Severe Colitis in 2 Patients with Melanoma Treated with BRAF/MEK Inhibitors: Case Report and Literature Review.

Introduction: Encorafenib and binimetinib, a combination of BRAF and MEK inhibitors, is a standard of care for patients with advanced BRAFV600-mutant melanoma. This combination is known to have gastrointestinal side effects, most of which are mild and managed symptomatically. However, very few studies have reported severe colitis. Case Presentation: We report here 2 patients with advanced melanoma who developed severe ulcerated right colitis manifested by diarrhea and hematochezia while being treated with encorafenib and binimetinib after immune checkpoint therapy. Conclusion: This rare but serious adverse event was not described in early phase 3 trials but has emerged in recent years, particularly with the sequential use of immune checkpoint inhibitors followed by BRAF/MEK inhibitors. In a comprehensive review of the existing literature, we identified 20 cases of severe colitis due to BRAF/MEK inhibitors. Clinical, endoscopic, and histological features are described to provide insight into the current understanding of this poorly understood clinical entity.

Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma.

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

[Renal carcinoma: what therapeutic options in 2024?] / Carcinome rénal : quelles attitudes thérapeutiques en 2024 ?

The most important modifiable risk factors of renal cell carcinoma are smoking, obesity and hypertension. A biopsy of the renal tumour is not always necessary. It is important in situations where it can change the therapeutic attitude and should be discussed in particular for tumors < 4 cm in size and in metastatic stage. Treatment of localized and locoregional disease consists mainly of surgical removal of the tumor. Local ablative therapy (radiofrequency, thermoablation) or active surveillance are options for small tumors < 4 cm and frail patients with high surgical risk. Systemic treatment of metastatic disease consists of antiangiogenic tyrosine kinase inhibitors and immunotherapy with checkpoint inhibitors.

Les facteurs de risque modifiables du carcinome à cellules rénales les plus importants sont le tabagisme, l'obésité et l'hypertension. Une biopsie de la néoplasie rénale n'est pas toujours nécessaire. Elle est importante dans les situations où elle peut conduire à un changement d'attitude thérapeutique et devrait être discutée notamment pour les néoplasies dont la taille est < 4 cm et lors de situation métastatique. Le traitement de la maladie localisée consiste surtout en une exérèse chirurgicale. Un traitement ablatif local (radiofréquence, thermoablation) ou une surveillance active sont des options pour les petites néoplasies < 4 cm et pour les patients ayant un risque chirurgical élevé. Le traitement systémique de la maladie métastatique comprend les immunothérapies et les inhibiteurs de tyrosine kinases antiangiogéniques.

[PARP inhibitors - A better selection of patients]. / Inhibiteurs de la PARP : une meilleure sélection des patient-e-s.

PARP inhibitors (PARPi) have established themselves as a class of essential anti-cancer drugs. They inhibit PARP proteins involved in DNA damage repair. Their anti-tumor action requires a concomitant abnormality in DNA damage repair, the homologous recombination deficiency (HRD). The genomic instability being too substantial, the tumor cell goes into apoptosis (concept of synthetic lethality). This last decade, the selection of patients benefiting from PARPi has been refined with convincing results for ovarian cancers, but also breast, prostate and pancreatic cancers. This article presents recent data that have impacted our clinical practice and the PARPi authorized in Switzerland.

Les inhibiteurs de la PARP (poly-ADP-ribose-polymérase : iPARP) se sont imposés comme une classe de médicaments anticancéreux incontournable. Ils inhibent les protéines PARP impliquées dans la réparation de l'ADN. Leur action antitumorale nécessite une anomalie concomitante dans la réparation de l'ADN, le déficit de recombinaison homologue (HRD). L'instabilité génomique devenant trop conséquente, la cellule tumorale entre en apoptose (concept de synthetic lethality). La sélection des patient-e-s bénéficiant des iPARP s'est affinée cette dernière décennie avec des résultats probants pour les cancers de l'ovaire, mais aussi du sein, de la prostate et du pancréas. Cet article présente les données récentes ayant impacté notre pratique clinique et les iPARP autorisés en Suisse.

