[PAL-PRAT study: Healthcare workers' knowledge and perception of palliative practices in a Cancer Center]. / Quelle connaissance et quelle perception ont les professionnels de santé d'un Centre de lutte contre le cancer à propos des pratiques palliatives encadrées par la loi Claeys-Leonetti : étude PAL PRAT.

INTRODUCTION: The issue of end-of-life care is the subject of a sensitive debate in French society, particularly regarding the possibility for certain patients to have access to medical assistance in dying. The aim of this study was to assess the knowledge and opinion of healthcare providers on the care practices for patients at the end of life, as well as to highlight any specificities in their discourse. METHOD: A survey of healthcare providers' opinions, composed of closed and open questions, that were analyzed using a lexicometric approach, was distributed in a cancer center. RESULTS: The results of the study reveal a good knowledge of the different procedures. Professionals considered that advance directives should be systematically collected; a majority of them differentiated euthanasia from deep continuous sedation and perceived the latter as a means of relieving patients' suffering without inducing death. The different procedures related to the active assistance in dying were known by a majority of professionals and the survey did not identify a dominant trend concerning the will to practice euthanasia if the legal framework allowed it. Half of the participants considered their training insufficient, indicating the need to fill this gap. DISCUSSION: This survey underlines the importance of training and support for the professionals caring for patients in palliative situation and their relatives in France.

Legalisation of euthanasia and assisted suicide: advanced cancer patient opinions - cross-sectional multicentre study.

OBJECTIVES: The French government voted a new law in February 2016 called the Claeys-Leonetti Law, which established the right to deep and continuous sedation, confirmed the ban on euthanasia and ruled out physician-assisted suicide. The aim of this work was to gather the opinion of patients on continuous sedation and the legalisation of medical assistance in dying and to explore determinants associated with favourable and unfavourable opinions. METHODS: This was a French national prospective multicentre study between 2016 and 2020. RESULTS: 331 patients with incurable cancer suffering from locally advanced or metastatic cancer in 14 palliative care units were interviewed. 48.6% of participants expressed a favourable opinion about physician-assisted suicide and 27.2% an unfavourable opinion about its legalisation. Regarding euthanasia, 52% of patients were in favour of its legalisation. In univariate analysis, the only factor determining opinion was belief in God. CONCLUSIONS: While most healthy French people are in favour of legalising euthanasia, only half of palliative care patients expressed this opinion. Medical palliative care specialists were largely opposed to euthanasia. The only determining factor identified was a cultural factor that was independent of the other studied variables. This common factor was found in other studies conducted on cohorts from other countries. This study contributes to the knowledge and thinking about the impact of patients' personal beliefs and values regarding their opinions about euthanasia and assisted suicide. TRIAL REGISTRATION NUMBER: NCT03664856.

Contribution of collegial support meetings (CSM) in the management of complex situations of patients with advanced cancer.

PURPOSE: Collegial support meetings (CSM) have been set up in the Gustave Roussy Cancer Center for inpatients whose complex care requires a multi-professional approach involving many participants: oncologists but also health-caregivers, a member of the palliative care team, an intensivist, and a psychologist. This study is aimed at describing the role of this newly multidisciplinary meeting implemented in a French Comprehensive Cancer Center. METHODS: Each week, the health-caregivers decide which situations should be examined, depending on the difficulty of a case. The discussion goes on to include the goal of treatment, the intensity of care, ethical and psychosocial issues, and the patient's life plan. Finally, to obtain feedback from the teams, a survey has been distributed to assess the interest in the CSM. RESULTS: In 2020, 114 inpatients were involved, and 91% were in an advanced palliative situation. During the CSMs, 55% of the discussions focused on whether to continue specific cancer treatment-29% about whether to continue invasive medical care-50% about optimizing supportive care. We estimate that between 65 and 75% of CSMs influenced further decisions. Death occurred during the hospitalization for 35% of the patients that were discussed. The lapse of time between last chemotherapy and death was 24 days (IQR, 28.5). CSMs were well received, since 80% of the teams find these meetings useful. CONCLUSIONS: CSMs reach conclusions for medical and nursing staff involved, in order to improve the management of inpatients with cancer in advanced palliative situation and to define the better goals of care.

