Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

BACKGROUND: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. PATIENTS AND METHODS: Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. RESULTS: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5-187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. CONCLUSIONS: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Peptide and pseudo-peptide.

In recent years, the introduction of theranostic twins for specific diagnosis and treatment in patients with neuroendocrine tumors became a nuclear medicine success story. 64Cu/18F labeled prostate specific membrane antigen (PSMA) for molecular imaging with PET-CT and peptide radioligand therapy with 177Lu labeled PSMA inhibitors will favorably become the next theranostic twins in nuclear medicine history. 68Ga/ 64Cu/18F PSMA PET/CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity. In addition, it can be used to select patients for radioligand therapy and evaluate therapy response. 64Cu-labeled radiopharmaceuticals such as 64Cu-PSMA, and 64Cu-somatostatin analogs are promising imaging tools in the assessment of primary disease and also in the detection of disease recurrence and to evaluate therapy response. The long half-life of 64Cu allows the distribution of the tracer to PET centers as a satellite concept, who otherwise has no access to 68Ga generators.

Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.

Intra-arterial thrombolysis of digital artery occlusions in a patient with polycythemia vera.

There are limited therapeutic options for the resolution of digital artery occlusions. Intra-arterial thrombolysis with anticoagulative and thrombolytic drugs successfully restored the blood flow in the affected digital arteries.

Symptom clusters associated with complementary and alternative medicine use by cancer patients: A cross-sectional study.

BACKGROUND: Complementary and alternative medicine (CAM) is a commonly used approach among cancer patients, with a reported prevalence of 14.8 to 73.1% depending on multiple factors. Even though a typical patient-reported reason for using CAM is symptom control, no conclusive evidence could be established for specific symptoms being a predictor for CAM use. Symptom clusters are a novel approach for assessing a multidimensional symptom burden, reflecting the impact of diseases on the patient's quality of life and considering the tendency of symptoms to occur in groups. MATERIAL AND METHODS: A single-center cross-sectional study on cancer patients during oncological or palliative care was conducted to identify socio-demographical and clinical characteristics, including symptom clusters of CAM users and non-users. Symptom clusters were defined using latent profile analysis, and multivariable analyses were performed to assess significant factors influencing CAM use. RESULTS: Of 171 cancer patients in this study, 63.7% used CAM alongside oncological treatment or palliative care. The most common CAM therapies were biological and physical therapies, including homeopathy (30.3%), supplements (27.4%), herbs (26.6%), massage (24.8%), and acupuncture (22.0%). Four distinct symptom clusters were identified, of which the cluster drowsiness-depression-anxiety was associated with a 3.83-fold increased chance of using CAM compared to low-symptomatic cancer patients. Multivariate analysis did not show any additional significant predictors of socio-demographical factors. CONCLUSION: Using the concept of symptom clusters revealed a significant predictor for CAM use, suggesting to be a more conclusive method for assessing symptom burden in cancer patients. In addition, understanding why and how cancer patients turn to CAM can enhance the quality of multidisciplinary communication about its use.

Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

PURPOSE: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. METHODS: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. RESULTS: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. CONCLUSIONS: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

Evaluation of autoantibodies as predictors of treatment response and immune-related adverse events during the treatment with immune checkpoint inhibitors: A prospective longitudinal pan-cancer study.

BACKGROUND: The presence of autoantibodies in the serum of cancer patients has been associated with immune-checkpoint inhibitor (ICI) therapy response and immune-related adverse events (irAEs). A prospective evaluation of different autoantibodies in different cancer entities is missing. MATERIALS AND METHODS: In this prospective cohort study, we included a pan-cancer cohort of patients undergoing ICI treatment and measured a comprehensive panel of autoantibodies at treatment start and at the time point of first response evaluation. The presence and induction of autoantibodies (ANA, ENA, myositis, hepatopathy, rheumatoid arthritis) in different cancer entities were assessed and the association between autoantibodies and disease control rate (DCR), objective response rate (ORR), and progression-free survival (PFS), as well as the development of grade 3 or higher irAEs were evaluated by logistic regression models, cox proportional hazard models, and Kaplan-Meier estimators. RESULTS: Of 44 patients with various cancer entities, neither the presence of any positive autoantibody measurement nor the presence of positive antinuclear antibodies (ANA) [≥1:80] at baseline was associated with the examined clinical endpoints (DCR, ORR, PFS) in univariable and multivariable analyses. After 8-12 weeks of ICI treatment, DCR, ORR, and PFS did not significantly differ between patients with and without any positive autoantibody measurement or positive ANA titers. The frequency of irAEs did not differ depending on autoantibody status of the patients. CONCLUSION: Autoantibodies at treatment initiation or induction after 8-12 weeks of ICI treatment are not associated with treatment efficacy as indicated by DCR, ORR, and PFS or higher grade irAEs.

