Christos Sachpekidis

NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model.

Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell‐derived neurofibromas or melanocytic lesions called café‐au‐lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1+/−‐induced pluripotent stem cell (iPSC)‐based model. We demonstrate that NF1 patient‐derived fibroblasts can be successfully reprogrammed in NF1+/− iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patients‐derived CALMs, revealing a new role for NF1 in the melanocyte lineage.

Positron Emission Tomography as a Surrogate Marker for Evaluation of Treatment Response in Patients with Desmoid Tumors under Therapy with Imatinib

We used 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate patients with desmoid tumors undergoing therapy with imatinib. The study included 22 patients with progressive disease (PD) of a biopsy proven desmoid tumor treated orally with imatinib 800 mg daily. Patients were examined using PET prior to onset of therapy and during treatment. Restaging was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI). Outcome of 22 evaluable patients was as follows: five patients with partial response (PR); twelve patients with stable disease (SD) accounting for 77% with non-progressive disease; five patients showed PD. A 30% decrease of the mean average standardized uptake value (SUV) of sequential PET examinations could be demonstrated; no patient demonstrated a substantial increase in SUV. Patients with PR/SD were matched to a group of nonprogressive disease and tested versus PD. The initial average SUV and SUVmax seem to be candidates for a response prediction with an approximate P-value of 0.06553 and 0.07785, respectively. This is the first larger series of desmoid patients monitored using PET showing that early SUV changes may help to discriminate responders from nonresponders and, thus, to decide whether imatinib therapy should be continued.

18F-FDG dynamic PET/CT in patients with multiple myeloma: Patterns of tracer uptake and correlation with bone marrow plasma cell infiltration rate

Purpose The value of 18F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of 18F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of 18F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. Procedures The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of 18F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolute quantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. 18F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. Results Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P < 0.01). Correlative analyses revealed that bone marrow plasma cell infiltration rate correlated significantly with SUVaverage, SUVmax, and the parameters K1, influx, and fractal dimension of 18F-FDG in reference bone marrow (P < 0.01). In addition, whole-body static PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative 18F-FDG–avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET/CT and bone marrow infiltration was detected. Conclusions The 18F-FDG kinetic parameters K1, influx, and fractal dimension as well as SUVaverage from reference tissue correlated significantly with bone marrow malignant plasma cell infiltration rate. Patients with negative PET/CT demonstrated the lowest bone marrow infiltration by malignant plasma cells, whereas those with a mixed pattern of tracer uptake had the highest infiltration.

Ipilimumab has efficacy in metastatic Merkel cell carcinoma: a case series of five patients

and complement C3 were all improved. Twenty-four-hour urinary protein showed 1100 mg/24 h. Urinalysis showed 8500 red blood cells/high-power field. BUN and Cr were normal. Renal ultrasonography indicated normal renal size. The 6MWT was 690 m, and the SLEDAI score decreased to 3. She had stable pulmonary function at the 6-month follow-up. SLE-associated ILD is one of the main complications seen in patients with SLE. Pirfenidone is a novel oral antifibrotic agent, with anti-inflammatory properties including inhibition of proinflammatory cytokines and inflammatory cell proliferation. It reduces fibroblast proliferation, inhibits transforming growth factor-b-stimulated collagen production and reduces the production of fibrogenic mediators. Although no outcomes of clinical trials of pirfenidone for connective tissue disease-associated ILD have been reported, some case reports have been published regarding the efficacy of pirfenidone for patients with connective tissue disease-associated ILD. We reported a case of SLE-associated ILD in a Chinese woman who showed an excellent response to pirfenidone combined with corticosteroids, with no obvious adverse effects. Pirfenidone combined with corticosteroid may be an effective option for treating connective tissue disease-associated ILD.

Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review

PurposeImprovement of the therapeutic approaches in gastrointestinal stromal tumors (GIST) by the introduction of targeted therapies requires appropriate diagnostic tools, which allow sufficient assessment of therapeutic response, including differentiation of true progression from pseudoprogression due to myxoid degeneration or intratumoral hemorrhage. In this literature review the impact and limitations of different imaging modalities used in GIST therapy monitoring are discussed.MethodsPubMed and Cochrane library search were performed using appropriate keywords. Overall, 39 original papers fulfilled the defined criteria and were included in this systematic review.ResultsMorphological imaging modalities like computed tomography (CT) are primarily used for both diagnosis and therapy monitoring. However, therapy with tyrosine kinase inhibitors and other targeted therapies in GIST may lead only to a minor tumor volume reduction even in cases of response. Therefore, the use of Response Evaluation Criteria in Solid Tumors (RECIST) has limitations. To overcome those limitations, modified response criteria have been introduced for the CT-based therapy assessment, like the Choi criteria as well as criteria based on dual energy CT studies. Functional imaging techniques, mostly based on FDG PET-CT are in use, in particular for the assessment of early treatment response.ConclusionsThe impact and the limitations of PET-based therapy monitoring, as well as its comparison with CT, MRI and survival data are discussed in this review. CT is still the standard method for the evaluation of therapy response despite its several limitations. FDG PET-CT is helpful for the assessment of early therapy response; however, more prospective data are needed to define its role as well as the appropriate time intervals for therapy monitoring. A multiparametric evaluation based on changes in both morphological and functional data has to be assessed in further prospective studies.