[Implementation of a multimodal strategy for information and collection of advance directives in a comprehensive cancer center]. / Mise en place d'une stratégie multimodale d'information et de recueil des directives anticipées dans un Centre de lutte contre le cancer (CLCC).

INTRODUCTION: In France, advance directives (AD) remain unknown and underused by healthcare users and professionals. This is particularly true in oncology. This work was carried out with patients and caregivers of a Comprehensive Cancer Center to improve their appropriation and information. METHODS: The project, built by the Ethics Committee, the Patients Committee and the Palliative Care Team, made it possible to develop over 6 months a training program, an information procedure and several original documents. RESULTS: A total of 34 one-hour training courses for all professionals were organized. A procedure for making information available, including the right to draft ADs, has been implemented. This procedure is personalized, gradual and multi-professional. When a patient wishes to write his AD, he is accompanied by a dedicated team and benefits from a specific form, which enlighten values and preferences before addressing the desired level of therapeutic commitment. Communication elements were diffused, and a specific training on "anticipated discussions" was created. A dedicated space in the computerized chart makes it possible to locate the existence of ADs and to display them instantaneously. DISCUSSION - CONCLUSION: Based on the observation of the obstacles to the use of ADs, the strategy we implemented aims to provide information that is both efficient and ethically respectful for both patients and caregivers. ADs are only one element facilitating autonomy and anticipation, and must be associated with a shared continuous definition of the project and of the goals of care.

[End of life and cancer: Understanding the ethical issues of voluntary assisted dying]. / Fin de vie et cancer : comprendre en 2023 les enjeux de la demande d'aide active à mourir.

In its advice No. 139 entitled "Ethical issues related to end-of-life situations: autonomy and solidarity", the National Ethics Committee opens for the first time in France the way to a possible active assistance in dying (assisted suicide or euthanasia). Such an ethical, legal and medical evolution would have major consequences in the palliative approach proposed to cancer patients. This clarification aims to enlighten the reflection, in a very complex societal debate. About thirty issues of the supporters and opponents of the legalization of active assistance in dying are first detailed. The values of autonomy and freedom are confronted with those of medical care and solidarity; the individual approach clashes with the collective interest; the interest of the patient and the place of the physician are considered from different angles. Finally, we propose a reflective path, in order to examine step by step the stakes, by examining successively the diagnosis of end of life conditions in France, then the questions asked and the proposals about: suicide; the principle of active assistance in dying; the procedures for reviewing a request for active assistance in dying; the modalities of implementation (assisted suicide or euthanasia); the place of the physician as agent of this decision. Only an analytical approach will make it possible to avoid amalgams and cognitive biases in a debate that closely mixes rationality and emotions.

PALLIA 10 score in phase I cancer studies.

OBJECTIVE: Phase I clinical trials usually include patients with advanced disease who have failed standard therapies and should benefit from early palliative care. We try to assess whether PALLIA 10, a score developed in France to help identify patients who might benefit from a palliative care referral, could be used in a phase I department trial. METHODS: We assessed PALLIA 10 score and other prognostic factors in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during two periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done in C2 by a palliative care specialist and a nurse. RESULTS: From 1 July 2018 to 1 November 2018 (C1) and from 1 December 2020 to 16 April 2021 (C2), 86 patients were assessed in C1 and 302 in C2. Median PALLIA 10 was very low in both cohorts (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1-6) and phase I nurse (median 3, range 1-8) (p<0.001). CONCLUSION: Median PALLIA 10 score was low when assessed by the phase I physician, which suggests the need for a better tool and appropriate clinician's education to implement early palliative care in clinical practice and trials.

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study.

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Development of a Decision-Aid Form (DAF) for the stratification of care in a French comprehensive cancer center, a tool to support identification of care goals.