ALK-negative anaplastic large cell lymphoma with DUSP22 rearrangement has distinctive disease characteristics with better progression-free survival: a LYSA study.

ALK-negative anaplastic large cell lymphoma (ALCL) comprises subgroups harboring rearrangements of DUSP22 (DUSP22- R) or TP63 (TP63-R). Two studies reported 90% and 40% 5-year overall survival (OS) rates in 21 and 12 DUSP22-R/TP63- not rearranged (NR) patients, respectively, making the prognostic impact of DUSP22-R unclear. Here, 104 newly diagnosed ALK-negative ALCL patients (including 37 from first-line clinical trials) from the LYSA TENOMIC database were analyzed by break-apart fluorescence in situ hybridization assays for DUSP22-R and TP63-R. There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R case. DUSP22-R tumors more frequently showed CD3 expression (62% vs. 35%, P=0.01), and less commonly a cytotoxic phenotype (27% vs. 82%; P<0.001). At diagnosis, DUSP22- R ALCL patients more frequently had bone involvement (32% vs. 13%, P=0.03). The patient with DUSP22-R/TP63-R ALCL had a rapidly fatal outcome. After a median follow-up of 4.9 years, 5-year progression-free survival (PFS) and OS rates of 84 patients without TP63-R treated with curative-intent anthracycline-based chemotherapy were 41% and 53%, respectively. According to DUSP22 status, 5-year PFS was 57% for 39 DUSP22-R versus 26% for 45 triple-negative (DUSP22-NR/TP63-NR/ALK-negative) patients (P=0.001). The corresponding 5-year OS rates were 65% and 41%, respectively (P=0.07). In multivariate analysis, performance status and DUSP22 status significantly affected PFS, and distinguished four risk groups, with 4-year PFS and OS ranging from 17% to 73% and 21% to 77%, respectively. Performance status but not DUSP22 status influenced OS. The use of brentuximab vedotin in relapsed/refractory patients improved OS independently of DUSP22 status. Our findings support the biological and clinical distinctiveness of DUSP22- R ALK-negative ALCL. Its relevance to outcome in patients receiving frontline brentuximab vedotin remains to be determined.

Safety and Efficacy of Ipilimumab plus Nivolumab and Sequential Selective Internal Radiation Therapy in Hepatic and Extrahepatic Metastatic Uveal Melanoma.

To assess the safety and efficacy of ipilimumab plus nivolumab around selective internal radiation therapy (SIRT) in patients with metastatic uveal melanoma (mUM). We present a retrospective, single center study of 32 patients with mUM divided into two groups based on the treatment received between April 2013 and April 2021. The SIRT_IpiNivo cohort was treated with Yttrium-90 microspheres and ipilimumab plus nivolumab before or after the SIRT (n = 18). The SIRT cohort underwent SIRT but did not receive combined immunotherapy with ipilimumab plus nivolumab (n = 14). Twelve patients (66.7%) of the SIRT_IpiNivo arm received SIRT as first-line treatment and six patients (33.3%) received ipilimumab plus nivolumab prior to SIRT. In the SIRT group, seven patients (50.0%) received single-agent immunotherapy. One patient treated with combined immunotherapy 68 months after the SIRT was included in this group. At the start of ipilimumab plus nivolumab, 94.4% (n = 17) presented hepatic metastases and 72.2% (n = 13) had extra liver disease. Eight patients (44.4%) of the SIRT_IpiNivo group experienced grade 3 or 4 immune related adverse events, mainly colitis and hepatitis. Median overall survival from the diagnosis of metastases was 49.6 months (95% confidence interval (CI); 24.1-not available (NA)) in the SIRT_IpiNivo group compared with 13.6 months (95% CI; 11.5-NA) in the SIRT group (log-rank p-value 0.027). The presence of extra liver metastases at the time of SIRT, largest liver lesion more than 8 cm (M1c) and liver tumor volume negatively impacted the survival. This real-world cohort suggests that a sequential treatment of ipilimumab plus nivolumab and SIRT is a well-tolerated therapeutic approach with promising survival rates.

