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Cytomegalovirus (CMV) infection/disease has been repeatedly reported in patients treated with immune-checkpoint inhibitors (ICIs) and most commonly involves patients with relapsed/refractory (R/R) immune-related adverse events (irAEs). In the current study, we present a patient with melanoma who developed CMV gastritis during treatment with pembrolizumab in the absence of irAEs and without previous or current immunosuppression. Moreover, we review the literature regarding CMV infection/disease in patients treated with ICIs for solid malignancies. We present the currently available data on the pathogenesis, clinical characteristics, endoscopic findings, and histologic features and highlight the potential differences among cases complicating R/R irAEs versus those occurring in patients who are immunosuppression naive. Finally, we discuss the currently available data regarding potential useful diagnostic tools as well as the management of these patients.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a significant global issue that has major implications for the healthcare system. The mortality rates associated with SARS-CoV-2 infection vary according to the geographical region and are associated with age, comorbidities and vaccination status. Organ damage is caused by the cytokine release syndrome, which plays a crucial role in the course of coronavirus disease 2019 (COVID-19) infection. Innate and adaptive immune system stimulation in patients with COVID-19 results in inappropriate cytokine release. The anti-IL-6 receptor antagonist, tocilizumab, is used in the treatment of connective tissue diseases. The present single-center retrospective study on patients with COVID-19 admitted to hospital between September, 2020 and April, 2022 aimed to identify predictors of mortality and other unfavorable outcomes in patients treated with tocilizumab for COVID-19-associated pneumonia. Demographics, vaccination status against SARS-CoV-2, the Charlson comorbidity index (CCI), laboratory data and chest X-ray scores were recorded upon admission. In total, 174 subjects (121 males; mean age, 62.43±13.47 years) fulfilling the inclusion criteria were included. Among the 174 participants, 58 (33.3%) were intubated. The mortality rate was 35.1%. The non-survivors were older, mostly females, and had a higher CCI score. At the evaluation upon admission, the survivors presented with higher levels of alanine transferase and gamma glutamyl-transferase and with a greater number of platelets (PLTs), while patients that were intubated were also older, mostly females, and had a higher CCI score (P0.05). Age was identified as the only independent factor predicting mortality in the Cox proportional hazards multivariate regression analysis. By performing a sub-analysis regarding sex, it was revealed that the value of PLTs was an independent factor predicting intubation and 90-day mortality in male patients, and the lymphocyte count was the only factor associated with intubation in female patients. On the whole, the data of the present study may be used to identify patient subpopulations responding to treatment with tocilizumab in prospective clinical trials.

The exact impact of immune checkpoint inhibitors in the course and outcome of COVID-19 in cancer patients is currently unclear. Herein, we present the first description of an elderly melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin in combination with an investigational PEGylated interleukin (IL-2). We present the clinical characteristics and the laboratory and imaging findings of our patient during the course of COVID-19 pneumonia. Moreover, we discuss the currently available data regarding the mechanism of action of immune checkpoint inhibitors and IL-2 analogs in the treatment of COVID-19. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in an elderly melanoma patient.Immune checkpoint inhibitors represent a major advance in the treatment of several solid malignancies, including melanoma. Bempegaldesleukin is an investigational PEGylated IL-2 that is being evaluated, in combination with nivolumab, in the management of a variety of cancers. The immunomodulation caused by these agents may also modify the immune response in COVID-19. Currently available data regarding the impact of immune checkpoint inhibitors in reducing the severity of COVID-19 in patients with cancer are mixed, whereas no clinical data are available for bempegaldesleukin. Herein, we report the case of an elderly female melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in our patient.

Introduction. The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern about the triggering of immune related adverse events (irAEs) by the vaccine has also been raised. Patients and methods. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0-4 days before the first and 12-21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody with an ELISA and immunophenotyping of the T and myeloid cell subpopulations. Active recording of the AEs for a two-month period was conducted. Results. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case or arthritis exacerbation was noted.Discussion. The seroconversion rate in the studied population was high, comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect on the blood cell immunophenotype status of anti-SARS-Cov-2 vaccines in patients with melanoma treated with ICIs.