Additional lesions detected in therapeutic scans with 177Lu-DOTATATE reflect higher affinity of 177Lu-DOTATATE for somatostatin receptors.

OBJECTIVE: Peptide receptor-targeted radionuclide therapy (PRRT) of somatostatin receptor (SR)-expressing neuroendocrine tumors (NETs) has become an established therapeutic option in patients with advanced NETs. The aim of this study was to compare the lesion detection rate of (99m)Tc-EDDA/HYNIC-TOC, a newly developed tracer for NET imaging, with (177)Lu-DOTATATE used for PRRT. METHODS: 8 patients (4 women, 4 men, age range 46-76 years) with histologically proven NETs, who showed high SR loads by (99m)Tc-EDDA/HYNIC-TOC scintigraphy, were treated with (177)Lu-DOTATATE. After treatment, all patients were subjected to whole-body scintigraphy with additional low-dose single-photon emission computed tomography (SPECT-CT) of the chest and abdomen. RESULTS: All patients demonstrated (177)Lu-DOTATATE accumulation in all lesions previously detected by (99m)Tc- EDDA/HYNIC-TOC scintigraphy. Three patients showed additional lesions in the liver and lungs. CONCLUSIONS: SPECT-CT after (177)Lu-DOTATATE therapy may be helpful in detecting additional lesions not seen using (99m)Tc-EDDA/HYNIC-TOC. This could reflect the broader affinity of (177)Lu-DOTATATE for SRs compared with (99m)Tc-EDDA/HYNIC-TOC.

Single-Center Comparison of [64Cu]-DOTAGA-PSMA and [18F]-PSMA PET-CT for Imaging Prostate Cancer.

INTRODUCTION: the diagnostic performance of [64Cu]-DOTAGA-PSMA PET-CT imaging was compared retrospectively to [18F]-PSMA PET-CT in prostate cancer patients with recurrent disease and in the primary staging of selected patients with advanced local and possible metastatic disease. METHODS: We retrospectively selected a total of 100 patients, who were consecutively examined in our department, with biochemical recurrence after radical prostatectomy or who had progressive local and possible metastatic disease in the last 3 months prior to this investigation. All patients were examined with a dedicated PET-CT scanner (Biograph; Siemens Healthineers). A total of 250 MBq (3.5 MBq per kg bodyweight, range 230-290 MBq) of [64Cu]-DOTAGA-PSMA or [18-F]-PSMA was applied intravenously. PET images were performed 1 h post-injection (skull base to mid-thigh). The maximum standardized uptake values (SUVmax) of PSMA-positive lesions and the mean standardized uptake value (SUVmean) of the right liver lobe were measured. RESULTS: All but 9/50 of the patients (18%; PSA range: 0.01-0.7 µg/L) studied with [64Cu]-DOTAGA-PSMA and 6/50 of the ones (12%; PSA range: 0.01-4.2) studied with [18F]-PSMA had at least one positive PSMA lesion shown by PET-CT. The total number of lesions was higher with [64Cu]-DOTAGA-PSMA (209 vs. 191); however, the median number of lesions was one for [64Cu]-DOTAGA-PSMA and two for [18F]-PSMA. Interestingly, the median SUVmean of the right liver lobe was slightly higher for [18F]-PSMA (11.8 vs. 8.9). CONCLUSIONS: [64Cu]-DOTAGA-PSMA and [18F]-PSMA have comparable detection rates for the assessment of residual disease in patients with recurrent or primary progressive prostate cancer. The uptake in the liver is moderately different, and therefore at least the SUVs of the lesions in both studies would not be comparable.

Advanced isolated light chain amyloid cardiomyopathy with negative immunofixation and normal free light chain ratio.

Amyloid light chain (AL) cardiomyopathy is the most malignant specific cardiomyopathy. According to international recommendations, it should be ruled out non-invasively using the serum free light chain (FLC) ratio and immunofixation electrophoresis in both serum and urine. Here, we report on a 69-year-old female patient with new-onset heart failure with mid-range ejection fraction. Cardiac imaging was highly suggestive of cardiac amyloidosis. Amyloid scintigraphy showed faint myocardial tracer uptake according to Perugini Score 1, but immunofixation was negative and the FLC ratio was normal, despite a slight increase in lambda FLCs. Endomyocardial biopsy revealed advanced myocardial lambda immunoglobulin light chain deposition. Clinically relevant extracardiac amyloid organ infiltration could not be detected. Conclusively, non-invasive testing can in rare cases fail to exclude isolated AL amyloid cardiomyopathy. We suggest that even slight increases in serum lambda or kappa FLCs should be considered abnormal in suspected cardiac amyloidosis if non-invasive testing delivers discrepant results.