Estimated Costs of the Ipilimumab-Nivolumab Therapy and Related Adverse Events in Metastatic Melanoma.

Combined ipilimumab and nivolumab significantly improve outcomes in metastatic melanoma patients but bear an important financial impact on the healthcare system. Here, we analyze the treatment costs, focusing on irAE. We conducted a retrospective analysis of 62 melanoma patients treated with ipilimumab-nivolumab at the Lausanne University Hospital between 1 June 2016 and 31 August 2019. The frequency of irAEs and outcomes were evaluated. All melanoma-specific costs were analyzed from the first ipilimumab-nivolumab dose until the therapy given subsequently or death. A total of 54/62 (87%) patients presented at least one irAE, and 31/62 (50%) presented a grade 3-4 irAE. The majority of patients who had a complete response 12/14 (86%) and 21/28 (75%) of overall responders presented a grade 3-4 toxicity, and there were no responses in patients without toxicity. Toxicity costs represented only 3% of the total expenses per patient. The most significant contributions were medication costs (44%) and disease costs (39%), mainly disease-related hospitalization costs, not toxicity-related. Patients with a complete response had the lowest global median cost per week of follow up (EUR 2425) and patients who had progressive disease (PD), the highest one (EUR 8325). Except for one patient who had a Grade 5 toxicity (EUR 6043/week), we observe that less severe toxicity grades (EUR 9383/week for Grade 1), or even the absence of toxicity (EUR 9922/week), are associated with higher median costs per week (vs. EUR 3266/week for Grade 4 and EUR 2850/week for Grade 3). The cost of toxicities was unexpectedly low compared to the total costs, especially medication costs. Patients with higher toxicity grades had better outcomes and lower total costs due to treatment discontinuation.

[Immunotherapy with immune checkpoint inhibitor and skin toxicity]. / Immunothérapie par inhibiteurs de points de contrôle immunitaire et toxicité dermatologique.

Dermatologic toxicities appear to be the most prevalent immunotherapy related adverse effects, both with anti-PD-1 and anti-CTLA-4 agents, as well as with the newly developed anti-PD-L1. They occur in more than one-third of the patients treated with immune check point inhibitors, regardless of the cancer being treated. They mainly manifest in the form of self-limiting maculopapular rashes and pruritus. Early recognition and management are essential in order to mitigate the severity of the lesions. A multidisciplinary team is crucial for optimal management.

Les toxicités cutanées sont les effets indésirables les plus fréquents des inhibiteurs des points de contrôle immunitaire, que ce soit avec les anti-Programmed Cell Death 1, les anti-Cytotoxic T Lymphocyte Antigen-4 ou les nouveaux anti-Programmed Cell Death-Ligand 1. Ils surviennent chez plus d'un patient sur trois, et ce quel que soit le cancer traité. Ils se manifestent le plus souvent par un rash maculopapuleux limité au niveau du tronc et des membres et un prurit. Des toxidermies graves (syndromes de Lyell, de Stevens-Johnson ou d'hypersensibilité médicamenteuse) ainsi que des dermatoses autoimmunes (maladies bulleuses, lupus érythémateux disséminé) sont plus rares, mais leur reconnaissance et leur prise en charge précoces sont essentielles. Une évaluation multidisciplinaire est, dans ces cas, souvent indispensable pour une prise en charge optimale de la toxicité et ne pas prétériter la poursuite du traitement.

[Locally advanced and metastatic melanoma : novelties]. / Mélanome localement avancé et métastatique : nouveautés.

