 Mar 18;5(1):19. Epub 2021 Mar 18.

Computer-Aided Molecular Engineering, Department of Oncology, Ludwig Institute for Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1038/s41698-021-00156-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973488PMC
March 2021

Probing the Conformational Dynamics of Affinity-Enhanced T Cell Receptor Variants upon Binding the Peptide-Bound Major Histocompatibility Complex by Hydrogen/Deuterium Exchange Mass Spectrometry.

Biochemistry 2021 03 9;60(11):859-872. Epub 2021 Mar 9.

Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark.

Binding of the T cell receptor (TCR) to its cognate, peptide antigen-loaded major histocompatibility complex (pMHC) is a key interaction for triggering T cell activation and ultimately elimination of the target cell. Despite the importance of this interaction for cellular immunity, a comprehensive molecular understanding of TCR specificity and affinity is lacking. We conducted hydrogen/deuterium exchange mass spectrometry (HDX-MS) analyses of individual affinity-enhanced TCR variants and clinically relevant pMHC class I molecules (HLA-A*0201/NY-ESO-1) to investigate the causality between increased binding affinity and conformational dynamics in TCR-pMHC complexes. Differential HDX-MS analyses of TCR variants revealed that mutations for affinity enhancement in TCR CDRs altered the conformational response of TCR to pMHC ligation. Improved pMHC binding affinity was in general observed to correlate with greater differences in HDX upon pMHC binding in modified TCR CDR loops, thereby providing new insights into the TCR-pMHC interaction. Furthermore, a specific point mutation in the β-CDR3 loop of the NY-ESO-1 TCR associated with a substantial increase in binding affinity resulted in a substantial change in pMHC binding kinetics (i.e., very slow , revealed by the detection of EX1 HDX kinetics), thus providing experimental evidence for a slow induced-fit binding mode. We also examined the conformational impact of pMHC binding on an unrelated TRAV12-2 gene-encoded TCR directed against the immunodominant MART-1 cancer antigen restricted by HLA-A*0201. Our findings provide a molecular basis for the observed TRAV12-2 gene bias in natural CD8 T cell-based immune responses against the MART-1 antigen, with potential implications for general ligand discrimination and TCR cross-reactivity processes.
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http://dx.doi.org/10.1021/acs.biochem.1c00035DOI Listing
March 2021

Cystathionine-gamma-lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy.

Cancer Sci 2021 May 12;112(5):1723-1734. Epub 2021 Mar 12.

Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Université de Nantes, Nantes, France.

T cells could be engineered to overcome the aberrant metabolic milieu of solid tumors and tip the balance in favor of a long-lasting clinical response. Here, we explored the therapeutic potential of stably overexpressing cystathionine-gamma-lyase (CTH, CSE, or cystathionase), a pivotal enzyme of the transsulfuration pathway, in antitumor CD8 T cells with the initial aim to boost intrinsic cysteine metabolism. Using a mouse model of adoptive cell transfer (ACT), we found that CTH-expressing T cells showed a superior control of tumor growth compared to control T cells. However, contrary to our hypothesis, this effect was not associated with increased T cell expansion in vivo or proliferation rescue in the absence of cysteine/cystine in vitro. Rather than impacting methionine or cysteine, ACT with CTH overexpression unexpectedly reduced glycine, serine, and proline concentration within the tumor interstitial fluid. Interestingly, in vitro tumor cell growth was mostly impacted by the combination of serine/proline or serine/glycine deprivation. These results suggest that metabolic gene engineering of T cells could be further investigated to locally modulate amino acid availability within the tumor environment while avoiding systemic toxicity.
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http://dx.doi.org/10.1111/cas.14862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088958PMC
May 2021

Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.

J Immunother Cancer 2021 02;9(2)

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Background: Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.

Objectives: The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.

Methods: Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.

Results: 88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).

Conclusion: This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
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http://dx.doi.org/10.1136/jitc-2020-001701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898852PMC
February 2021

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

J Med Chem 2021 02 8;64(4):2205-2227. Epub 2021 Feb 8.

Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01968DOI Listing
February 2021

Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity.

Cancer Discov 2021 03 14;11(3):714-735. Epub 2020 Dec 14.

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.

MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with , and mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8 T cells, and durable tumor regression elicited by this combination requires CD8 T cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy. SIGNIFICANCE: Type I RAFi + MEKi are indicated only in certain cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8 T cells are mechanisms that may be further exploited..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933113PMC
March 2021

Trametinib Induces the Stabilization of a Dual p.Gly48Leu- and p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology.

Int J Mol Sci 2020 Oct 28;21(21). Epub 2020 Oct 28.

Computer-aided molecular engineering group, Department of Fundamental Oncology, Lausanne University, Ludwig Lausanne Branch, 1066 Epalinges, Switzerland.