Cost of transfusion-dependent myelodysplastic syndrome (MDS) from a German payer's perspective.

No curative treatment exists for patients with myelodysplastic syndrome (MDS) besides allogeneic stem cell transplantation. Hence, palliative treatment is provided for a life time accruing high health care cost. As no study in cost of MDS exists in Germany, the objective of this study was to assess and analyze costs of transfusion-dependent low/intermediate-1-risk MDS in Germany from a payers' perspective. From seven centers, 116 low/intermediate-1-risk transfusion-dependent MDS patients with and without isolated 5q-deletion were identified. Claims data and patient records of the previous 5 years were used to collect health care utilization data retrospectively. Publicly available tariff books and remuneration schemes were applied to evaluate mean costs per year in Euro with 2007 as base year. The annual cost of MDS patients was estimated at 14,883. Subgroup analyses showed differences in patient's characteristics and outcomes among patients treated at a hospital-based vs. an office-based setting. Patients treated at the hospital-based registry show higher cost, whereas the reasons for that still need to be detected. Overall, per annum direct costs range from 12,543 (SD 12,967) to 24,957 (SD 36,399) in different subgroups of patients. In both groups, patients with 5q-deletion use more medication than those without deletion. Mean costs for medication in the office-based setting are 5,902 for patients with isolated 5q-deletion vs. 3,932 for patients with no deletion, respectively. MDS leads to a high health care utilization and resulting costs for the health care system which requires a detailed analysis of underlying services.

Agenesis of the dorsal pancreas and associated diseases.

BACKGROUND: Agenesis of the dorsal pancreas is a very rare congenital pancreatic malformation and is associated with some other diseases. METHODS: A PubMed search revealed 53 cases of agenesis of the dorsal pancreas. RESULTS: In 28 patients with this congenital malformation hyperglycemia was demonstrated, 27 had abdominal pain, 16 had pancreatitis, 14 had an enlarged or prominent pancreatic head visible on computed tomography, and in a few cases, polysplenia, which may occur with various congenital anomalies of visceral organs, was described. CONCLUSIONS: Difficulties involved in obtaining a firm diagnosis have led to a variety of terms being used to describe this congenital disease. Diagnosis of agenesis of the dorsal pancreas is inconclusive without demonstration of the absence of the dorsal pancreatic duct. Here we describe the embryological development of the pancreas, the so-far known cases of agenesis of the dorsal pancreas with associated medical problems, and the diagnostic measures to find the right conclusions.

Estimating DXA total body fat percentage by lipometer subcutaneous adipose tissue thicknesses.

DXA is an accepted reference method to estimate body composition. However several difficulties in the applicability exist. The equipment is rather expensive, not portable, impractical for measurement of big study populations and it provides a minimal amount of ionizing radiation exposure. The optical device Lipometer (EU Pat.No. 0516251) provides non-invasive, quick, precise and safe measurements of subcutaneous adipose tissue (SAT) layer thicknesses at any site of the human body. Compared to DXA there are some advantages in the Lipometer approach, because this device is portable, quick, not expensive and no radiation is involved. To use these advantages in the field of total body fat% (TBF%) assessment, an acceptable estimation of DXA TBF% by Lipometer SAT thicknesses is necessary, which was the aim of this study. Height, weight, waist and hip circumferences, DXA TBF% and Lipometer SAT thicknesses at fifteen defined body sites were measured in 28 healthy men (age: 33.9 +/- 16.6 years) and 52 healthy women (age: 40.1 +/- 10.7 years). To estimate Lipometer TBF% stepwise multiple regression analysis was applied, using DXA TBF% as dependent variable. Using the fifteen Lipometer SAT thicknesses together with age, height, weight and BMI as independent variables provided the best estimations of Lipometer TBF% for both genders with strong correlations to DXA TBF% (R = 0.985 for males and R = 0.953 for females). The limits of agreement were -2.48% to +2.48% for males and -4.28% to + 4.28% for females. For both genders we received a bias of 0.00%. The results of this paper extend the abilities of the Lipometer by a precise estimation of TBF% using DXA as golden standard.

99mTc-apcitide scintigraphy in patients with clinically suspected deep venous thrombosis and pulmonary embolism.

