[Pathological pelvic lymph node involvement in muscle-invasive bladder cancer patients treated with radical cystectomy: A narrative review]. / Envahissement ganglionnaire pelvien anatomopathologique après cystectomie totale pour le traitement des tumeurs de vessie infiltrant le muscle : une revue narrative de la littérature.

OBJECTIVE: To perform a narrative review of the contemporary literature on the diagnosis, prognosis and adjuvant management of muscle-invasive bladder cancer (MIBC) patients with pathological pelvic lymph node involvement (pN+) at radical cystectomy. METHOD: A narrative review of the contemporary literature available on Medline was conducted to report studies evaluating the diagnosis, prognosis and/or adjuvant treatments for MIBC patients with pN+ disease at radical cystectomy. RESULTS: Open or robotic extended pelvic lymph node dissection up to the crossing of the ureter with common iliac vessels can enhance the diagnosis of pN+ MIBC, especially using separate packages for the submission of a maximum number of lymph nodes. The main prognosis factors for pN+ patients are the number of positive and retrieved lymph nodes, lymph node density, extranodal extension as well as lymph node metastasis diameter. Adjuvant chemotherapy is likely to prolong overall survival in pN+ patients treated with radical cystectomy alone while adjuvant immunotherapy using nivolumab has been shown to decrease the risk of recurrence in all pN+ patients, especially those with ypN+ disease after neoadjuvant chemotherapy followed by radical cystectomy. However, few data are currently available on the role of adjuvant radiation therapy, which remains currently experimental for these patients. CONCLUSION: Multiple parameters have been reported to impact the diagnosis and prognosis of patients with pN+ MIBC at radical cystectomy. Adjuvant management is currently based on chemotherapy and immunotherapy with preliminary data on radiation therapy.

[Pathological complete response of a metastatic MisMatch Repair deficient/MicroSatellite Instable colon cancer after immunotherapy: A case report]. / Réponse histologique complète d'un cancer colique métastatique de phénotype MisMatch Repair déficient/MicroSatellite Instable après immunothérapie : à propos d'un cas.

Immunotherapies are part of the therapeutic strategy in many cancers and are indicated for metastatic colorectal adenocarcinoma with loss of expression of MisMatch Repair system proteins or with microsatelite instability (dMMR/MSI) in the United States. The rate of pathological response to immunotherapy remains poorly documented, but several cases of complete or major pathological response have recently been described. We decided to report the case of a complete pathological response to immunotherapy of a dMMR/MSI colorectal adenocarcinoma in a 74-year-old patient, initially inoperable due to duodenal invasion. Three months after the introduction of immunotherapy, the patient developed drug-induced colitis that contraindicated further treatment. Histological examination of the subtotal colectomy specimen revealed no residual tumour cells. The patterns of tumour regression were mainly represented by colloid regression, infarctoid-type necrosis and a resorptive inflammatory reaction. Although the operative indications for patients with metastatic dMMR/MSI colorectal cancer treated by immunotherapy are still very limited, the number of such specimens is expected to increase rapidly. The management of these specimens, as well as the possibility of a complete histological response, must be known by pathologists who play a key role in the pathophysiological knowledge of these lesions.

French AFU Cancer Committee Guidelines - Update 2022-2024: management of kidney cancer.

