We speculate that this may be the reflection of an immune-privileged site

We speculate that this may be the reflection of an immune-privileged site. Immunostimulatory agents are coming into wider use outside of clinical trials in the form of anti-CTLA4 and anti-PD-1/PD-L1 antibodies. opportunistic, pneumocystis, pneumonia, steroids == Abbreviations == antitumor necrosis factor Chronic Lymphocytic Leukemia cytotoxic lymphocyte antigen interleukin immune-related adverse events T regulatory wild type. == Introduction == In recent years, immune therapy has become a successful modality for treating patients with advanced melanoma and other tumor types.1,2Ipilimumab is an anti-CTLA-4 antibody that enhances immune response (IR), enabling antitumor activity. In patients with advanced melanoma, ipilimumab has led to increased overall survival when compared to chemotherapy with durable benefit in approximately 20% of patients.1Although well tolerated in general, ipilimumab causes immune-related adverse events (irAEs) that are now well described.3When these irAEs are severe or persistent, the recommended treatment is the use of steroids Rutin (Rutoside) in the first line instance and, when this is insufficient, the administration of potent immunosuppressants such as infliximab (anti-TNF).4The main concern when using immunosuppressants is the potential adverse effect on tumor immune control, leading to worse clinical outcome, although this seems not to be the case for low-dose steroid treatment. 5A second concern is that iatrogenic immune suppression may increase the risk of opportunistic infections.6,7In our institution, we have treated 150 patients with ipilimumab DLL1 for advanced melanoma. Here we present two cases of patients treated with immunosuppressants for ipilimumab-related toxicity that developedPneumocystispneumonia. == Case 1 == A 69 y old lady with a history of Chronic Lymphocytic Leukemia (CLL) since 1995, had been treated with chlorambucil, fludarabine and a single dose of rituximab to stable disease in 2006. She was diagnosed with a cutaneous,BRAFwild type (WT) melanoma on the right arm in November 2010 (Stage IIIb). A sentinel lymph node biopsy revealed one isolated micrometastasis and CLL. No further nodes were involved by melanoma at subsequent lymphadenectomy Rutin (Rutoside) of the right axilla in February 2011. Two right axillary recurrences were treated surgically. However, a CT scan performed in July 2011 demonstrated further recurrent axillary disease and lung metastases. In January 2012, the patient received two cycles of dacarbazine with progressive disease in the mediastinum and lung (Fig. 1A). In March 2012, she started treatment with ipilimumab 3mg/kg and completed four cycles. She presented with grade 2 diarrhea after the fourth cycle and disease evaluation by CT scan at that point, showed mixed response. The diarrhea progressed to grade 3 colitis and in July 2012, the patient was admitted for assessment and treatment with intravenous steroids. A flexible sigmoidoscopy confirmed the suspected ipilimumab related colitis; as symptoms did not improve on steroids, the patient received a single infliximab dose (5 mg/kg). Forty-eight hours later the GI toxicity had dramatically improved and the patient was discharged with 60 mg of oral prednisolone that was tapered over 12 weeks. The CT scan performed in August 2012 demonstrated a late response to ipilimumab with improvement in all sites of disease (Fig. 1B). Concomitantly, her peripheral count of lymphocytes dropped from 45.000 and has fluctuated around 10x10E9/l after December 2012 with platelets around 100.000 x10E9/l and a stable hemoglobin without substitution. == Figure 1. == Case 1. (A) Enlarged left hilar adenopathy (white arrow); (B) Complete response of the left hilar node after treatment with ipilimumab; (C) Hazy ground glass opacities in the apical segment of the left lower lobe compatible with Pneumocystis pneumonia. At the end of September 2012 she was admitted in hospital with shortness of breath and hypoxia and a CT scan revealed ground glass lesions compatible with an atypical infection (Fig. 1C). A bronchoscopy with bronchial lavage confirmed the growth ofPneumocystis jiroveci. Treatment with intravenous cotrimoxazole for 10 d resulted in improvement of the respiratory crisis and the patient was discharged on oral cotrimoxazole. At the last follow up (March 2015), the patient has no evidence of recurrent melanoma and no progression of her CLL. A Rutin (Rutoside) significant humoral immune defect, diagnosed with a total IgG of 0.4 g/L in February 2013 requires ongoing monthly immunoglobulin substitution. The patient has had no further episodes of clinically significant infections and remains on cotrimoxazole Rutin (Rutoside) prophylaxis. == Case 2 == A 63 y old lady was diagnosed with a cutaneousBRAFWT melanoma on the right shoulder in November 2011. Initial surgical excision of the lesion confirmed a superficial spreading melanoma, Breslow 3.4 mm, mitotic rate 5/mm2. Wide local excision and axillary block dissection were performed in February 2014 showing involvement 5 out of 14 lymph nodes and extracapsular spread. Macroscopically the nodal recurrence was deeply pigmented. The patient started treatment with ipilimumab in March 2014. Rutin (Rutoside) After the third cycle, the patient was treated for grade 3 diarrhea with oral steroids (40 mg prednisolone) with rapid symptom improvement. In June 2014, the patient.