AIM: Detection of acute deep venous thrombosis (DVT) in patients presenting with clinical symptoms suggesting DVT and pulmonary embolism (PE) with (99m)Tc-apcitide, a synthetic polypeptide, binding to glycoprotein IIb/IIIa receptors expressed on activated platelets is the objective of the study. MATERIALS AND METHODS: Nineteen patients (11 males, eight females) received within 24h after admission to the hospital a mean of 841 MBq (range 667 to 1,080) (99m)Tc-apcitide i.v. followed by planar recordings 10, 60, and 120 min after injection. Images were compared to the results of compression ultrasonography and/or phlebography. Patients with clinically suspected PE underwent spiral computed tomography or lung perfusion scans. RESULTS: (99m)Tc-apcitide scintigraphy showed acute clot formation in 14 out of 16 patients where the other imaging modalities suggested DVT. Positive scintigraphic results were seen up to 17 days after the onset of clinical symptoms. In three out of three patients without any proof of DVT, (99m)Tc-apcitide scintigraphy was truly negative. Glycoprotein receptor imaging showed only one segmental PE in six patients with imaging-proven subsegmental (N = 3) or segmental PE (N = 3). CONCLUSION: (99m)Tc-apcitide scintigraphy may be an easy and promising tool for the detection of acute clot formation in patients with DVT up to 17 days after the onset of clinical symptoms with a sensitivity of 87% and a specificity of 100%. However, it failed to demonstrate PE in 83% of examined patients with proven PE.

Evaluation of conditions associated with glycated hemoglobin values below the reference range.

BACKGROUND: Evaluation of conditions associated with glycated hemoglobin (HbA1c) values below the reference range in HbA1c determinations. METHODS: Over a time period of 5 years, HbA1c results were determined with the ion-exchange high-performance liquid chromatography (HPLC) method HA-8140 Menarini. RESULTS: Of approximately 20 000 HbA1c results analyzed, 9 were below the reference range. The reason for HbA1c values below the reference range was found to be liver cirrhosis in 6 patients, anemia with hematological neoplasms in 2 patients, and elevated fetal hemoglobin > 1.5% in one patient. The silent hemoglobin (Hb) variant Hb Graz in 6 patients, Hb Sherwood Forest in 1 patient, homozygote HbS in one patient, and gross hypertriglyceridemia in one patient demonstrated no HbA1c result. CONCLUSIONS: In patients with liver cirrhosis, HbA1c measurements should be used with caution when evaluating long-term glucose control, and samples with suspected Hb variants should be analyzed by hemoglobin electrophoresis. Our study underscores the need for clinical laboratories and physicians to be aware of the limitations of their HbA1c assay methods as well as of the importance of visual inspection of ion-exchange chromatograms to detect HbA1c values below the reference range and abnormalities caused by the interference factors described here.

Downgrading of a G3 Neuroendocrine Tumor to a G2 Tumor: Can First-Line Cytotoxic Chemotherapy Change the Tumor Biology?

The antiproliferative treatment options for neuroendocrine tumors (NET)/neuroendocrine carcinomas of the gastrointestinal tract critically depend on the proliferation rate, evaluated by immunohistochemical staining for Ki-67. According to their grading, tumors are treated with somatostatin analogs, mTOR inhibitors, or cytotoxic substances. This case illustrates downgrading of a primarily highly proliferative NET achieved by a variation of cytotoxic chemotherapy regimens, followed by a combination therapy using everolimus together with lanreotide. The latter medication might lead to a good clinical response as far as tumor growth is concerned.

Functional Imaging in the Follow-Up of Enteropancreatic Neuroendocrine Tumors: Clinical Usefulness and Indications.

Context: Functional imaging tests (FITs) detecting somatostatin receptor expression [i.e., somatostatin receptor scintigraphy, 68Ga-DOTA positron emission tomography/computed tomography (CT)] have a pivotal role in the diagnosis of neuroendocrine tumors (NETs), although their indication during follow-up still needs to be clarified. Objective: Investigate the role of FITs after diagnosis of metastatic enteropancreatic NETs, identifying patients who might benefit from these exams. Design: Multicenter retrospective analysis of metastatic enteropancreatic NETs. Setting: Analysis of imaging tests performed between January 1995 and December 2015 in Rome, Berlin, Milan, Marburg, or Graz. Subjects: One hundred forty-three patients with metastatic pancreatic NETs and small intestine NETs, at least 2-year follow-up, and positive FITs. Interventions: Patients had received CT every 6 months (unless clinical conditions and tumor behavior required shorter intervals) and FIT every 12 months. Main Outcome Measures: Clinical usefulness of FITs, defined as changes in patient management (indication to biopsy, medical therapy, surgery, or further imaging tests) due only to FITs. Results: FITs affected management in 73.4% of patients, mostly when G2 vs G1 [odds ratio (OR), 2.40; 95% confidence interval (CI), 1.09 to 5.27; P = 0.03]. Changes were observed in a 12-month time frame especially with pancreatic NETs vs small intestine NETs (OR, 2.89; 95% CI, 1.09 - 7.67; P = 0.03) or metastases since diagnosis vs developed during follow-up (OR, 4.00; 95% CI, 1.43 to 11.17; P < 0.01). Conclusions: FITs used in addition to CT in the follow-up of stage IV enteropancreatic NETs improve patient management (especially for G2 tumors). Follow-up program should be tailored according to tumor features.