Introduction: The use of immune checkpoint inhibitors has revolutionized cancer treatment, and their application to older people is considered safe by the scientific community. However, immune-related adverse events (irAEs) remain common, and their management poses significant challenges, especially in this population. Case Presentation: We report the case of a fit 82-year-old woman who developed immune-mediated colitis and Fanconi syndrome during treatment with ipilimumab and nivolumab for metastatic melanoma. Treatment consisted of discontinuation of immunotherapy, use of systemic corticosteroids, and second-line immunosuppressants. Despite well-managed treatment, the patient did not recover and died from a gastrointestinal infection. Conclusion: Although studies have shown identical efficacy and safety in younger patients compared to older patients, the consequences of irAEs can potentially be more serious in the older population. The fatal outcome despite well-managed treatment highlights the need to identify predictive factors of immunotherapy-related adverse events in the older population.

Cutaneous melanoma can metastasize to almost any organ, including in-transit metastases, lymph nodes, liver, lungs, brain, and bones. Spread to the gastrointestinal tract is less common and generally concerns the small bowel, colon, and stomach. Gallbladder involvement is rarer, and only few cases describe it as the sole site of metastasis upon diagnosis. Melanoma metastases to the gallbladder are usually detected on staging or surveillance imaging, as patients usually show few or no symptoms. In resectable stage IV melanoma patients, complete surgical resection appears to improve the prognosis. However, due to the rarity of isolated gallbladder metastasis of melanoma, there are no guidelines regarding the optimal surgical approach (endoscopic or open cholecystectomy). Here, we report the case of isolated gallbladder melanoma metastasis found after laparoscopic cholecystectomy performed in a 46-year-old female patient with no known history of cancer presenting with acute cholecystitis symptoms. Six weeks after surgery, the patient developed trocar site recurrence. This case highlights the importance of a planned and open surgery for resectable melanoma metastases rather than a laparoscopic approach.

