Early Identification Of Responders Research Articles

Efficacy of pasireotide LAR for acromegaly: a prolonged real-world monocentric study.

Acromegaly is caused by excessive growth hormone (GH) and insulin-like growth factor 1 (IGF1). Medical therapy plays a role as a treatment option for persistent disease after non-curative surgery or as a first-line therapy when surgery is not feasible. Pasireotide-LAR (Pas-LAR) is recommended for patients with acromegaly as second-line treatment. To evaluate the patients characteristics predictive of an adequate response to Pas-LAR and the long-term efficacy and safety of the Pas-LAR treatment. Data from 19 patients with active acromegaly, who were and resistant or intolerant to first-line medical therapy and were switched to pas-LAR have been retrospectively collected. We compared the baseline clinical and biochemical characteristics of patients who were found to respond to Pas-LAR therapy (responders, n=14) with those of patients who did not respond (non-responders, n=5). We then evaluated the Pas-LAR efficacy and safety during long-term follow-up in responders. IGF1 normalization occurred in 71.4% of responders after one injection. IGF1 levels, [median(interquartile range) of the upper limit of the normal range (ULN) fold increase] were higher in non-responders compared to responders within the initial month of therapy [1.40(1.30-2.34) vs 0.70(0.55-1.25), respectively, p=0.009] and after three [1.77(1.74-2.29) vs 0.94(0.82-1.13), respectively, p=0.029] and six months [1.68(1.33-1.72) vs 1.00(0.65 -1.28), respectively, p=0.002]. Out of 6 patients with symptomatic headache (all in responder group), 5 and 1 reported the resolution and improvement of headache, respectively, already after the first injection. Median HbA1c levels tended to increase from baseline to 6 months both in responder (36 mMol/Mol to 42 mMol/Mol) and non-responder patients (45 mMol/Mol to 48 mMol/Mol). During long term follow up, in the responder group 2 new patients developed diabetes. Tumor shrinkage was observed in 6 out of 7 evaluated responders, with no cases of size increase during the long-term follow-up. Pas-LAR is effective and safe and the early identification of responders is possible just after the first administration.

Noninvasive Monitoring of Immunotherapy in Lung Cancer by Lymphocyte Activation Gene 3 PET Imaging of Tumor-Infiltrating Lymphocytes.

Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of invitro and invivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

Clinical Predictors of Response to Anti-PD-1 First-Line Treatment in a Single-Centre Patient Cohort: A Real-World Study

AimsCutaneous melanoma is one of the most immunogenic tumours. Immunotherapy with checkpoint inhibitors, such as anti-PD-1 antibodies, has significantly improved the prognosis in metastatic melanoma. However, only half of the patients respond to this therapy and have a favourable outcome. Identifying factors associated with treatment failure and early identification of responders are both important to select the best treatment approach for each patient. The aim of our study was to investigate clinical biomarkers of response to treatment with anti-PD-1 antibodies. Materials and methodsWe selected all patients with stage IV melanoma (n = 147), subjected to first-line treatment with anti-PD-1 in the last 10 years. We investigated the associations between patients' different clinical features and progression-free survival, using the Cox proportional hazards models. ResultsIn the multivariate analysis, an increased risk of disease progression was observed among patients with stage M1d metastases (hazard ratio 3.30; 95% confidence interval 1.58–6.91), compared with patients with stage M1a-M1b. Moreover, the risk of progression was greater in patients with the Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (hazard ratio 2.04; 95% confidence interval 1.02–4.06) and in patients with ECOG PS ≥ 2 (hazard ratio 2.19; 95% confidence interval 1.05–4.55) compared with ECOG PS 0. High levels of lactate dehydrogenase (hazard ratio 2.06; 95% confidence interval 1.18–3.59) and the presence of respiratory diseases (hazard ratio 4.14; 95% confidence interval 1.42–12.0) at the beginning of anti-PD-1 treatment were also associated with an increased risk of disease progression. In a subgroup analysis, neutrophil count and neutrophil/lymphocyte ratio before anti-PD-1 treatment were higher in patients who underwent disease progression. ConclusionIn our study population, independent predictors of disease progression among patients treated with first-line anti-PD-1 were as follows: ECOG PS, staging, lactate dehydrogenase and the presence of respiratory diseases.