AIM: To update the recommendations for the management of kidney cancers. METHODS: A systematic review of the literature was conducted from 2015 to 2022. The most relevant articles on the diagnosis, classification, surgical treatment, medical treatment and follow-up of kidney cancer were selected and incorporated into the recommendations. Therefore, the recommendations were updated while specifying the level of evidence (high or low). RESULTS: The gold standard for the diagnosis and evaluation of kidney cancer is contrast-enhanced chest and abdominal CT. MRI and contrast-enhanced ultrasound are indicated in special cases. Percutaneous biopsy is recommended in situations where the results will influence the therapeutic decision. Renal tumours should be classified according to the pTNM 2017 classification, the WHO 2022 classification and the ISUP nucleolar grade. Metastatic kidney cancer should be classified according to the IMDC criteria. Partial nephrectomy is the gold standard treatment for T1a tumours and can be performed by an open approach, by laparoscopy or by robot-guidance. Active surveillance of tumours less than 2cm in size can be considered regardless of the patient's age. Ablative therapies and active surveillance are options in elderly patients with comorbidity. T1b tumours should be treated by partial or radical nephrectomy depending on the complexity of the tumour. Radical nephrectomy is the first-line treatment for locally advanced cancers. Adjuvant treatment with pembrolizumab should be considered in patients at intermediate and high risk for recurrence after nephrectomy. In metastatic patients: Immediate cytoreductive nephrectomy may be offered to oligometastatic patients in combination with local treatment of metastases if this can be complete and delayed cytoreductive nephrectomy can be proposed for patients with a complete response or a significant partial response. Medical treatment should be proposed as first-line therapy for patients with a poor or intermediate prognosis. Surgical or local treatment of metastases can be proposed in case of single or oligo-metastases. The recommended first-line drugs for metastatic patients with clear cell renal carcinoma are the combinations axitinib/pembrolizumab, nivolumab/ipililumab, nivolumab/cabozantinib and lenvatinib/pembrolizumab. Cabozantinib is the recommended first-line treatment for patients with metastatic papillary carcinoma. Cystic tumours should be classified according to the Bosniak classification. Surgical removal should be proposed as a priority for Bosniak III and IV lesions. It is recommended that patient monitoring be adapted to the aggressiveness of the tumour. CONCLUSION: These updated recommendations are a reference that will allow French and French-speaking practitioners to improve kidney cancer management.

[Path of a fighter]. / La désensibilisation allergénique au secours de la récidive.

Allergy is a frequent and often disabling condition for the patients. In the context of allergic rhinitis and asthma or anaphylactic shock to hymenoptera venom, allergenic desensitization can be proposed to limit the symptoms or recurrence of major reactions. Access to this treatment is made difficult by a lack of allergists, a lack of products or, more recently, by the Covid-19 crisis.

[Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. / Régression de carcinomes basocellulaire et épidermoïde cutanés sous pembrolizumab.

BACKGROUND: The recommended treatments for advanced squamous cell carcinoma (SCC) (chemotherapy, radiotherapy, anti-EGFR) and advanced basal cell carcinoma (BCC) (vismodegib and sonidegib) have many side effects. Nivolumab (anti-PD1 antibody) may be used as second-line therapy in SCC of the head and neck. We report the case of a patient with advanced SCC and BCC which regressed under pembrolizumab. PATIENTS AND METHODS: A 69-year-old man consulted for a large vertex SCC measuring 15cm in diameter. He also had BCC on the left nostril and sternal Bowen disease. Radiological assessment revealed cervical and parotid lymph node involvement. Treatment with pembrolizumab 2mg/kg every 3 weeks was decided at a Multidisciplinary Concertation Meeting. Tumor regression of the vertex SCC was noted at the third course of treatment, as well as regression of the nasal BCC and the sternal Bowen disease. A complete response was observed after 11 courses of treatment for SCC, 7 courses for BCC, and 10 courses for Bowen disease. CONCLUSION: We report an original case of cure of BCC with anti-PD1 (pembrolizumab) prescribed for locally advanced inoperable SCC. The place of this treatment in the therapeutic arsenal remains to be defined. Clinical trials are in progress concerning use of this treatment in advanced cutaneous SCC and inoperable BCC.

[Impact on quality of life and autonomy of patients aged over 75 years treated with anti-PD-1 for metastatic melanoma: A single-centre prospective study]. / Impact sur la qualité de vie et l'autonomie des patients de plus de 75 ans traités par anti-PD-1 pour un mélanome métastatique : étude prospective monocentrique.

