The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Jejunal Diverticulosis Probably Leading to Pylephlebitis of the Superior Mesenteric Vein

Thrombophlebitis of the portal vein (pylephlebitis) is a rare but serious condition with a high mortality rate of 11-50%. A 56-year-old male patient presented with a two-day history of postprandial, colic-like epigastric pain, nausea, fever, chills, and diarrhea. Clinical workup showed peritonism, leukocytosis, and elevated C-reactive protein (CRP). A computed tomography (CT) scan revealed a long-segment, partial thrombosis of the superior mesenteric vein as well as gas in the portal venous system. Additionally, extensive jejunal diverticulosis was present. Pylephlebitis mostly results from intestinal infections, e.g., appendicitis or diverticulitis. We assumed that the patient had suffered from a self-limiting episode of jejunal diverticulitis leading to septic thrombosis. Initially, antibiotic therapy and anticoagulation with heparin were administered. The patient deteriorated, and due to increasing abdominal defense, fever, and hypotension, a diagnostic laparoscopy was performed. Bowel ischemia could be ruled out, and after changing antibiotic therapy, the patient’s condition improved. He was discharged without any further complications and without complaints on day 13. An underlying coagulopathy like myeloproliferative neoplasm or antiphospholipid syndrome could be ruled out

More Adverse Events after Osteosyntheses Compared to Arthroplasty in Geriatric Proximal Humeral Fractures Involving Anatomical Neck

The purpose of this study was to compare adverse events and clinical outcomes of geriatric proximal humerus fractures (PHF) involving the anatomical neck (type C according to AO classification) treated with open reduction and internal fixation (ORIF) using locking plate vs. arthroplasty. In this retrospective cohort study, geriatric patients (>64 years) who underwent operative treatment using ORIF or arthroplasty for type C PHFs were included. Complications, revisions and clinical outcomes using Constant Murley Score (CMS) and Disabilities of the Arm, Shoulder and Hand (DASH) Score were assessed and compared between groups. At a mean follow up of 2.7 ± 1.7 years, 59 patients (mean age 75.3 ± 5.5 years) were included. In 31 patients ORIF was performed and 29 patients underwent arthroplasty. Complications and revision surgeries were significantly more frequent after ORIF (32.6% vs. 7.1%, p = 0.023 and 29.0% vs. 7.1%, p = 0.045). In contrast, clinical outcomes showed no significant differences (DASH 39.9 ± 25.7 vs. 39.25 ± 24.5, p = 0.922; CMS 49.7 ± 29.2 vs. 49.4 ± 25.2, p = 0.731). ORIF of type C PHFs in geriatric patients results in significantly more complications and revision surgery when compared to arthroplasty. Therefore, osteosynthesis of geriatric intraarticular fractures of the proximal humerus must be critically evaluated

Ipilimumab-induced ischemic gastritis.

<p>Hematoxillin eosin staining showed edematous hypervascularized lamina propria mucosae, foveolar hyperplasia and regenerative basal crypts at 10× magnification (A) and 50× magnification (B). Endoscopic narrow band imaging (NBI) showed signs of reactive chronic inflammation of the gastric corpus mucosa with prominent vascular pattern consistent with an ischemic gastritis (C). Positron emission tomography (PET) scan illustrated high level tracer uptake in the gastric wall consistent with inflammation (D) and its spontaneous resolution after four months with a remaining thickening of the gastric wall (E).</p

Ipilimumab-induced cutaneous reactions.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>MelanA-specific vaccination.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; TKI, tyrosine kinase inhibitor; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response; CR, complete response; MAH, melanoma-associated hypopigmentation.</p

Ipilimumab-induced skin reactions and nephritis.

<p>Melanoma-associated hypopigmentation (MAH) in a patient exhibiting a partial clinical response (A). Masson’s trichome staining showed lymphocytic nephritis in a patient with an ipilimumab-induced drug rash with eosinophilia and systemic symptoms (DRESS) (B). Skin toxicity with the formation of blisters upon induction of treatment with ipilimumab in an area that had been radiated, five weeks earlier, in a patient with previous resection of the distal part of digit II due to an acrolentiginous melanoma (C).</p

Ipilimumab-induced side effects of the endrocrine system.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor-free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p>d<p>limb perfusion with melphalan.</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; GIT, gastrointestinal tract; IGF-1, insulin-like growth factor-1; TSH, thyroid-stimulating hormone; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response.</p

Ipilimumab-induced reactions of the nervous system.

*<p>case is detailed in the result section.</p>a<p>listed treatments are systemic treatments unless otherwise specified.</p>b<p>tumor-free high-risk stage III melanoma (AJCC 2009); adjuvant administration of ipilimumab.</p>c<p>stage IV metastatic disease (AJCC 2009).</p><p>M indicates male; F, female; LN, lymph nodes; IFN-α, interferon-α; DTIC, dacarbazine; TKI, tyrosine kinase inhibitor RAF265; GIT, gastrointestinal tract; PR, partial response; SD, stable disease; PD, progressive disease.</p