Levels of mRNA for dopaminergic receptor D₅ in circulating lymphocytes may be associated with subsequent response to interferon-β in patients with multiple sclerosis.

Interferon (IFN)-β is among the first-line therapies for multiple sclerosis (MS), however the clinical response varies among individuals, and early identification of responders and non-responders would be of critical importance. Here we show that before treatment circulating lymphocytes of MS patients who will respond to IFN-β have higher mRNA levels for the D1-like dopaminergic receptor (DR) D5 in comparison to cells from those who will not respond. Lymphocyte DR D5 is reduced in MS and IFN-β restores their expression and responsiveness. DR D5 mRNA levels in circulating lymphocytes might represent an early marker of response to IFN-β in MS patients.

Identifying responders and nonresponders to interferon therapy in multiple sclerosis.

Interferon beta is a well established disease-modifying agent used for relapsing-remitting multiple sclerosis. Despite treatment, a relevant proportion of patients continue to experience clinical (ie, relapses, worsening of disability) and magnetic resonance imaging (MRI) activity. Early identification of responders and nonresponders to interferon beta is strongly recommended to select patients who need a prompt switch to another disease-modifying agent and to ultimately avoid accumulation of fixed disability over time. Detecting responders and nonresponders to interferon beta can be challenging, mainly because of the lack of a clear and shared clinical definition of response to treatment. Clinical features at the start of treatment should be considered as prognostic factors, but MRI parameters assessed during treatment, such as contrast-enhancing lesions or new T2-hyperintense lesions, may be sensitive markers of response to interferon beta. Quantitative scoring systems derived from a combination of relapses and MRI activity have recently been proposed as practical tools for use in the everyday clinical setting. Blood biomarkers, such as neutralizing antibodies to interferon beta and Myxovirus resistance protein A, provide further useful information for detecting responders and nonresponders to interferon beta. However, since the presence of neutralizing antibodies can only partially explain the nonresponse to interferon beta, biomarkers of interferon beta activity possibly related to the pathogenesis of the disease could represent a future step toward a tailored, long-lasting effective treatment against multiple sclerosis.

18F-FDG and 18F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors: Studies in Human Tumor Xenografts in Mice

IntroductionThe mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.MethodsThe effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10.ResultsEverolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016), day 7 (164±7% vs. 226±13%; p<0.001) and at day 10 (194±10% vs. 281±18%; p<0.001). Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027).ConclusionEverolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.

115IN - Addressing Clinical Challenges in Targeted Therapies with Advanced Imaging

ABSTRACT Advanced imaging techniques are being developed to provide information relevant for patient management beyond changes in tumor size. Treatment with novel targeted therapies showed that conventional RECIST measurements are insufficient to assess response as changes in tumor size occur relatively late, if at all. It has been shown that molecular imaging techniques provide predictive and prognostic information at baseline or by comparing baseline scans to scans obtained very early after the start of treatment. It aims at the (very) early identification of responders before tumor shrinkage occurs, but also indicating a high likelihood of relapse even before tumor growth is apparent. Furthermore, molecular imaging with radiopharmaceuticals may aid in identifying receptor overexpression or pathway activation in tumors before treatment with targeted therapies is initiated. The ability of FDG-PET to predict response of metastatic GIST to imatinib became the role model for the potential of molecular imaging to provide clinically relevant answers within days after the start of treatment. Since the introduction of integrated PET/CT the acceptance of the technology enormously increased. A large number of PET/CT studies was performed in patients treated with various targeted therapies (both antibodies and TKIs) in a wide variety of tumor types with both FDG and other radiopharmaceuticals such as FLT, a marker of proliferation. Similary, advanced CT (perfusion) and MRI (dynamic MRI, DWI, MRS) techniques have taken advantage of the development of technology. Following the introduction of therapeutic monoclonal antibodies such as bevacuzimab and trastuzumab, studies with the radiolabeled derivatives have been used to image the tumor-associated factors and receptors, targeted by these antibodies (immunoPET and immunoSPECT). It has been shown that this approach could successful visualize the antibody targets. More recently, small molecules (e.g. paclitaxel, lapatinib) have been radiolabeled and used in clinical studies. Following the numerous proof of principle and translational research studies, the time has come time to develop the role of the advances towards evidence-based imaging in clinical practice by systematically positioning advanced imaging for treatment selection in clinical trials. Disclosure The author has declared no conflicts of interest.