Immature granulocytes (IGs) include metamyelocytes, myelocytes and promyelocytes, and are the precursors of neutrophils. Increased IG counts found in peripheral blood indicate an enhanced bone marrow activity. In addition, IGs have been evaluated in numerous clinical conditions, such as severe acute pancreatitis, systemic inflammatory response syndrome and infectious complications following open‑heart surgery under cardiopulmonary bypass. Neutrophils are considered to play a crucial role in the host defense during bacterial and fungal infections, and are involved in the antiviral immune response. Numerous studies have reported the role of neutrophils in coronavirus disease 2019 (COVID‑19) infection, concluding that the percentage of neutrophils may be a predictor of the severity of COVID‑19 infection. There has been limited research regarding the role of neutrophil precursors in viral infections, including severe acute respiratory syndrome coronavirus 2 infection. The present thus aimed to evaluate the role of the IG count in patients hospitalized due to COVID‑19 infection. The patients were predominantly infected with the alpha variant and were all unvaccinated. The IG count was measured and was found to be associated with disease severity, with patient outcomes, with the duration of hospitalization and with the development of complications. The IG count was a significantly associated with the severity of COVID‑19 infection, with greater IG count values being detected in severe and critical cases. In addition, greater IG count values were associated with a longer duration of hospitalization. Furthermore, the IG count was found to be an independent prognostic biomarker of intubation and mortality in patients with COVID‑19, according to multivariate logistic regression analysis, including age, the male sex and the presence of comorbidities as confounders.

Patient: Male, 62-year-old Final Diagnosis: BCGitis Symptoms: Fever • general fatigue Medication: — Clinical Procedure: Bone marrow biopsy • liver biopsy Specialty: Infectious Diseases • General and Internal Medicine Objective: Rare coexistence of disease or pathology Background: Bladder cancer (BC) is the second most common cancer involving the urinary system. In non-muscle-invading BC, transurethral resection of a bladder tumor followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) is the usual treatment. Disseminated (or systemic) BCG infection (BCGitis) represents the most severe adverse effect of intravesical BCG therapy, presenting with high-grade fever, with or without symptoms in the urinary tract, leading to severe sepsis and death if left untreated. The treatment of choice consists of isoniazid, rifampicin, and ethambutol (with or without corticosteroids) for 6 months, and the recovery rate is extremely high. Given the fact that these drugs are hepatotoxic, treating a patient with liver cirrhosis is challenging. Case Report: We present a patient with a medical history of BC treated with transurethral resection and intravesical BCG therapy, presenting with fever, transaminasemia, and generalized weakness. Liver and bone marrow biopsies revealed liver cirrhosis and granulomas in both organs. A diagnose of BCGitis was made and the patient was treated with isoniazid, rifampicin, and ethambutol; rifampicin was substituted with moxifloxacin after 1 month due to worsening of liver laboratory results, and moxifloxacin was substituted with levofloxacin later on due to tonic-clonic seizures. The patient was treated for 4 more months with levofloxacin and for 7 more months with isoniazid and ethambutol, with no other adverse effects, preserving liver function and achieving cure of BCGitis. Conclusions: We present the case of a cirrhotic patient presenting with fever and deterioration of liver laboratory results, found to have BCGitis, and discuss possible difficulties in diagnosing and treating such patients.