BackgroundWith the increasing use of immunotherapy (IT), immune-related adverse events (irAEs) are more prevalent in the oncologist's practice. Unlike AEs from other systemic therapies, irAEs are incompletely characterized in phase II/III trials. Clinical practice is variable due to the common exclusion of patients with autoimmune diseases or an organ transplant from trials and the lack of long-term data on managing irAEs. Moreover, the impact of immunosuppressant use on the oncological outcome is unclear. As AEs can affect any organ system and sometimes be life-threatening, multidisciplinary collaboration is essential.MethodsBITOX is a biweekly virtual meeting between oncologists and organ specialists accessible to all Belgian hospitals. Health care providers submit questions regarding diagnosis, management, and prevention of irAEs via a form on the BSMO website. During the meetings, diagnostic and therapeutic suggestions are made and communicated to the treating physician. The aim is to share experiences and standardize the approach for irAEs, along with identifying clinically relevant research questions.ResultsThe meetings started in March 2021 and so far, 44 cases have been discussed. The majority (n=28, 64%) concerned questions regarding differential diagnosis and management of AEs. Other questions concerned prescribing IT in patients with (autoimmune) comorbidities. Most patients were treated with anti-PD(L)1 monotherapy (n=22, 50%), followed by combination of anti-PD(L)1 + anti-CTLA4 (n=13, 30%). The type of AEs was variable, with neurological (n=6, 14%) and digestive/hepatobiliary irAEs (n=4, 10%) being the most frequently discussed.ConclusionsDespite their frequency, solid data regarding the optimal management and impact of irAEs are lacking. With this national multidisciplinary board, we aim to accessibly offer evidence-based approaches and harmonize expert consensus. We are planning a collaboration with the Belgian health authorities to gather more real-world data on complex irAEs. In the future, expanding across national borders might help to share our knowledge about the toxicity of IT, aiming to improve patient care.Legal entity responsible for the studyThe authors.FundingBristol Myers Squibb, MSD, Pfizer, Merck, Roche, AstraZeneca, Sanofi.DisclosureS. Aspeslagh: Non-Financial Interests, Personal, Advisory Board: MSD; Non-Financial Interests, Personal, Advisory Board: Sanofi; Non-Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Sponsor/Funding: Sanofi. M. Brandao: Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Roche/Genentech; Financial Interests, Institutional, Sponsor/Funding: Pfizer; Financial Interests, Institutional, Sponsor/Funding: Amgen; Financial Interests, Institutional, Sponsor/Funding: Merck; Financial Interests, Institutional, Sponsor/Funding: iTEOS; Financial Interests, Personal, Invited Speaker: Roche/Genentech. J. Dekervel: Financial Interests, Institutional, Sponsor/Funding: Bayer; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche. B. Neyns: Financial Interests, Personal and Institutional, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Roche; Financial Interests, Personal, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Merck Sharp & Dohme; Financial Interests, Personal and Institutional, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Novartis; Financial Interests, Personal and Institutional, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Pfizer; Financial Interests, Personal, Advisory Board, public speaking, consultancy and participation in advisory board meetings: Amgen; Financial Interests, Personal, Advisory Board, public speaking, consultancy and participation in advisory board meetings: AstraZeneca; Financial Interests, Institutional, Funding: Merck-Serono. A. Rutten: Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Pierre Fabre; Financial Interests, Personal and Institutional, Advisory Board: MSD; Financial Interests, Personal and Institutional, Advisory Board: Novartis; Financial Interests, Personal and Institutional, Advisory Board: sun Pharma. E. Seront: Non-Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Advisory Board: MSD; Non-Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Board: Merck. E. Wauters: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board: MSD. A. Drowart: Financial Interests, Personal and Institutional, Invited Speaker: Novartis. All other authors have declared no conflicts of interest. BackgroundWith the increasing use of immunotherapy (IT), immune-related adverse events (irAEs) are more prevalent in the oncologist's practice. Unlike AEs from other systemic therapies, irAEs are incompletely characterized in phase II/III trials. Clinical practice is variable due to the common exclusion of patients with autoimmune diseases or an organ transplant from trials and the lack of long-term data on managing irAEs. Moreover, the impact of immunosuppressant use on the oncological outcome is unclear. As AEs can affect any organ system and sometimes be life-threatening, multidisciplinary collaboration is essential. With the increasing use of immunotherapy (IT), immune-related adverse events (irAEs) are more prevalent in the oncologist's practice. Unlike AEs from other systemic therapies, irAEs are incompletely characterized in phase II/III trials. Clinical practice is variable due to the common exclusion of patients with autoimmune diseases or an organ transplant from trials and the lack of long-term data on managing irAEs. Moreover, the impact of immunosuppressant use on the oncological outcome is unclear. As AEs can affect any organ system and sometimes be life-threatening, multidisciplinary collaboration is essential. MethodsBITOX is a biweekly virtual meeting between oncologists and organ specialists accessible to all Belgian hospitals. Health care providers submit questions regarding diagnosis, management, and prevention of irAEs via a form on the BSMO website. During the meetings, diagnostic and therapeutic suggestions are made and communicated to the treating physician. The aim is to share experiences and standardize the approach for irAEs, along with identifying clinically relevant research questions. BITOX is a biweekly virtual meeting between oncologists and organ specialists accessible to all Belgian hospitals. Health care providers submit questions regarding diagnosis, management, and prevention of irAEs via a form on the BSMO website. During the meetings, diagnostic and therapeutic suggestions are made and communicated to the treating physician. The aim is to share experiences and standardize the approach for irAEs, along with identifying clinically relevant research questions. ResultsThe meetings started in March 2021 and so far, 44 cases have been discussed. The majority (n=28, 64%) concerned questions regarding differential diagnosis and management of AEs. Other questions concerned prescribing IT in patients with (autoimmune) comorbidities. Most patients were treated with anti-PD(L)1 monotherapy (n=22, 50%), followed by combination of anti-PD(L)1 + anti-CTLA4 (n=13, 30%). The type of AEs was variable, with neurological (n=6, 14%) and digestive/hepatobiliary irAEs (n=4, 10%) being the most frequently discussed. The meetings started in March 2021 and so far, 44 cases have been discussed. The majority (n=28, 64%) concerned questions regarding differential diagnosis and management of AEs. Other questions concerned prescribing IT in patients with (autoimmune) comorbidities. Most patients were treated with anti-PD(L)1 monotherapy (n=22, 50%), followed by combination of anti-PD(L)1 + anti-CTLA4 (n=13, 30%). The type of AEs was variable, with neurological (n=6, 14%) and digestive/hepatobiliary irAEs (n=4, 10%) being the most frequently discussed. ConclusionsDespite their frequency, solid data regarding the optimal management and impact of irAEs are lacking. With this national multidisciplinary board, we aim to accessibly offer evidence-based approaches and harmonize expert consensus. We are planning a collaboration with the Belgian health authorities to gather more real-world data on complex irAEs. In the future, expanding across national borders might help to share our knowledge about the toxicity of IT, aiming to improve patient care. Despite their frequency, solid data regarding the optimal management and impact of irAEs are lacking. With this national multidisciplinary board, we aim to accessibly offer evidence-based approaches and harmonize expert consensus. We are planning a collaboration with the Belgian health authorities to gather more real-world data on complex irAEs. In the future, expanding across national borders might help to share our knowledge about the toxicity of IT, aiming to improve patient care.