BACKGROUND: For cancer patients, life-threatening complications may be difficult to anticipate, which can lead to complex medical decision-making processes. Since 2015, the Gustave Roussy Cancer Center has used a Decision-Aid Form (DAF), which contains an estimated gradation of care in cases where patients' conditions worsen. In this study, we assessed the acceptability of the DAF and the predictive value of the proposed stratification of care with regard to care delivered and patient's outcomes. METHODS: During a 5-month period, all patients who had been transferred from Site 1 to Site 2 of the hospital were prospectively included. RESULTS: A DAF was completed for 89.3% of the 206 patients included. Planned stratification of care was indicated in nearly all cases. The involvement of the palliative care team was indicated in only 29% of the DAF. The value of the WHO/ECOG Performance Status (PS) was limited. Finally, the field "information for patients and relatives" was infrequently completed. Although the possibility of transfer to the Intensive Care Unit was proposed for two-thirds of the patients, 76% of the 35 patients experiencing an acute event received only medical or palliative care. Overall, the level of therapeutic commitment suggested by the DAF was most often revised towards less aggressive care. CONCLUSIONS: The results of our study suggest that implementing an advanced stratification record is possible in a French cultural setting. To achieve complete cultural acceptance, our large integrated institutional program continues to play a key role in anticipating intent, tracing and sharing information with patients and their relatives.

Using targeted therapies at the end of life.

The prescription of chemotherapy during the last weeks of a patient's life is a recognised criterion of decreasing quality of life but also survival. Targeted therapies have a particular efficiency and tolerance profile raising the question of their use in a palliative setting. Two patients were treated for a melanoma, at terminal stage, with poor efficiency of the symptomatic treatments. We introduced targeted therapies, which was previous treatments used in both patients.The evolution and benefits of the treatment was very different in our two patients and make us discuss the interest of targeted therapies in an end-of-life context and propose criteria for their maintenance or introduction in this indication. This discussion requires close collaboration between oncologists and palliative physicians and a very clear information given to patients and their relatives.

Absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti-programmed death protein (ligand) 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune-related toxicities.

AIM: Despite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. METHODS: In this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD-(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. RESULTS: Overall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. CONCLUSION: Most patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

[An updated synthesis of the international recommendations about the use of non-pharmacological interventions in the treatment of fatigue]. / Synthèse actualisée des recommandations internationales sur le traitement de la fatigue par des interventions non pharmacologiques.

INTRODUCTION: Fatigue is a frequent and disturbing symptom in oncology but remains undertreated. Given the absence of effective drug treatment, non-pharmacological interventions have a prominent place in the treatment of fatigue. However, they are relatively unknown by professionals who lack of clear points of reference to refer patients with confidence. This article aims to improve the knowledge about this therapeutic field through an updated synthesis of the levels of recommendations and available evidence. METHODS: A three-step approach was conducted, including (1) a synthesis of international guidelines on non-pharmacological interventions in the treatment of fatigue among adults in oncology, (2) a systematic review of recent data in the literature, (3) a comparison between the synthesis of guidelines and the systematic review with the aim of updating the levels of evidence. RESULTS: Five guidelines were synthesized; 111 systematic reviews were analyzed. Their comparison mainly showed: (1) a convergence in favor of the use of physical activity, educational interventions and cognitive-behavioral therapies, with levels of evidence ranging from moderate to high; (2) a consolidation of short-term efficacy evidence to support the use of mindfulness-based approaches and yoga; 3) the persistence of a lack of sufficiently reliable data to establish the efficacy of other types of intervention. DISCUSSION: Supported by international guidelines and recent data, the use of non-pharmacological interventions in the treatment of fatigue is critical and has to become better known.

Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma.

BACKGROUND: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. RESULTS: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. CONCLUSION: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. TRIAL REGISTRATION NUMBER: NCT01557114.

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.

The 2016-2019 ImmunoTOX assessment board report of collaborative management of immune-related adverse events, an observational clinical study.

PURPOSE: We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs). EXPERIMENTAL DESIGN: The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019. RESULTS: Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216). CONCLUSION: The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.

An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells.

Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5'-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance.

Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients.