Background Immune‐checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune‐related endocrinopathies, especially hypophysitis and thyroid dysfunction. Methods To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune‐checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow‐up. Results The total incidence of endocrinopathies was 11.8%, 13.4% due to anti‐PD1/PDL1, 5% due to anti‐CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty‐one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow‐up. Endocrinopathies occurred after a median of 22 weeks (range: 4‐156) from treatment initiation. Of note, sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism. Conclusions Our cohort demonstrated an increased incidence of hypophysitis with anti‐PD1/anti‐PDL1 in contrast to the rarity of primary thyroid dysfunction with anti‐CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy., A prospective observational study was conducted to assess the incidence and the spectrum of endocrinopathies in 339 melanoma patients treated with immune checkpoint inhibitors. Sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy, while only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism.

Objective To assess the predictive value for infection with multidrug-resistant organisms (MDROs) of reasons for empirical prescription of restricted antibiotics (rABX), in a setting with high resistance rates. Methods We prospectively studied all rABX prescriptions in a 550-bed tertiary teaching hospital from April 15 to June 14, 2018 and from September 1 to October 30, 2018. Prescribing physicians had to justify their decision by choosing one or more prespecified reasons. Results We reviewed 172 empirical prescriptions of rABX, which accounted for 67.2% of all rABX prescriptions. Stated reasons for empirical prescription of rABX were recent hospitalization (72.7%), escalation due to non-response to previous antimicrobials (47.7%), treatment for severe sepsis/septic shock (45.9%), escalation due to recurrence or deterioration (22.1%), prior MDRO infection (12.8%), and prior MDRO colonization (7.6%). Empirical treatment for septic shock or severe sepsis was the only significant predictor of MDRO isolation (OR = 5.26, 95% CI: 1.5–18.4, P = 0.009), while recent hospitalization had a high negative predictive value for MDRO (97.4%). Fourteen per cent of microbiologically documented infections were associated with MDROs resistant to the prescribed rABX. Conclusions Empirical treatment for severe sepsis or septic shock was the only independent predictor of MDRO isolation. Recent hospitalization had a high negative predictive value for MDRO infection. The isolation of pathogens resistant to the prescribed rABX suggests that in a setting with widespread antimicrobial resistance, it could be difficult to reduce the empirical use of rABX without risking inadequate treatment.

Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.

The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with ‘collision of tumors,’ and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities.

Immune checkpoint inhibitors (ICI) have altered the prognosis of patients with melanoma over the past few years, with immune-related adverse effects (irAEs) being the only factor limiting their use. Neurologic and cardiac irAEs are rare, but usually severe. We reviewed the files of patients with melanoma treated with ICIs in one center to retrieve data from patients with neurologic irAEs. Patients with a combination of neurologic and cardiac manifestations were further analyzed. We also reviewed the literature for similar syndromes. Five out of 482 (1.01%) patients developed a neurologic syndrome and we present three patients with a constellation of neurologic and cardiac irAEs. A 66-year-old woman and a 68-year-old man presented with a constellation of findings after being treated with ipilimumab and nivolumab, respectively, for melanoma in the adjuvant setting and were eventually diagnosed with myasthenia gravis with cardiac involvement. An 80-year-old woman developed diffuse asymmetric muscle weakness, bilateral ptosis and asymptomatic high serum troponin levels after adjuvant treatment with nivolumab and ipilimumab for a stage IIIB melanoma. After excluding ischemic heart disease, she was diagnosed with axonal polyradiculoneuropathy and myocarditis. Neurologic or cardiac irAEs in patients treated with ICIs are uncommon (