The standard of care of melanoma patients has evolved at a rapid pace with the advent of immune checkpoint inhibitors and BRAF and MEK inhibitors. ESMO guidelines were revised in September 2019 to integrate the results of recent studies that broaden the indication of these treatments to the adjuvant setting and validated new limitations to completion lymph node dissection in the case of a positive sentinel lymph node biopsy in locally advanced melanoma. We hereby detail the main novelties of the revised ESMO 2019 guidelines.

L'évolution de la prise en charge des patients atteints d'un mélanome a été accélérée avec l'avènement des inhibiteurs de points de contrôle immunitaire et des inhibiteurs BRAF et MEK. Les guidelines de la Société européenne d'oncologie médicale (ESMO) ont été révisées en septembre 2019 pour intégrer les résultats des récentes études, élargissant les indications de ces traitements en situation adjuvante. La place du curage ganglionnaire en cas d'atteinte du ganglion sentinelle dans les mélanomes localement avancés est aussi rediscutée. Nous détaillons ici les principales nouveautés des guidelines de l'ESMO 2019.

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

Multiple nivolumab-induced CNS demyelination with spontaneous resolution in an asymptomatic metastatic melanoma patient.

BACKGROUND: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity. CASE PRESENTATION: We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy. He developed asymptomatic multifocal diffuse white matter lesions consistent with active central nervous system demyelination seen on brain MRI. One month after cessation of the immunotherapy, spontaneous regression of the demyelinating lesions was observed, suggesting a nivolumab-related toxicity. CONCLUSION: We report the first case of a melanoma patient with an asymptomatic and spontaneously reversible central nervous system demyelination following nivolumab immunotherapy. This case highlights the need for better recognition of such atypical and rare neurological toxicities which could be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution.

Sinonasal relapses of a primary isolated extranodal NK/T-cell lymphoma of the testis.

WHO first recognised extranodal NK/T-cell lymphoma (ENKTCL) in 2001, thanks to technical advances in anatomopathology and immunohistochemistry. It is divided into nasal and extranasal subgroups depending on the primary site. Primary isolated NK/T-cell lymphoma of the testis is rare. Typical recurrence sites of primary testicular NK/T-cell lymphoma are the gastrointestinal tract, lymph nodes, skin, spleen and central nervous system. Nasal relapses of a primary NK/T-cell lymphoma of the testis are very rare and according to our knowledge, no other case has been reported yet in the literature. The authors report the case of a 35-year-old Caucasian man relapsing twice in the nasal cavity 1 year after initial diagnosis and treatment of a primary isolated, stage IE, ENKTCL of the testis. We report the clinical and radiological presentation of the nasal relapses and the different modalities of treatment that were applied. Sinonasal relapses of an isolated primary NK/T-cell lymphoma of the testis are very rare. ENKTCL is a very aggressive entity, even at an early stage, therefore, requiring a multimodal treatment approach including chemotherapy and radiotherapy. New strategies to treat this disease are needed.

[Immunotherapy with immune checkpoint inhibitors and hepatitis]. / Immunothérapie par inhibiteurs de points de contrôle immunitaire et hépatite.

Immunotherapy, with « checkpoint ¼ inhibitors (CPIs), has become an essential therapeutic weapon against cancer. Autoimmune disorders related to overactivation of the immune system are well known side effects. The risk of reactivation of the hepatitis B and C viruses and exacerbation of the hepatitis, known from the introduction of immunosuppressive drugs such as chemotherapy, is poorly documented under immunotherapy. In this article, we discuss the issue of immunotherapy in patients presented with hepatitis using two approaches: the risks of immunotherapy in these situations and the management by disruption of liver tests under immunotherapy.