We report a case of an uveal melanoma patient with p.Gly48Leu who responded to MEK inhibition. At the time of the molecular analysis, the pathogenicity of the mutation was unknown. A tridimensional structural analysis showed that Gα can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form. This strongly suggests that p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer. Based on these analyses, the patient received the MEK inhibitor trametinib with a lasting clinical benefit. This work highlights the importance of molecular modelling for personalized oncology.
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http://dx.doi.org/10.3390/ijms21218021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662249PMC
October 2020

Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.

Cancer Cell 2020 11 5;38(5):602-604. Epub 2020 Oct 5.

Medical Oncology Department, Thoracic Cancer and Early Drug Development Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.

To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1016/j.ccell.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534826PMC
November 2020

Evolving impact of long-term survival results on metastatic melanoma treatment.

J Immunother Cancer 2020 10;8(2)

Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy

Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.
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http://dx.doi.org/10.1136/jitc-2020-000948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549477PMC
October 2020

[ENT management of head and neck cutaneous melanoma].

Rev Med Suisse 2020 Oct;16(709):1853-1859

Service d'ORL et de chirurgie cervico-faciale, CHUV, 1011 Lausanne.

A quarter of cutaneous melanomas occur on the head and neck. Despite close collaboration between the dermatology, oncology, pathology, nuclear medicine and otorhinolaryngology departments, the survival of patients presenting with this type of melanomas remains inferior to that of other parts of the body. The morbidity of head and neck surgery significantly alters the quality of life. Therefore, specific multidisciplinary expertise is required. We present here the specificities of ENT management.
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October 2020

What Role Can Process Mining Play in Recurrent Clinical Guidelines Issues? A Position Paper.

Int J Environ Res Public Health 2020 09 11;17(18). Epub 2020 Sep 11.

Dipartimento di Scienze Cliniche e Sperimentali dell'Università degli Studi di Brescia, 25128 Brescia, Italy.

In the age of Evidence-Based Medicine, Clinical Guidelines (CGs) are recognized to be an indispensable tool to support physicians in their daily clinical practice. Medical Informatics is expected to play a relevant role in facilitating diffusion and adoption of CGs. However, the past pioneering approaches, often fragmented in many disciplines, did not lead to solutions that are actually exploited in hospitals. Process Mining for Healthcare (PM4HC) is an emerging discipline gaining the interest of healthcare experts, and seems able to deal with many important issues in representing CGs. In this position paper, we briefly describe the story and the state-of-the-art of CGs, and the efforts and results of the past approaches of medical informatics. Then, we describe PM4HC, and we answer questions like how can PM4HC cope with this challenge? Which role does PM4HC play and which rules should be employed for the PM4HC scientific community?
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http://dx.doi.org/10.3390/ijerph17186616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557817PMC
September 2020

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes.

J Immunother Cancer 2020 08;8(2)

Immuno-oncology Service, Department of Oncology, CHUV, Lausanne, Vaud, Switzerland.

Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered.

Case Presentation: We report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect.

Conclusion: We describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities.
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http://dx.doi.org/10.1136/jitc-2020-001155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451492PMC
August 2020

Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives.

Br J Cancer 2020 09 27;123(6):885-897. Epub 2020 Jul 27.

Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany.

The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.
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http://dx.doi.org/10.1038/s41416-020-0994-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492252PMC
September 2020

SPHN/PHRT - MedCo in Action: Empowering the Swiss Molecular Tumor Board with Privacy-Preserving and Real-Time Patient Discovery.

Stud Health Technol Inform 2020 Jun;270:1161-1162

EPFL.

MedCo is the first operational system that makes sensitive medical-data available for research in a simple, privacy-conscious and secure way. It enables a consortium of clinical sites to collectively protect their data and to securely share them with investigators, without single points of failure. In this short paper, we report on our ongoing effort for the operational deployment of MedCo within the context of the Swiss Personalized Health Network (SPHN) for the Swiss Molecular Tumor Board.
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http://dx.doi.org/10.3233/SHTI200345DOI Listing
June 2020

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

Lancet Oncol 2020 07 12;21(7):914-922. Epub 2020 Jun 12.

Oncology Department, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland.

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.

Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.

Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.

Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292610PMC
July 2020

[Cardiotoxicity of immune checkpoint inhibitors used in cancer treatment].

Rev Med Suisse 2020 Jun;16(696):1165-1168

Service de cardiologie, CHUV, 1011 Lausanne.

Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, by reshaping the prognosis of many cancers and are progressively becoming the standard of care. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), of which cardiovascular irAEs are particularly feared. ICI-induced myocarditis is often a diagnostic challenge because of the vast heterogeneity of clinical presentations, and it is associated with a high mortality rate of around 50%. The present article summarizes the cardiac manifestations, the diagnostic strategy and the therapeutic management of patients with ICI-induced myocarditis used in the treatment of cancer.
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June 2020
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