Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients.

Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine.

Doxazosin for the treatment of nightmare disorder: A diary-based case study.

The α1-adrenergic antagonist prazosin has showed good effect against posttraumatic stress disorder-related nightmares in several randomized controlled trials. The α1-adrenergic antagonist doxazosin, which has a longer half-live than prazosin, has received far less attention in the treatment of such nightmares. Here, we report a case of a patient suffering from severe nightmares following an erroneous medical administration of adrenaline (causing severe physiological hyper-activation) who was treated with doxazosin. Over a period of 280 days, the patient kept a nightmare diary and took 0, 4, or 8 mg doxazosin. The analyses showed that 8 mg doxazosin (55.2% nightmare-free nights) worked better (odds ratio = 28.2; 95% confidence interval = 3.7-213.9) compared to nights without doxazosin (4.3% nightmare-free nights). Except dizziness, which was not regarded as particularly bothersome by the patient, doxazosin was well tolerated. It is concluded that doxazosin may be indicated as a pharmacological treatment for patients suffering from posttraumatic stress disorder-related nightmares.

Clinical significance of signs of autoimmune colitis in 18F-fluorodeoxyglucose positron emission tomography-computed tomography of 100 stage-IV melanoma patients.

Aim: Autoimmune colitis is a typical and possible severe side effect among patients treated with ipilimumab. Patients & methods: We prospectively included 100 patients with metastasized melanoma under ipilimumab treatment in a radiological study of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT). PET evidence of pancolitis ('PET-colitis') was correlated with clinical variables. Results: We observed a significant correlation between PET-colitis and clinically significant diarrhoea, although PET-colitis was more frequent (49 vs 29% of patients, respectively). Neither PET-colitis nor diarrhoea was significantly correlated with response to therapy. Other immune-related adverse events, however, such as hypophysitis and hepatitis were associated with response to therapy and overall survival. Conclusion: Increased 18F-FDG uptake in the colon correlated with clinical symptoms but did not predict clinical outcome to ipilimumab.

Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature.

Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.

Amyloidosis Cutis Dyschromica, a Rare Cause of Hyperpigmentation: A New Case and Literature Review.

Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper- and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered.

Making the invisible visible: improved electrospray ion formation of metalloporphyrins/-phthalocyanines by attachment of the formate anion (HCOO(-)).

A protocol is developed for the coordination of the formate anion (HCOO(-)) to neutral metalloporphyrins (Pors) and -phthalocyanines (Pcs) containing divalent metals as a means to improve their ion formation in electrospray ionization (ESI). This method is particularly useful when the oxidation of the neutral metallomacrocycle fails. While focusing on Zn(II)Pors and Zn(II)Pcs, we show that formate is also readily attached to Mn(II), Mg(II) and Co(II)Pcs. However, for the Co(II)Pc secondary reactions can be observed. Upon collision-induced dissociation (CID), Zn(II)Por/Pc·formate supramolecular complexes can undergo the loss of CO2 in combination with transfer of a hydride anion (H(-)) to the zinc metal center. Further dissociation leads to electron transfer and hydrogen atom loss, generating a route to the radical anion of the Zn(II)Por/Pc without the need for electrochemical reduction, although the Zn(II)Por/Pc may have a too low electron affinity to allow electron transfer directly from the formate anion. In addition to single Por molecules, multi Por arrays were successfully analyzed by this method. In this case, multiple addition of formate occurs, giving rise to multiply charged species. In these multi Por arrays, complexation of the formate anion occurs by two surrounding Por units (sandwich). Therefore, the maximum attainment of formate anions in these arrays corresponds to the number of such sandwich complexes rather than the number of porphyrin moieties. The same bonding motif leads to dimers of the composition [(Zn(II)Por/Pc)2·HCOO](-). In these, the formate anion can act as a structural probe, allowing the distinction of isomeric ions with the formate bridging two macrocycles or being attached to a dimer of directly connected macrocycles.

Comparison of the psychometric properties of two fatigue scales in multiple sclerosis.

OBJECTIVE: To compare psychometric functioning of the Fatigue Severity Scale (FSS; Krupp, LaRocca, Muir-Nash, & Steinberg, 1989) and the Modified Fatigue Impact Scale (MFIS; MSCCPG, 1998) in a community sample of persons with multiple sclerosis (MS). METHOD: A self-report survey including the FSS, MFIS, demographic, and other health measures was completed by 1271 individuals with MS. Analyses evaluated the reliability and validity of the scales, assessed their dimensional structures, and estimated levels of floor and ceiling effects. Item response theory (IRT) was used to evaluate the precision of the MFIS and FSS at different levels of fatigue. RESULTS: Participants had a mean score on the FSS of 5.1 and of 44.2 on the MFIS. Cronbach's alpha values for FSS and MFIS were all 0.93 or greater. Known-groups and discriminant validity of MFIS and FSS scores were supported by the analyses. The MFIS had low floor and ceiling effects, and the FSS had low floor and moderate ceiling effects. Unidimensionality was supported for both scales. IRT analyses indicate that the FSS is less precise in measuring both low and high levels of fatigue, compared with the MFIS. CONCLUSIONS: Researchers and clinicians interested in measuring physical aspects of fatigue in samples whose fatigue ranges from mild to moderate can choose either instrument. For those interested in measuring both physical and cognitive aspects of fatigue, and whose sample is expected to have higher levels of fatigue, the MFIS is a better choice even though it is longer. IRT analyses suggest that both scales could be shortened without a significant loss of precision.

Accuracy of automated attenuation-based 3-dimensional segmentation: in the analysis of left ventricular function compared with magnetic resonance imaging.

We evaluated attenuation-based 3-dimensional segmentation for the analysis of left ventricular function, using as our standard of reference magnetic resonance imaging and dual-source computed tomography with traditional short-axis planimetry.Twenty patients with known or suspected coronary artery disease were examined prospectively. In all magnetic resonance and computed tomographic datasets, global functional values were determined by 2-dimensional planimetry. Computed tomographic scans were further evaluated by automated 3-dimensional segmentation, and the results were compared by Pearson correlation and Bland-Altman analysis.Agreement between magnetic resonance imaging and dual-source computed tomographic 2-dimensional planimetry was good for all values (end-diastolic volume, bias= -4.2, r=0.99; end-systolic volume, bias= -1.7, r=0.99, stroke-volume, bias= -2.4, r=0.98; ejection fraction, bias=0.26, r=0.94; and myocardial mass, bias= 2.5, r=0.90). By contrast, dual-source computed tomographic 3-dimensional segmentation overestimated end-diastolic volume (bias= -19.1, P <0.001), stroke-volume (bias= -16.9, P <0.001), and myocardial mass (bias= -34.4, P <0.001). Moreover, correlation with magnetic resonance imaging proved disappointing for ejection fraction (r=0.72). Results were similar in a direct comparison between dual-source computed tomographic 2-dimensional planimetry and 3-dimensional segmentation (end-diastolic volume, bias= -14.9, r=0.94; end-systolic volume, bias= -0.5, r=0.90; stroke volume, bias= -14.5, r=0.83; ejection fraction, bias= -2.8, r=0.74; and myocardial mass, bias= -36.8, r=0.79).Due to significant overestimation of volumes and poor correlation of ejection fraction with cine magnetic resonance imaging results, attenuation-based 3-dimensional segmentation compares unfavorably with traditional planimetry. Hence this method should be used with caution, and its time benefits should be weighed against its imprecision of functional analysis.