L'immunothérapie, avec les inhibiteurs de points de contrôle immunitaire « immune checkpoint inhibitors ¼, est devenue une arme thérapeutique essentielle contre de nombreux cancers. Les troubles autoimmuns liés à la suractivation du système immunitaire sont des effets secondaires bien connus. Le risque de réactivation des virus de l'hépatite B et C ou d'exacerbation de l'hépatite, connu lors de l'introduction de médicaments immunosuppresseurs telles les chimiothérapies, est peu documenté sous immunothérapie. Dans cet article, nous aborderons la question de l'immunothérapie chez des patients présentant une hépatite B ou C selon deux approches : les risques encourus à introduire une immunothérapie dans ces situations et la gestion d'une perturbation des tests hépatiques sous immunothérapie.

Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial.

PURPOSE: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses. EXPERIMENTAL DESIGN: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination. Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells. RESULTS: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients. CONCLUSIONS: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies.

[Diarrhea caused by systemic anti-cancer treatments]. / Diarrhées provoquées par les traitements systémiques anticancéreux.

Diarrhea is one of the most common complaints in oncologic patients. Causes are multiple including bowel resection, infections, radiation and systemic anti-cancer treatments. In the latter case, the pathophysiology is partially elucidated and requires the etiology to be precisely identified : chemotherapy, targeted therapy or immunotherapy. Loperamide remains central in uncomplicated cases. However, with development of immunotherapy, autoimmune mechanism should be recognized and requires different approach based mainly on corticosteroids. Physician taking care of patients with diarrhea should therefore identify possible causes in order to offer adapted treatments and therefore reduce morbidity and mortality.

Les diarrhées sont l'une des plaintes les plus fréquentes chez les patients oncologiques. On retrouve des étiologies multiples comme la résection digestive, les infections, la radiothérapie et les traitements anticancéreux systémiques. Dans ce dernier cas, la pathophysiologie est partiellement élucidée et nécessite d'en différencier l'étiologie : chimiothérapie, thérapie ciblée ou immunothérapie. Le lopéramide reste le traitement standard des cas non compliqués. Avec le développement de l'immunothérapie, un mécanisme auto-immun doit être reconnu car il nécessite une prise en charge différente reposant principalement sur l'utilisation des corticoïdes. Le médecin faisant face à un patient présentant une diarrhée doit de ce fait identifier la ou les causes possibles et ainsi adapter le traitement afin d'en réduire la morbidité et la mortalité.

Accuracy of sentinel lymph node dissection for melanoma staging in the presence of a collision tumour with a lymphoproliferative disease.

Sentinel lymph node dissection (SLND) identifies melanoma patients with metastatic disease who would benefit from radical lymph node dissection (RLND). Rarely, patients with melanoma have an underlying lymphoproliferative disease, and melanoma metastases might develop as collision tumours in the sentinel lymph node (SLN). The aim of this study was to measure the incidence and examine the effect of collision tumours on the accuracy of SLND and on the validity of staging in this setting. Between 1998 and 2012, 750 consecutive SLNDs were performed in melanoma patients using the triple technique (lymphoscintigraphy, gamma probe and blue dye). The validity of SLND in collision tumours was analysed. False negativity was reflected by the disease-free survival. The literature was reviewed on collision tumours in melanoma. Collision tumours of melanoma and chronic lymphocytic leukaemia (CLL) were found in two SLN and in one RLND (0.4%). Subsequent RLNDs of SLND-positive cases were negative for melanoma. The patient with negative SLND developed relapse after 28 months with an inguinal lymph node metastasis of melanoma; RLND showed collision tumours. The literature review identified 12 cases of collision tumours. CLL was associated with increased melanoma incidence and reduced overall survival. This is, to our knowledge, the first assessment of the clinical value of SLND when collision tumours of melanoma and CLL are found. In this small series of three patients with both malignancies present in the same lymph node basin, lymphocytic infiltration of the CLL did not alter radioisotope uptake into the SLN. No false-negative result was observed. Our data suggest the validity of SLND in collision tumours, but given the rarity of the problem, further studies are necessary to confirm this reliability.

Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.

T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.