The Association of Radiotherapy and Chemotherapy: Esophageal Cancer

Over the past 30 years, significant advances have been made in the integration of radiation therapy and chemotherapy in the treatment of patients with esophageal malignancies. The therapeutic goal of chemoradiotherapy is to enhance local control resulting in improved loco-regional control and survival of these patients. To define the optimal sequence, the need of combination with surgery, and the efficacy of these modalities, several trials have been conducted, mainly as phase II studies and often underpowered or flawed phase III studies. The clinical evidence strongly suggests that preoperative chemoradiotherapy improves outcome. Therefore, this strategy has replaced single-modality approaches (surgery, radiotherapy) becoming a standard treatment option in patients with operable advanced disease. Moreover, recent published studies indicate that patients treated with definitive chemoradiotherapy have similar survival to patients undergoing neoadjuvant chemoradiotherapy followed by surgery. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing radiation dose have not been successful. The use of other novel agents (camptothecin, taxane …) combined with radiation has altered the toxicity profile, but substantial prognostic improvement has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents and the use of molecular predictors of response as a strategy to select the treatment. Early identification of responders will also be required in order to guide and select the therapy. This overview highlights current results, controversies and potential future directions in the chemoradiotherapeutic treatment of selected esophageal cancer.

Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis

It has been well established that raloxifene (RLX) improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure how to monitor the therapeutic effects of RLX, while numerous clinical trials for other antiresorptive agents have suggested that greater short-term reductions of bone turnover markers (BTMs) can predict greater increases in BMD and greater reduction in risk of future fractures. The purpose of this study was to investigate associations between short-term reductions of BTMs and subsequent changes of BMD after 1-year treatment with RLX. Seventy-three Japanese postmenopausal women with untreated osteoporosis were selected for this study. Reductions in BTMs [bone-specific alkaline phosphatase (BAP) or serum N-terminal telopeptide of type I collagen (NTx)] after 3 months did not correlate with increases of BMD at any major sites (lumbar spine, femoral neck, total neck, and distal 1/3 radius) either after 6 months or after 12 months. Our results suggest that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict increases of BMD. However, this does not directly mean that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict risk reduction of future fractures or the ultimate effects of RLX on bone. Further studies with fracture endpoints in longer observation and larger number of patients are warranted to establish how to monitor the therapeutic effects of RLX or early identification of responders or nonresponders to RLX treatment.

Sorafenib (S) and dacarbazine (D) combination in patients (pts) with advanced malignant solid tumors: Phase I study with tumor biopsy genomic analysis and dynamic contrast enhanced ultrasonography (DCE-US)