The introduction of immune checkpoint inhibitor (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death receptor 1 has dramatically improved clinical outcome for cancer patients. Nevertheless, this treatment can be associated with immune-related adverse events (irAEs) which sometimes need management with prolonged immune suppression. In order to analyze the risk of Pneumocystis jiroveci pneumonia (PJP) in this population, all PJP cases at our oncological hospital between 2004 and 2019 were searched. Only two cases were found in patients treated with ICI (480 patients received ICI during that period). The first was treated with both ipilimumab and nivolumab for metastatic melanoma and required long-term corticosteroids plus infliximab for immune-related colitis. The second received both pembrolizumab and brentuximab for Hodgkin's lymphoma and received corticosteroids for macrophage-activating syndrome. These two cases illustrate that PJP is rare but might be severe in the ICI population and should be differentiated from tumor progression or irAE.

The population of older patients is growing with a rising prevalence of cancer diagnoses and cancer-related pain syndromes. Older patients are also vulnerable to misleading pain evaluations and under treatment with opioids. Barriers to the effective and safe management of analgesics include pain assessments and the complex management of the best analgesic choice and dose-titration while achieving the fewest side effects. In this review, we will provide an overview of the challenges present in assessment and treatment choices, along with practical tips for routine clinical practice.

Introduction. - Sweet's syndrome is an acute neutrophilic dermatosis characterized by abrupt onset of skin lesions accompanied by fever, arthralgia, leukocytosis and diffuse neutrophilic infiltration of the dermis, as well as an excellent response to corticosteroid therapy. Case report. - A 46-year-old patient with myelodysplastic syndrome was admitted for chemotherapy. On the eighth day of chemotherapy, he received a single dose of pegfilgrastim. Three days later, he developed pyrexia, conjunctivitis, arthralgia and erythematous and painful papulo-nodular lesions. Broad-spectrum empiric antibiotic therapy was started but the patient's condition deteriorated. Biology showed pancytopenia and inflammatory syndrome. Microbiological tests, autoimmune serologies and chest-computed tomography were negative. Cutaneous biopsy was compatible with Sweet's syndrome. A diagnosis of Sweet's syndrome induced by pegfilgrastim was made and intravenous corticosteroid therapy was started with a rapid favorable outcome. Conclusion. - Sweet's syndrome is a rare adverse effect of G-CSF. (C) 2018 Published by Elsevier Masson SAS on behalf of Societe Nationale Francaise de Medecine Interne (SNFMI).