INTRODUCTION: We previously studied anti-PD-1 safety in elderly (≥80 years) patients and reported a retrospective two-centre cohort with a similar safety profile in elderly and in younger patients. Quality-of-life evaluation data is still lacking in this specific population. MATERIALS AND METHODS: A prospective, single-centre study in patients aged over 75 years presenting metastatic melanoma treated with anti-PD-1. The endpoint was monitoring of quality of life (by a specific survey) and onco-geriatric assessment at the beginning of therapy, then at 3 and 6 months (nutritional status, comorbidities, autonomy, thymic and cognitive disorders). RESULTS: Fourteen patients were included of median age 86.5 years [range: 78-94] from March to September 2018. General status was good, with a median Charlson score of 0 [extremes 0-4]. Nine patients were evaluated at 3 months and six patients at 6 months. There was no significant difference in quality-of-life scores obtained at baseline, 3 months and 6 months. DISCUSSION: This study shows that neither quality of life nor autonomy appears to be affected by anti-PD-1 treatment in patients aged over 75 years. However, these results should be interpreted with caution due to the small number of patients included, the short follow-up period and the single-centre data. Nevertheless, the prospective analysis and the complete onco-geriatric evaluation and monitoring yielded unique and original data.

[Thoracic oncology and tumor mutational burden: Towards new challenges for the pathologist?] / Oncologie thoracique et charge tumorale mutationnelle : vers un nouveau défi pour le pathologiste ?

Among the different promising predictive biomarkers in immuno-oncology, the tumor mutational burden (TMB) may soon impose itself in clinical routine practice, in association with PD-L1 immunohistochemistry testing. However, the TMB is used currently in clinical trials only, in particular in the thoracic oncology field. If this biomarker becomes mandatory in the near future, the pathologist will have to respond to new challenges in tight collaboration with the activity of molecular pathology platforms. Given the high incidence of lung cancer in France, this new development could have a strong impact on the daily life of the laboratories. This review addresses the different challenges which could be soon proposed to the laboratories and the pathologists due to the use of TMB assays on a daily practice.

[New guidelines for stage III melanoma (the French Cutaneous Oncology Group)]. / Actualisation des données concernant le mélanome stade III : nouvelles recommandations du groupe français de cancérologie cutanée.

Improved knowledge of sentinel node procedures coupled with the results of adjuvant clinical trials in stage III melanoma have prompted the French Cutaneous Oncology Group to propose new guidelines for the management of stage III melanoma. These guidelines comply with the principles of the evidence-based medicine.

[Primary central nervous system lymphoma following immunotherapy for metastatic melanoma]. / Lymphome cérébral primitif après immunothérapie d'un mélanome métastatique.

BACKGROUND: Anti-PD-1 and anti-CTLA-4 monoclonal antibodies are used in melanoma, while anti-PD-1 are also used in Hodgkin's lymphoma. Primary central nervous system lymphoma is a rare form of non-Hodgkin's lymphoma with few effective treatments. However, several recent studies have reported multiple cases of non-Hodgkin's lymphoma and primary central nervous system lymphoma treated by anti-PD-1 antibodies with favourable responses. PATIENTS AND METHODS: This study focuses on the case of a 59-year-old man with metastatic melanoma treated by immunotherapy (anti-CTLA-4 followed by anti-PD-1). He underwent 28 courses of therapy with pembrolizumab. Treatment was stopped after clinical and radiological remission. The patient presented left hemiparesis and a primary central nervous system lymphoma was diagnosed two months after discontinuation of immunotherapy. He started urgent high-dose methotrexate chemotherapy but without significant results. Despite second-line chemotherapy with R-ICE (rituximab-ifosfamide, carboplatin and etoposide), the patient died. DISCUSSION: Several hypotheses may be advanced regarding a possible relationship between immunotherapy and the occurrence of this primary central nervous system lymphoma. The lymphoma may have been pre-existing and controlled by immunotherapy, but progressing rapidly after treatment, or it may have been induced by the immunotherapy. However, immunotherapy may have played no role; the relationship between melanoma and lymphoma is well known. CONCLUSION: While immunotherapy cannot be unequivocally incriminated in primary central nervous system lymphoma, this case raises many questions about the imputability of immunotherapy in the occurrence of secondary cancers, including lymphomas.

[Treatment of high-risk leukaemia: allograft and immunotherapy]. / Traitement des leucémies à haut risque : allogreffe et immunothérapie.