In the evolving immune-oncology landscape, numerous patients with cancer are constantly treated with immune checkpoint inhibitors (ICPIs) but among them, only sporadic cases with pre-existing hepatitis B virus (HBV) and hepatitis C virus (HCV) are recorded. Despite the global dissemination of HBV and HCV infections, viral hepatitis-infected patients with cancer were traditionally excluded from ICPIs containing trials and current evidence is particularly limited in case reports, retrospective cohort studies and in few clinical trials on advanced hepatocellular carcinoma. Thus, many concerns still remain about the overall oncological management of this special subpopulation, including questions about the efficacy, toxicity and reactivation risks induced by ICPIs. Here, we examine the natural course of both HBV and HCV in cancer environment, review the latest antiviral guidelines for patients undergoing systematic cancer therapies, estimating treatment-related immunosuppression and relocate immunotherapy in this therapeutic panel. Among the ICPIs-treated cases with prior viral hepatitis, we focus further on those experienced HBV or HCV reactivation and discuss their host, tumor and serological risk factors, their antiviral and immunological management as well as their hepatitis and tumor outcome. Based on a low level of evidence, immunotherapy in these specific cancer cases seems to be associated with no inferior efficacy and with a relevantly low reactivation rate. However, hepatitis reactivation and subsequent irreversible complications appeared to have poor response to deferred antiviral treatment. While, the prophylactic use of modern antiviral drugs could eliminate or diminish up front the viral load in most cases, leading to cure or long-term hepatitis control. Taking together the clinical significance of preventive therapy, the low but existing reactivation risk and the potential immune-related hepatotoxicity, a comprehensive baseline assessment of liver status, including viral hepatitis screening, before the onset of immunotherapy should be suggested as a reasonable and maybe cost-effective strategy but the decision to administer ICPIs and the necessity of prophylaxis should always be weighed at a multidisciplinary level and be individualized in each case, up to be established by future clinical trials.

Background Invasive mould infections (IMIs) are very rare in patients with lymphoid malignancies. However, IMIs, mostly due to Aspergillus species, have been increasingly reported in such patients receiving ibrutinib (IBR). There is paucity of information regarding non-Aspergillus invasive mould infections (NAIMIs) in this setting, OBJECTIVES: To review our recent experience and the published literature on the topic. Patients/methods We present a case of invasive sinusitis caused by Fusarium in a patient with refractory chronic lymphocytic leukaemia (CLL) who was treated with IBR and review the 12 published cases of NAIMIs during IBR. Results Nearly all cases of NAIMIs in the setting of IBR use were encountered in patients with CLL. Mixed fungal infections, brain involvement and late-onset infections were common. Conclusions Although rare, NAIMIs should be considered in patients who receive IBR.

The widespread use of immune checkpoint inhibitors has shed light to several unusual immune-related adverse effects of the drugs. Severe cutaneous adverse reactions are generally rare with anti-PD1 agents. We present in this paper the case of a 48-year-old patient with melanoma who developed bullous pemphigoid-like skin lesions along with fever, arthralgia and overt eosinophilia following adjuvant treatment with nivolumab. The condition was successfully treated with corticosteroids and a rechallenge with another anti-PD1 agent did not lead to recurrence of the skin lesions. We also reviewed the literature on the epidemiologic, clinical, and histopathologic characteristics of bullous pemphigoid as well as on the treatment and prognosis of this dermatologic condition in patients with melanoma or other malignancies under treatment with immune checkpoint inhibitors.

Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every organ, but the skin, intestine, lung, eye, and liver are the most commonly affected organs. Here, we present the case of a 62-year-old female patient with stage IIIc melanoma treated with nivolumab in an adjuvant setting who sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and pneumonitis. Six months before the emergence of pneumonitis, the patient had discontinued treatment with nivolumab because of acute hepatitis. Information on pneumonitis after nivolumab discontinuation in the literature is scarce, whereas most of the cases emerge during the first 2.5 months of treatment. Patients with multiple immune-related AEs comprise a group of special interest as the identification of factors affecting the susceptibility of patients to immune-related AEs of PD-1 inhibitors may lead to a more rational use of these drugs. Human leukocyte antigen haplotype and Fcγ receptor polymorphisms are possible targets of the relevant research.

Background Approximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease. Subjects, Materials, and Methods In order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life. Results Reviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis. Conclusion More data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status. Implications for Practice The prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.