3556 Background: S is a multikinase inhibitor targeting VEGFR-1, -2, -3, PDGFR-a and -β and Raf kinase. The combination of S (400 mg bid) and D (1,000 mg/m2, 21-day [d] cycle [C]) was previously defined as maximum tolerated dose. Objectives were to define the pharmacokinetic (PK) profile of D ± S, assess safety of the combination and collect antitumor activity data by genomic analysis and by DCE-US. Methods: All pts received D (1,000 mg/m2 by 1-hr infusion) with continuous oral S 400 mg bid (except Day1C1). PK was performed during 1st and 2nd infusions. RNA expression profiling was performed on sequential tumor biopsies at baseline (BL) and Day 21. DCE-US was assessed at BL and Day 8, 21 of C1. Results: 23 pts treated (median age 59 y) had melanoma (4), leiomyosarcoma (4), adenocarcinoma (5), mesothelioma (3), neuro-endocrine tumor (3) and other (4). 22 had = 1 prior chemotherapy (range, 1–7). Median (range) number of D cycles was 4 (1–9), median (range) duration of S treatment was 15 wks (3–48). Toxicities were manageable and included diarrhea (48% any grade [G], no G3/4), hand-foot skin reaction (48% any G, 4% G3), fatigue (26% G3), thrombopenia (22% G4), and neutropenia (13% G4). Of 22 evaluable pts, 1 (melanoma) had confirmed PR, 13 pts had SD as best response, with a median (range) duration of 161 d (75–258). 7 pts continue with SD. PK (n=15) showed increased mean AUC by 41% and mean Cmax of AIC (an inactive D metabolite that is formed in an equal proportion to the active moiety, diazomethane, that cannot be analytically measured) by 45%. Genomic analysis in 10 pts with PFS =3 mos and in 7 with PFS &lt;3 mos identified a subset of 4 genes whose modulation differentiates these groups with 100% accuracy. 99 DCE-US performed in 17 pts showed 3/7 with short PFS had increased volume on Day 21 and in 3 an increase in maximal intensity &gt;50% on Day 8. Of 10 pts with long PFS, maximal intensity decreased by &gt;50% on Day 21 in 8 pts. Conclusion: Combination of D and S is manageable with clear evidence of antitumor activity. Preliminary data strongly suggest a new paradigm based on sequential tumor genomic analysis allowing early identification of responders. Early stage DCE-US may predict PFS duration. No significant financial relationships to disclose.

Telemonitoring of blood pressure self measurement in the OLMETEL study

To investigate the feasibility of blood pressure (BP) telemonitoring in previous uncontrolled hypertensives treated with olmesartan medoxomil in a clinical practice setting. Patients (n = 53) with untreated, uncontrolled or insufficiently treated hypertension were selected by physicians to receive olmesartan medoxomil 10-40 mg/day for 12 weeks. Office BP values were determined by a physician at baseline and after 12 weeks' treatment; BP self-measurement (BPSM) was conducted throughout the 12-week treatment period using a TensioPhone TP2 telemonitoring device; BP values were stored and automatically downloaded to a remote service centre via standard telephone lines. Olmesartan medoxomil produced statistically significant reductions from baseline in both systolic and diastolic office BP and BPSM values. In contrast to office BP, telemonitoring of BPSM allowed the early identification of responders (e.g., after 2-3 weeks' treatment). Blood pressure reduction with olmesartan medoxomil was greater for office BP than for BPSM values. Normalization of BP was achieved in 64.2% of the patients using office BP measurement compared with 36.4% using BPSM. Blood pressure self-measurement showed no significant difference between morning and evening BP measurements or between the morning : evening BP ratio at baseline and after nine weeks of olmesartan medoxomil treatment. Compliance and tolerability were good or very good in most patients. In a 'real-life' clinical practice setting, telemonitoring of BPSM was an effective technique that was partially affected by patient non-compliance. Olmesartan medoxomil provided effective and reliable BP-lowering, which was maintained throughout the 24-hour period.

Optimizing Treatment of Carcinoma of the Esophagus and Gastroesophageal Junction

Overall prognosis in patients with carcinoma of the esophagus and Gastroesophageal junction remains poor mainly because of the late presentation and advanced stage of the disease at the time of diagnosis. Over the last decades, clinical staging has improved, especially since the introduction of CT scan and echo-endoscopy; however, the clinical definition of potential curative tumors still remains unsatisfactory. More recently, the introduction of PET scanning seems to offer better perspective for more precise staging and evaluation of response. In centers with large experience, cure rates today are exceeding 30% after primary surgery. To improve the cure rate, much attention is paid to neoadjuvant multimodality regimens. In resectable tumors, induction therapy offers little or no benefit. In locally advanced tumors especially, the combination of induction chemoradiotherapy results in a complete response in a substantial number of patients. This subset of patients seems to benefit in terms of survival and cure, whereas the others do not. Future research, therefore, needs to focus on early identification of responders (e.g., through molecular biology) and new chemotherapeutic drugs with higher impact on tumor response and fewer side effects.