Leukaemia results from a malignant proliferation of cells in the bone marrow. The prognosis is defined by the disease's biological characteristics. Treatment is based on chemotherapy. In cases of high-risk leukaemia, an allograft may be proposed. The arrival of targeted therapies and immunotherapy has revolutionised the prognosis of the disease. The challenge of the next few years will be to define the place of these therapies.

Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.

Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.

Traitement médical des carcinomes basocellulaires avancés: Medical treatment of advanced basal cell carcinoma.

Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge®) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo®) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. © 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

[Market access agreements: Definition and features. Could MAA be defined as a solution for immunotherapy funding by French health system?] / Les contrats d'accès au marché : définition et caractéristiques. Une solution pour garantir la prise en charge de l'immunothérapie par le système de santé français ?

Over the last few years, many therapeutic innovations have been approved and marketed in France, within a strained financial setting. Legal dispositions allowed manufacturers (LEEM - les enterprises du medicament) and the economic committee for health products (CEPS) to contract various confidential market access agreements to contain health product expenses. The purposes of this article are to define and describe these different existing market access agreements and to open discussion on their applicability to the problematic of immune-oncology drugs financing. Financial agreements, which led to major savings (discounts refunded to the public payer), have not responded completely to the therapeutic innovations financing problems. Performance agreements (funding based on real-life data and effectiveness of the drug) constitute a hope for health products financing, but major methodological challenges for their use in routine restrict them to rare cases only today. Even though several financial agreements could partly respond to this problematic, use of performance agreements could really constitute an interesting track to tackle this issue.

[Immunotherapy in renal cell carcinoma: A booming clinical research]. / L'immunothérapie dans le cancer du rein : un développement clinique en plein essor.

CONTEXT: Nivolumab, an anti-PD1 immune control point inhibitor, is the first treatment that has improved the overall survival of patients after first-line metastatic renal cell carcinoma in 2015. Over the past two years, a large number of trials on these treatments and the interest of associations are being evaluated. OBJECTIVE: In this article, we propose to summarize the clinical development of checkpoint inhibitors to assess the direction of clinical research in this area. DOCUMENTARY SOURCE: A systematic review of the literature was performed in PubMed/Medline database and Meeting Library Asco by searching for articles in French or English published on immunotherapy in renal cell carcinoma. The research was limited to abstracts and articles published from 2014 to 2017. SELECTION OF TRIALS: We identified 349 publications and abstracts and selected 17 references from prospective studies. RESULTS: Recent data on checkpoint inhibitors, as well as their combination with tyrosine kinase inhibitors or with anti-angiogenic agents or with indoleamine 2, 3-dioxygenase 1 in renal cell carcinoma and the latest advances in vaccine therapy have been reported. CONCLUSION: In 2017, immunotherapy combined with other treatments is likely to lead to a paradigm shift in the clinical management of patients. The combination of nivolumab and ipilimumab in the first line will revolutionize the therapeutic management of patients with metastatic renal cell carcinoma.

[Management of metastatic renal cell carcinomass]. / Prise en charge des métastases du cancer du rein.

The management of metastatic renal cell carcinoma had changed over the last ten years with the apparition of new treatments and advances in surgery and ablative techniques. The therapies for metastatic patients have also been personalized and different prognostic groups have been established to adapt the treatment to the severity of the disease. Surgical excision, radiotherapy or ablative therapy could be proposed for patients with isolated metastasis and good condition to delay the systemic therapy initiation. Until 2006, in case of metastatic renal cell carcinoma, immunotherapy (IL-2 and TNF-alpha) was proposed. Targeted therapies acting on angiogenesis mechanisms have also been developed. Recently, immunotherapy has revolutionized the therapeutic management and has improved the overall survival of patients with metastatic renal carcinoma. For each patient, a multidisciplinary management is organized with a personal therapeutic project. This global management needs coordination with the medical team and also need a good communication with the patient, his entourage and his doctor.

[The "immune checkpoints", how does it work]. / Les « immune checkpoints ¼, comment ça marche.