Immune checkpoint inhibitors (ICBs) have revolutionized cancer treatment producing remarkable and durable responses for a range of malignancies. However, the additional modulation of immune response by ICBs may rarely cause immune-related infectious complications, including re-activation of latent tuberculosis infection (LTBC) with detrimental effects on those patients’ outcome. Here, we present two “real-world” melanoma cases that were treated in our department with blockade of PD-1/PD-L1 and developed active Mycobacterium tuberculosis (MTB) during immunotherapy. In view of these cases, we review the literature for ICB-associated MTB reactivation and discuss our considerations about the possible interactions of immunotherapy and the underlying co-existent mycobacterial infection. Based on the current evidence from preclinical findings prior to this experience, we raise questions regarding cancer patients who are at higher risk for developing MTB infection, whether ICB-treated patients should be considered immunocompromised, and how they should be managed for latent and/or active tuberculosis. Aside from the well-established clinical benefit of immunotherapy, the blockade of PD-1/PD-L1 axis may concurrently disrupt the immune control of specific opportunistic infections such as tuberculosis that should be carefully and expectantly managed in order to avoid compromising the outcome of cancer treatment and the affected patient’s survival.

Survivin represents a key anti-apoptotic molecule that is highly expressed in the vast majority of tumors. The aim of the study was to examine the significance of survivin mRNA blood levels in melanoma patients.In this prospective translational research study, survivin mRNA blood levels were measured in melanoma patients treated with adjuvant interferon or systemic treatment for advanced disease.Sixty-four patients with melanoma and 40 healthy controls were included. The majority of them had tumor stages III and IV. The upper 95% confidence interval (95%CI) of survivin levels in controls was set as normal cut-off. Fifty-two (81.3%) patients had survivin levels above normal cut-off. Melanoma patients had higher survivin levels than controls (p0.0001). Survivin levels were non-significantly higher in stage III compared to stage IV patients. Patients with survivin levels above vs. below median had median progression-free survival (PFS) 19.5 months vs. 7.4 months (p=0.045), but median overall survival (OS) not reached vs. 18.4 months (p=0.091). Cox proportional hazard models showed that only tumor stage was associated with PFS and OS. There was no statistically significant change in survivin levels between baseline and during treatment (p=0.845) or during follow-up (p=0.101).Although melanoma patients had significantly higher survivin levels than controls, the study showed that survivin mRNA blood levels did not represent an independent prognostic factor for patients with melanoma. The role of circulating survivin should be further examined in larger studies.

Unleashing adaptive immunity via immune checkpoint inhibitors (ICPIs) in many cancer types led to durable antitumor responses and prolonged survivals and also added some new immune-related adverse events (irAEs) to the ‘old-fashioned’ safety profile of chemotherapy. Among bowel and endocrine irAEs, immune-mediated hepatotoxicity/hepatitis is a less common and far less well-studied toxicity, which, however, could develop into a serious complication, especially when it becomes persistent or refractory to steroids. Its incidence, onset and severity vary widely, depending on the type of underlying treated cancer, the class, the dosage and the duration of immunotherapy as well as the way of its administration (as a single agent or in combination with other ICPI or chemotherapy). In this study, we present a patient with metastatic melanoma who developed severe steroid-resistant ir-hepatitis after treatment with ipilimumab and required triple concurrent immunosuppression with prednisolone, mycofenolate mofetil and tacrolimus in order for his liver toxicity to be resolved. Intrigued by this case, we focused further on melanoma, as the disease-paradigm of immunotherapy in cancer, reviewed the reported incidence of hepatotoxicity among phase III ICPIs-containing trials on melanoma and discussed the main clinical considerations regarding the diagnosis and the management of persistent/steroid-refractory ir-hepatitis. As more clinical experience is gradually gained on this challenging topic, better answers are provided to questions about the appropriate diagnostic workup, the necessity of liver biopsy, the available immunosuppressive options beyond corticosteroids (their combinations and/or their sequence) as well as the correct decision on withdrawing or resuming immunotherapy. Nonetheless, a thorough multidisciplinary discussion is still required to individualize the overall approach in each case after failure of steroids.