Rationale: Tuberculosis (TB) remains a major cause of mortality. A better understanding of the immune responses to mycobacterial antigens may be helpful to develop improved vaccines and diagnostics.Objectives: The mycobacterial antigen heparin-binding hemagglutinin (HBHA) induces strong IFN-γ responses by circulating lymphocytes from subjects latently infected with Mycobacterium tuberculosis, and low responses associated with CD4+ regulatory T (Treg) cells in patients with TB. Here, we investigated HBHA-specific IFN-γ responses at the site of the TB disease.Methods: Bronchoalveolar lavages, pleural fluids, and blood were prospectively collected from 61 patients with a possible diagnosis of pulmonary or pleural TB. HBHA-specific IFN-γ production was analyzed by flow cytometry and ELISA. The suppressive effect of pleural Treg cells was investigated by depletion experiments.Measurements and Main Results: The percentages of HBHA-induced IFN-γ+ alveolar and pleural lymphocytes were higher for pulmonary (P < 0.0001) and for pleural (P < 0.01) TB than for non-TB controls. Local CD4+ and CD8+ T cells produced the HBHA-specific IFN-γ. This local secretion was not suppressed by Treg lymphocytes, contrasting with previously reported data on circulating lymphocytes.Conclusions: Patients with TB display differential effector and regulatory T-cell responses to HBHA in local and circulating lymphocytes with a predominant effector CD4+ and CD8+ response locally, compared with a predominant Treg response among circulating lymphocytes. These findings may be helpful for the design of new vaccines against TB, and the detection of HBHA-specific T cells at the site of the infection may be a promising tool for the rapid diagnosis of active TB.

The mycolyl transferase antigen 85 complex is a major secreted protein family from mycobacterial culture filtrate, demonstrating powerful T cell stimulatory properties in most HIV-negative, tuberculin-positive volunteers with latent M.tuberculosis infection and only weak responses in HIV-negative tuberculosis patients. Here, we have analyzed T cell reactivity against PPD and Ag85 in HIV-infected individuals, without or with clinical symptoms of tuberculosis, and in AIDS patients with disease caused by nontuberculous mycobacteria. Whereas responses to PPD were not significantly different in HIV-negative and HIV-positive tuberculin-positive volunteers, responses to Ag85 were significantly decreased in the HIV-positive (CDC-A and CDC-B) group. Tuberculosis patients demonstrated low T cell reactivity against Ag85, irrespective of HIV infection, and finally AIDS patients suffering from NTM infections were completely nonreactive to Ag85. A one-year follow-up of twelve HIV-positive tuberculin-positive individuals indicated a decreased reactivity against Ag85 in patients developing clinical tuberculosis, highlighting the protective potential of this antigen.

Background. The detection of latent tuberculosis infection (LTBI) is a major component of tuberculosis (TB) control strategies. In addition to the tuberculosis skin test (TST), novel blood tests, based on in vitro release of IFN-gamma in response to Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10 (IGRAs), are used for TB diagnosis. However, neither IGRAs nor the TST can separate acute TB from LTBI, and there is concern that responses in IGRAs may decline with time after infection. We have therefore evaluated the potential of the novel antigen heparin-binding hemagglutinin (HBHA) for in vitro detection of LTBI. Methodology and Principal Findings. HBHA was compared to purified protein derivative (PPD) and ESAT-6 in IGRAs on lymphocytes drawn from 205 individuals living in Belgium, a country with low TB prevalence, where BCG vaccination is not routinely used. Among these subjects, 89 had active TB, 65 had LTBI, based on well-standardized TST reactions and 51 were negative controls. HBHA was significantly more sensitive than ESAT-6 and more specific than PPD for the detection of LTBI. PPD-based tests yielded 90.00% sensitivity and 70.00% specificity for the detection of LTBI, whereas the sensitivity and specificity for the ESAT-6-based tests were 40.74% and 90.91%, and those for the HBHA-based tests were 92.06% and 93.88%, respectively. The QuantiFERON-TB Gold In-Tube (QFT-IT) test applied on 20 LTBI subjects yielded 50% sensitivity. The HBHA IGRA was not influenced by prior BCG vaccination, and, in contrast to the QFT-IT test, remote (. 2 years) infections were detected as well as recent (< 2 years) infections by the HBHA-specific test. Conclusions. The use of ESAT-6- and CFP-10-based IGRAs may underestimate the incidence of LTBI, whereas the use of HBHA may combine the operational advantages of IGRAs with high sensitivity and specificity for latent infection.