18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab.

Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.

Comparison of functional imaging in multiple myeloma patients: Indication for hybrid-imaging with PET/MRI?

Methods 24 primary and pre-treated patients diagnosed with multiple myeloma according to the International Myeloma Working Group criteria were examined by F-FDG PET/CT and whole-body MRI including DWI (b= 0, and b= 800 s/mm). F-FDG PET/MRI was used to achieve correct matching of findings in the corresponding PET/ CT study. Suspicious lesions were defined by the imaging gold-standard of nonenhanced T1-w/T2-wMRI and low-dose CT.

Impact of FDG-PET on the Detection of Patients with Lung Cancer at High Risk for ILD

Background/Aim: Idiopathic pulmonary fibrosis IPF is a type of interstitial lung disease (ILD) with poor prognosis. Lung cancer (LC) is a frequent complication in IPF, where all therapeutic options are potential triggers for acute exacerbation of IPF. Patients and Methods: Patients with 2-deoxy-2-fluoro-D-glucose-positron emission tomography/computer tomography (FDG-PET/CT) results before lobectomy for LC with and without (n=10 each) signs of ILD in initial imaging and after-care CT were retrospectively analyzed. FDG uptake was calculated as the maximum standardized uptake value (SUVmax) in the lung periphery divided by the SUVmax of the mediastinal blood pool (rSUVmax). Regional increase of fibrosis and ground-glass features in lobe-based CT analysis was used as standard reference. Results: Patients with LC with ILD presented a significantly higher rSUVmax of 0.57 compared to patients without ILD with rSUVmax 0.47 (p<0.001). Conclusion: rSUVmax seems to be a valuable imaging surrogate in predicting patients with LC with increased risk for progressive ILD associated with thoracic surgery.

Longitudinal studies of the 18F-FDG kinetics after ipilimumab treatment in metastatic melanoma patients based on dynamic FDG PET/CT

BackgroundImmunotherapy has raised the issue of appropriate treatment response evaluation, due to the unique mechanism of action of the immunotherapeutic agents. Aim of this analysis is to evaluate the potential role of quantitative analysis of 2-deoxy-2-(18F)fluoro-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) data in monitoring of patients with metastatic melanoma undergoing ipilimumab therapy.Methods25 patients with unresectable metastatic melanoma underwent dynamic PET/CT (dPET/CT) of the thorax and upper abdomen as well as static, whole body PET/CT with 18F-FDG before the start of ipilimumab treatment (baseline PET/CT), after two cycles of treatment (interim PET/CT) and at the end of treatment after four cycles (late PET/CT). The evaluation of dPET/CT studies was based on semi-quantitative (standardized uptake value, SUV) calculation as well as quantitative analysis, based on two-tissue compartment modeling and a fractal approach. Patients’ best clinical response, assessed at a mean of 59 weeks, was used as reference.ResultsAccording to their best clinical response, patients were dichotomized in those demonstrating clinical benefit (CB, n = 16 patients) and those demonstrating no clinical benefit (no-CB, n = 9 patients). No statistically significant differences were observed between CB and no-CB regarding either semi-quantitative or quantitative parameters in all scans. On contrary, the application of the recently introduced PET response evaluation criteria for immunotherapy (PERCIMT) led to a correct classification rate of 84% (21/25 patients).ConclusionQuantitative analysis of 18F-FDG PET data does not provide additional information in treatment response evaluation of metastatic melanoma patients receiving ipilimumab. PERCIMT criteria correlated better with clinical response.

Functional Imaging with 18F-FDG PET/CT and Diffusion Weighted Imaging (DWI) in Early Response Evaluation of Combination Therapy of Elotuzumab, Lenalidomide, and Dexamethasone in a Relapsed Multiple Myeloma Patient

Elotuzumab is the first monoclonal antibody approved for the treatment of relapsed-refractory multiple myeloma (MM) in combination with lenalidomide, an immunodulatory drug, and dexamethasone. We report on a multiply pre-treated MM patient with disease progression due to appearance of new focal lesions on imaging modalities, who was started on a combination treatment of elotuzumab, lenalidomide, and dexamethasone. After completion of three cycles of the new therapy the patient responded very well with a major decline of serological myeloma activity parameters serum monoclonal protein, kappa light chains, free light chains (FLC) ratio. The patient was also monitored with the functional imaging modalities 18F-FDG PET/CT and diffusion weighted imaging (DWI), which exhibited a mismatch of almost complete metabolic remission on positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxy-d-glucose (18F-FDG) (consistent with the serological response), and signal elevation persistence on DWI. This case demonstrates the potentially superior performance of 18F-FDG PET/CT over DWI in early response evaluation of combined treatment with a monoclonal antibody, an immunomodulatory drug, and dexamethasone in MM.