This retrospective cohort study assessed the prognostic significance of distant metastasis-free interval (DMFI) in patients with relapsed BRAF-mutant melanoma treated with BRAF with or without MEK inhibitors (BRAFi ± MEKi). Patients with a DMFI of up to 24 months were compared with those with DMFI of more than 24 months, with regard to their postrelapse progression-free survival (PR-PFS) and overall survival (PR-OS). In total, 109 patients were included in the study. Median DMFI was 25.3 (range: 3.4-188.2) months. Median PR-PFS in patients with DMFI of more than 24 months was 7.9 months [95% confidence interval (CI): 6.2-9.7] compared with 5.4 (95% CI: 4.2-6.7) months of those with shorter DMFI (P = 0.016). Median PR-OS was 15.6 months (95% CI: 13.6-17.6) in patients with DMFI of more than 24 months and 12.0 months (95% CI: 9.0-15.0) with DMFI of up to 24 months (P = 0.289). Multivariate Cox regression analysis showed that DMFI was independently and strongly associated with improved PR-PFS (adjusted hazard ratio = 3.21, 95% CI: 1.78-5.77, ≤ 24 vs. > 24 months) and longer PR-OS (adjusted hazard ratio: 2.09, 95% CI: 1.15-3.80, ≤ 24 vs. > 24 months). The present cohort study is one of the first to confirm the association of DMFI of more than 24 months with an indolent disease course, as shown by longer PR-PFS and PR-OS, in patients with relapsed stage IV melanoma treated by BRAF inhibitor/MEK inhibitor.

Introduction: Immune checkpoint inhibitors (ICIs) represent an important advance in the treatment of melanoma. ICIs may induce autoimmune phenomena caused by concurrent activation of the immune system against normal cells. During the last years, cases of musculoskeletal side effects, especially immune-mediated arthritis (IA), have been increasingly reported. Patient concerns: We present a 59-year-old woman, who was treated with pembrolizumab for a relapsed BRAF V600E mutated cutaneous malignant melanoma. The patient presented with right knee arthritis on week 30. Diagnosis: The erythrocyte sedimentation rate and serum C-reactive protein levels were elevated, while rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Imaging confirmed the presence of fluid mainly in the suprapatellar bursa. Synovial fluid analysis revealed an inflammatory effusion, while other etiologies of inflammatory arthritis were excluded. Interventions: Arthritis improved with an intra-articular injection of 8 mg dexamethasone. Twelve days later the arthritis relapsed in both knees, and although it was resistant to nonsteroidal anti-inflammatory treatment, it improved with systemic steroids. Tapering of methylprednisolone dose was feasible with the coadministration of leflunomide and subsequently hydroxychloroquine. Outcomes: Arthritis resolved and the patient is free of complications and disease activity 20 months after the initiation of the second line systemic treatment. Conclusions: We present an unusual case of IA associated with pembrolizumab treatment. The originality of the current report is based on the late occurrence, the monoarticular initial distribution, and uncommon location of IA at the knee.

Ophthalmological complications constitute a class effect of treatment with BRAF inhibitors. Encorafenib is a new BRAF inhibitor currently being tested in phase 3 clinical trials for advanced or metastatic melanoma as monotherapy or in combination with the MEK-inhibitor binimetinib. In this study, we present a case of severe bilateral panuveitis and neurosensory hearing loss in an elderly patient treated with encorafenib and binimetinib for metastatic BRAF-mutant melanoma. This constellation of findings is compatible with incomplete Vogt-Koyanagi-Harada (VKH) disease. VKH disease is a rare multisystem disease characterized by granulomatous panuveitis, serous retinal detachments, and neurologic and dermatologic manifestations. In patients with melanoma, its emergence has been correlated to a favorable prognosis of the underlying melanoma by several authors. The patient reported here had a severe panuveitis and bilateral retinal detachments causing permanent visual impairment. She was treated with a long course of systemic corticosteroids, but at the same time, she achieved complete remission of the melanoma lasting for 26 months after permanent encorafenib and binimetinib discontinuation, without further antineoplastic treatment. VKH disease is a rare entity and the need for interdisciplinary cooperation for its diagnosis in patients with melanoma and uveitis is emphasized.