Costimulatory molecules allow the full lymphocyte activation, whereas co-inhibitory molecules are negative counterparts that act as immune regulators, avoiding excessive response. In some context of chronic inflammation such as cancer, co-inhibitory immune checkpoint as CTLA-4, PD-1, Lag-3, Tim-3 can accumulate at the membrane of T cells leading to a state of anergy and therefore the loss of tumor growth control. Consequently, these immune checkpoints are considered as potential target in the treatment of cancer. Immunotherapy by anti-CTLA-4 and anti-PD-1/PD-L1 early demonstrated very good proof of efficacy in the setting of several cancers types, supporting the role of these molecules in tumor immune escape. The aim of this review is to summarize the pathophysiology of immune checkpoints and their therapeutic applications in cancer.

[Tissue biomarkers of response to anti-PD-1 immunotherapies in melanoma]. / Biomarqueurs tissulaires des immunothérapies anti-PD-1 dans le mélanome.

Prognosis and treatment of advanced melanoma have been transformed by the success of immunotherapies, in particular agents targeting PD-1. PD-L1 expression assessed by immunohistochemistry in not an effective predictive biomarker to select patients in this tumor type, since significant clinical benefit was observed in the group of patients with negative tumors. The predictive value of PD-L1 testing to select patients for combination of anti-PD-1 and anti-CTLA-4 agents is under evaluation. Other tissue biomarkers are emerging to identify sensitive tumors to anti-PD-1 agents. In particular, assessment of immune infiltrates in tumor tissue, mutational load and tumor neoantigens seem promising in melanoma.

[Predictive biomarkers of efficacy of checkpoint blockade inhibitors in cancer treatment]. / Biomarqueurs prédictifs de l'efficacité des inhibiteurs de checkpoint immunitaire dans le traitement des cancers.

The remarkable efficacy of PD-1/PD-L1 and CTLA4 immune checkpoint inhibitors has led to numerous approvals in melanoma, non-small cell lung cancer, kidney cancer and several other cancers. Nevertheless, a response is observed in a variable proportion of patients, emphasizing the need for predictive biomarkers of efficacy of immune checkpoint inhibitors effectiveness. Several predictive biomarkers of efficacy are of interest: companion tests such PD-L1 immunohistochemistry, the mutational load, the immune status of the tumor and its molecular profile. They do not allow a perfect selection of the patients, but standardization procedures for certain techniques are ongoing. Moreover the emergence of new approaches, such as the multiplex in situ techniques and the microbiote analysis, may offer the opportunity to better select patients who really benefit from immunotherapy. The goal of this article is to discuss available and promising predictive biomarkers of efficacy for immunotherapy strategies.

[Current events in immunotherapy for upper aerodigestive tract cancer]. / Actualités sur l'immunothérapie en pathologie des voies aérodigestives supérieures.

Head and neck (HN) carcinomas (mostly represented by squamous cell carcinomas [SCC]) still have a poor prognosis, which could be dramatically improved with immunotherapy. Tumor's microenvironment changes, caused by many endogenous or exogenous events, can correlate with prognosis and therapeutic response. Here, we review recent data regarding HNSCC, nasopharyngeal carcinomas (NPC) and salivary gland malignant tumors, all three being potential target of immunotherapies. About half of HNSCC exhibit PD-L1 expression, this expression being upregulated in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1 has been obtained in patients with higher PD-L1 expression. Food and Drug Administration (FDA) approved the use of these therapeutics without the screening of patients regarding PD-L1 status. Activation status, density and localisation of TIL as well as PD-L2, γ-interferon, inflammatory cytokines, epithelial-mesenchymal transition phenotype and mutational burden may all be potential therapeutic response markers. In Epstein-Barr Virus (EBV)-induced nasopharyngeal non-keratinizing cancer, PD-L1 is over-expressed compared to EBV negative-tumors. A 22 % response rate has been observed under anti-PD-1 treatment, among PD-L1-positive HNSCC patients. There is little data regarding microenvironment of salivary gland cancer. PD-L1 shows great heterogeneity in localisation, when expressed. A 11 % response rate has been obtained under anti-PD-1 treatment among PD-L1-positive NPC patients. A better understanding of immune checkpoint regulation processes needs to be achieved to allow patients with HN carcinomas to benefit from these promising immunotherapies.