Immediate G-CSF application was started and 4?times later on, prednisone 1?mg/kg/d was added, that was switched to methylprednisolone treatment another 4?times later on. (B). A tumor stage IV (pT4b, N2b M1b), was treated with pembrolizumab (anti-PD1) and advanced in June 2016. A mixture therapy with ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) was initiated. At the start from the 4th cycle, a serious quality 4 neutropenia (0,01?G/l) with regular hemoglobin, lymphocyte and thrombocyte amounts was documented. An in depth time type of medicine part and application results is shown in Fig. ?Fig.1.1. A broad-spectrum antibiotic therapy was began and the individual was admitted to your ward. Because of the fact that the individual previously received a co-medication of metamizole (Novalgin?, Sanofi-Aventis AG) and clozapine (Leponex?, Novartis Pharma AG), with known unwanted effects of serious neutropenia, Tsc2 a drug-induced reason behind the isolated neutropenia was hypothesized. Bone tissue marrow puncture at the moment stage revealed a absent myelopoiesis without the additional abnormalities nearly. Histological analysis exposed little infiltrates 4′-Ethynyl-2′-deoxyadenosine of Compact disc8 predominant lymphocytes. Excitement with G-CSF (0,5?Mio.?IE/kg daily) was immediately started at day 1. Because of continual neutropenia for 9?times, corticosteroid treatment was added (methylprednisolone 1?mg/kg daily we.v.). Neutrophil recovery was reached 4?times later on, 35 overall?days following the last ICI software. Staging as of this timepoint demonstrated a incomplete response (Fig. ?(Fig.2).2). Upon interdisciplinary dialogue with the individual and complete quality from the neutropenia, he was re-exposed to nivolumab monotherapy with cautious monitoring and without metamizole co-medication as metamizole was regarded as the reason 4′-Ethynyl-2′-deoxyadenosine for neutropenia. A month later on, a recurrence of quality 4 neutropenia (0.01G/l) occurred. Corticosteroid treatment and G-CSF stimulation as stated over were restarted immediately. The neutrophil retrieved to normal ideals a week after supportive therapy was began. However, the individual experienced from a serious pulmonary disease and hemorrhagic diarrhea and died because of respiratory failing and septic surprise 1 week later on. The autopsy result demonstrated a sophisticated fungal lung disease, probably stemming through the repeated neutropenia, and a designated colitis with ulcerous miss lesion (Fig. ?(Fig.3).3). Histological results from the digestive tract demonstrated intestinal stromal infiltration of lymphocytes, coordinating an immune-related trigger. Strikingly, further results confirmed an entire remission from the advanced melanoma. Open up in another windowpane Fig. 1 Timeline of individual 1. Neutrophil count number over time pursuing administration of ipilimumab, nivolumab and metamizol aswell as following interventions (software of G-CSF and methylprednisolone) are demonstrated. The lower gray music group marks the thresholds of neutrophils in the bloodstream. The top grey band shows concurrent diarrhoea that was active between and during events of neutropenia intermittently. Numbers in yellowish indicate enough time stage of positron emission tomography (Family pet) with pictures demonstrated in Fig. ?Fig.2.2. The dark mix marks the loss of life of the individual Open up in another windowpane Fig. 2 Positron emission tomography (Family pet) images at that time factors as demonstrated in Fig. ?Fig.1.1. Family pet #1 1 depicts multiple metastasis (coeliacal, inguinal, pulmonary and retroperitonal). In Family pet picture?2 a progression with coeliacal, retroperitoneal, inguinal and paraaortal lymph node but lowering pulmonary melanoma manifestations was viewed as combined response following 3? cycles of nivolumab and ipilimumab therapy. Family pet image?3 displays complete remission of melanoma metastasis and a higher activity in the complete colon because of massive Defense Checkpoint Inhibitor induced colitis. A port-a-cath was received by The individual program between your 1st and second Family pet check out Open up in another windowpane Fig. 3 Autopsy outcomes: Post mortem evaluation revealed bowel wall structure injuries because of immune system related colitis and fungal pneumonia. a: Indicated by arrow, macroscopic (remaining) and microscopic (best) skipped lesion in the intestine. b: Pulmonary fungal infiltration with microscopic proven fungal hyphae (indicated by arrow)) The next case happened in November 2018. A 56-yr 4′-Ethynyl-2′-deoxyadenosine old individual with BRAFV600E metastatic melanoma stage IV (TxN3M1d), who was simply previously treated with chemotherapy (dacarbazine), BRAF inhibitor (vemurafenib), pembrolizumab and ipilimumab. In July 2018 After disease development,.