RATIONALE Tuberculosis (TB) remains a leading cause of death, and the role of T-cell responses to control Mycobacterium tuberculosis infections is well recognized. Patients with latent TB infection develop strong IFN-gamma responses to the protective antigen heparin-binding hemagglutinin (HBHA), whereas patients with active TB do not. OBJECTIVES We investigated the mechanism of this difference and evaluated the possible involvement of regulatory T (Treg) cells and/or cytokines in the low HBHA T-cell responses of patients with active TB. METHODS The impact of anti-transforming growth factor (TGF)-beta and anti-IL-10 antibodies and of Treg cell depletion on the HBHA-induced IFN-gamma secretion was analyzed, and the Treg cell phenotype was characterized by flow cytometry. MEASUREMENTS AND MAIN RESULTS Although the addition of anti-TGF-beta or anti-IL-10 antibodies had no effect on the HBHA-induced IFN-gamma secretion in patients with active TB, depletion of CD4(+)CD25(high)FOXP3(+) T lymphocytes resulted in the induction by HBHA of IFN-gamma concentrations that reached levels similar to those obtained for latent TB infection. No effect was noted on the early-secreted antigen target-6 or candidin T-cell responses. CONCLUSIONS Specific CD4(+)CD25(high)FOXP3(+) T cells depress the T-cell-mediated immune responses to the protective mycobacterial antigen HBHA during active TB in humans.

Ovarian metastasis as first dissemination site of a lung adenocarcinoma has not been described in the literature. We report the case of a 61-year-old woman who had a pneumectomy for a centrally located lung adenocarcinoma, which was discovered on a routine chest X-Ray. During the follow-up, a Positron Emission Tomography (PET)-Scan showed a hypercaptation in the pelvic region. Abdominal CT-scan confirmed the presence of a mass which was compatible with a primary ovarian tumor. The patient underwent a hysterectomy and bilateral salpingo-oophorectomy. Pathology reported an adenocarcinoma. Immunohistochemical staining revealed cells expression for Thyroid Transcription Factor 1 (TTF-1), cytokeratin 7 (CK-7) and focally cytokeratin 20 (CK-20). Clinical course, pathological and immunohistochemical data concluded to the diagnosis of ovarian metastasis of the lung adenocarcinoma. In conclusion, in the differential diagnosis of an ovarian metastasis, clinicians should not forget the lung as primary site since epidemiologic data of lung cancer in women show progressive incidence.

La découverte d'une métastase ovarienne comme premier site de dissémination métastatique d'un adénocarcinome bronchique n'a jamais été rapportée dans la littérature. Nous rapportons ici le cas d'une patiente âgée de 61 ans chez qui une tumeur bronchopulmonaire de type adénocarcinome a été découverte de manière fortuite et opérée, et chez qui la tomographie par émissions de positrons (TEP) effectuée trois mois plus tard a montré la présence d'une masse pelvienne hyperactive. La scanographie a confirmé la présence d'une masse compatible avec une tumeur ovarienne. La patiente a dès lors été opérée par hystérectomie avec annexectomie bilatérale. L'examen anatomopathologique a conclu à un adénocarcinome. Les examens immunohistochimiques ont révélé que les cellules exprimaient le Thyroid Transcription Factor 1 (TTF-1), la cytokératine 7 (CK-7) et focalement la cytokératine 20 (CK-20). L'ensemble des données tant cliniques que pathologiques et immunohistochimiques a permis de conclure au diagnostic de métastase ovarienne de l'adénocarcinome bronchique. En conclusion, devant les différents diagnostics différentiels de recherche de tumeur primitive d'une métastase ovarienne, le clinicien ne doit pas exclure l'origine pulmonaire, d'autant plus que l'incidence du cancer du poumon chez la femme croît progressivement.