PURPOSE: Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation. METHODS: An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy. RESULTS: One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%). CONCLUSION: Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.

Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.

The most recent progress in the oncology field has led to a paradigm shift in the management of cancer with the tsunami of immune checkpoint inhibitors that are associated with a particular pattern of immunological adverse events. This is a case of a 54-year-old woman that demonstrated a granulomatous reaction in the same dermatomal distribution of a previously treated shingles infection during treatment with an anti-programmed death 1 agent (pembrolizumab) for a newly diagnosed stage IV Hodgkin lymphoma. The purpose of this case is to increase the awareness of oncologists dealing with a new pattern of side effects taking into account the patient's background and recent exposures to latent viruses such as herpes zoster to prevent unnecessary diagnostic and therapeutic measures.

Renal toxicities associated with pembrolizumab.

OBJECTIVE: Expanded clinical experience with patients treated by pembrolizumab has accumulated. However, renal toxicities associated with this anti-programmed cell death 1 agent are poorly described because kidney histology is rarely sought. As a nephrology referral centre, we aimed to describe the clinic-biological and histopathological characteristics of pembrolizumab-related nephropathy and its response to treatment. METHODS: We conducted a monocentric large case series study, including all pembrolizumab-treated cancer patients presenting a renal toxicity addressed to our centre from 2015 to 2017. RESULTS: A total of 12 patients (7 men) out of 676 pembrolizumab-treated patients (incidence 1.77%) were included (median age 69.75 years). Patients were referred for acute kidney injury (n = 10) and/or proteinuria (n = 2). A kidney biopsy was performed in all patients, with a median duration of use of 9 months (range 1-24 months) after the beginning of treatment. Biopsy showed that four patients had acute interstitial nephritis (AIN), whereas five had acute tubular injury (ATI) alone, one had minimal change disease (MCD) and ATI, and one had MCD alone. Pembrolizumab withdrawal coupled with corticosteroid therapy was the most effective treatment for kidney function recovery. Drug reintroduction resulted in a more severe recurrence of AIN in one patient who required maintenance of pembrolizumab. Two patients died of cancer progression with one of them developing severe renal failure requiring dialysis. CONCLUSION: In our series, ATI, AIN and MCD are the most frequent forms of kidney involvement under pembrolizumab therapy. Kidney dysfunction is usually isolated but can be severe. Use of corticosteroids in case of AIN improves the glomerular filtration rate.

Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy.

PURPOSE: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1), or its ligand PD-L1, are the mainstay of metastatic cancer treatment. Patients receiving these treatments may develop immune-related adverse events (irAEs). This study aimed to estimate the prevalence and describe the clinical patterns of moderate-to-severe ocular irAEs-associated with anti-PD-(L)1 treatment. DESIGN: Prospective case series. METHODS: This study included patients recruited via (1) a single-center prospective cohort and (2) a national pharmacovigilance registry between June 2014 and March 2018, and focused on patients with moderate-to-severe ocular irAEs following anti-PD-(L)1. All patients underwent a comprehensive ophthalmologic assessment. The main outcome measure was the prevalence of moderate-to-severe ocular irAEs. RESULTS: Of a total of 745 patients included in the prospective cohort, 3 developed moderate-to-severe ocular irAEs, providing a prevalence of 0.4% and an incidence of 0.7 per 1000 patient-months of treatment. An additional 5 cases of moderate-to-severe ocular irAEs were reported through the national registry. From these 8 patients, 5 presented with intraocular inflammation, 2 with ocular surface disease, and 1 with orbital myopathy. Five patients (62.5%) experienced additional extraophthalmologic irAEs. Ocular irAEs led to permanent discontinuation of anti-PD-(L)1 in 4 patients. Treatment by local and/or systemic corticosteroids allowed resolution or control of the ocular symptoms in 7 of 8 patients. CONCLUSION: Although uncommon, anti-PD-(L)1-associated ocular complications may be sight-threatening and lead to discontinuation of anti-PD-(L)1 treatments. Patients complaining of eye problems while receiving ICI treatment should immediately be seen by an ophthalmologist.