Despite the recent introduction of mold-active agents (posaconazole and isavuconazole), in addition to amphotericin B products, to our armamentarium against mucormycosis, many uncertainties remain for the management of this uncommon opportunistic infection, as there are no data from prospective randomized clinical trials to guide therapy. In this mini-review, we present the current status of treatment options. In view of the heterogeneity of the disease (different types of affected hosts, sites of infection, and infecting Mucorales), mucormycosis management requires an individualized management plan that takes into account the net state of immunosuppression of the host, including comorbidities, certainty of diagnosis, site of infection, and antifungal pharmacological properties.

Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.

Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins.

Background Tyrosine kinase inhibitors (TKIs) are the current treatment of choice for chronic myeloid leukemia (CML). However, approximately 15% of patients fail first and second line therapy, creating the need for the development of additional pharmacological targets in CML. Kinases acting downstream of BCR-ABL as well as anti-apoptotic proteins such as BCL-2 are being in vitro investigated as therapeutic targets. Previous research has yielded contradictory results on the role of c-myc in CML. In one study, conditional overexpression of myc was shown to confer resistance to imatinib-induced apoptosis via downregulation of the cell cycle regulator p27Kip1. In another study, myc induced p53-dependent apoptosis of leukemia-initiating cells (LICs) in CML. However, there has been so far no attempt to correlate myc transcript and protein levels with those of the bcr-abl transcript. Mcl-1, a bcl-2 family member, has been shown to promote survival of Ph+ lymphoblasts. Mcl-1 mRNA and protein levels are downregulated by imatinib in Ph + cell lines, but its expression in CML patient samples has not been investigated. Aims We aimed to test whether expression of myc and mcl-1 is influenced by the levels of the BCR-ABL transcript and therefore compared transcript levels of these two individual genes before and during treatment with TKIs in CML patients. Methods We used RNA isolated from whole blood samples of thirty-six (36) patients with CML, obtained at diagnosis and during treatment with a TKI, at least three months after initiation of treatment. All samples collected during treatment had a bcr-abl/abl ratio less than 2%, while samples collected at diagnosis had bcr-abl/abl ratios ranging from 33 to 130 %. RNA samples were subjected to reverse transcription and cDNA was used in quantitative Real-Time PCR reactions employing Taqman assays for myc, mcl-1 and hprt1 (housekeeping gene). Fold induction or repression of genes after treatment was calculated via the ΔCt method, after calculation of PCR efficiencies. Statistical analysis was performed with the use of the Wilcoxon rank-sum test. Results Median mRNA levels of myc were shown to be increased 2.2 times and median mRNA levels of mcl-1 were shown to be increased 2.6 times after treatment with imatinib, at a statistically significant level (p value Conclusions New treatment targets, either BCR-ABL independent or targets lying downstream of BCR-ABL, are needed in the field of CML therapy in order to circumvent the problem of TKI resistance. In our study, transcription of the genes myc and mcl-1 was shown to be moderately induced by imatinib treatment, which means that non-leukemic Ph-negative white blood cells have a higher amount of myc and mcl-1 transcripts compared to Ph+ leukemic white blood cells. Whole blood RNA was used in the study, as the BCR-ABL kinase has been shown to be expressed in the mature progeny of all haemopoietic lineages except some T cell clones. A study of the protein levels of the two genes would also be warranted in order to elucidate their potential pathogenetic or protective role in CML. In vitro functional studies with specific pharmacological inhibitors would subsequently show if the MYC and MCL-1 proteins could become targets to activate or inhibit in CML. Disclosures: No relevant conflicts of interest to declare.