We report the case of a patient with pleural effusion associated wiht valproic acid.

Although post-translational modifications of protein antigens may be important componenets of some B cell epitopes, the determinants of T cell immunity are generally nonmodified peptides. Here we show that methylation of the Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA) by the bacterium is essential for effective T cell immunity to this antigen in infected healthy humans and in mice. Methylated HBHA provides high levels of protection against M. tuberculosis challenge in mice, whereas nonmethylated HBHA does not. Protective immunity induced by methylated HBHA is comparable to that afforded by vaccination with bacille Calmette et Guérin, the only available anti-tuberculosis vaccine. Thus, post-translational modifications of proteins may be crucial for their ability to induce protective T cell-mediated immunity against infectious diseases such as tuberculosis.

Because only 10% of individuals infected with Mycobacterium tuberculosis will eventually develop disease, antigens that are recognized differently by the immune systems of infected healthy and diseased subjects may constitute potential vaccine candidates. Here, the heparin-binding hemagglutinin adhesin (HBHA) is identified as such an antigen. Lymphocytes from 60% of healthy infected individuals (n=25) produced interferon (IFN)-gamma after stimulation with HBHA, compared with only 4% of patients with active tuberculosis (n=24). In the responders, both CD4(+) and CD8(+) cells secreted HBHA-specific IFN-gamma, and the antigen was presented by both major histocompatibility complex class I and II molecules. In contrast to the reduced ability of patients with tuberculosis to produce HBHA-specific IFN-gamma, most of them (82%) produced anti-HBHA antibodies, compared with 36% of the infected healthy subjects. These observations indicate that HBHA is recognized differently by the immune systems of patients with tuberculosis and infected healthy individuals and might provide a marker for protection against tuberculosis.

The subcomponents of bacille Calmette-Guérin (BCG) involved in the mechanism of action of intravesical BCG immunotherapy used for prophylaxis of superficial bladder cancer recurrences have been poorly investigated. We purified various BCG subcomponents and analyzed in vitro their ability to enhance a Th1 polarized immune response as well as to increase lymphocyte-mediated cytotoxicity against bladder tumors. Human peripheral blood mononuclear cells (PBMCs) from healthy purified protein derivative-positive subjects were incubated for 7 days with whole BCG and various fractions (BCG cell wall, plasma membrane, cytosol, purified polysaccharides as glucan or arabinomannan, purified native proteins from BCG culture filtrate, recombinant 22 kDa protein, phosphate transporter PstS-2 and -3 proteins). IFN-gamma, IL-12, IL-2, and IL-6 production by stimulated PBMCs was compared to unstimulated controls and the phenotype of expanded cells analyzed by flow cytometry (FACS analysis). A (51)Cr-release assay monitored the cytotoxicity of amplified effector cells against T24 bladder tumor cells. Live BCG and most of its subcomponents (with the exception of cytosol, PstS-2 and -3) significantly enhanced IFN-gamma and IL-12 secretion, expanded CD3(-)CD56(+) cells and the non-MHC-restricted cytotoxicity against bladder tumor cells compared to unstimulated controls (all P < 0.001, t-test). IL-2 receptor blockage resulted in a clear reduction in the cytotoxic activity of stimulated PBMCs. Numerous BCG subcomponents thus provide positive stimuli for Th1 cell differentiation and enhance in vitro, non-MHC-restricted cytotoxicity against bladder tumor cells. Our findings provide the basis for the therapeutic use of several of these subfractions in experimental animal models bearing bladder tumors.