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.

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.

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.

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.

Silent hemoglobin variants and determination of HbA(1c) with the high-resolution program of the HPLC HA-8160 hemoglobin analyzer.

OBJECTIVES: Evaluation of HbA1c determination with an automated ion-exchange high-performance liquid chromatography (HPLC) method in patients with clinically silent hemoglobin (Hb) variants. DESIGN AND METHODS: HbA1c values were determined with the Arkray HA-8160 ion-exchange HPLC using the high-resolution, 4.2-min beta-thalassemia screening mode in patients with silent hemoglobin (Hb) variants, namely, Hb Graz, Hb Sherwood Forest, Hb O Padova, and HbD. RESULTS: All of these hemoglobin variants caused additional peaks in the chromatograms, without HbA1c results in patients with Hb Graz and Hb Sherwood Forest, and demonstrated extra peaks with HbA1c results that were clinically too low for patients with Hb O Padova and in the patient with HbD. CONCLUSIONS: The development of this automated HPLC method modification with high-resolution beta-thalassemia screening mode aids identification of interference due to some clinically silent Hb variants in HbA(1c) determination.

Three-dimensional gadolinium-enhanced magnetic resonance angiography used as a "one-stop shop'' imaging procedure for venous thromboembolism: a pilot study.

Pulmonary embolism and deep venous thrombosis are individual manifestations of a single entity, venous thromboembolic disease. This study aimed to assess the feasibility of 3-dimensional gadolinium-enhanced magnetic resonance angiography used as an "one-stop shop'' imaging procedure visualizing both the pulmonary arteries and the deep lower venous system within a single investigation. The inclusion criterion was a proven or excluded venous thromboembolism. Diagnosis was based on an imaging work-up for pulmonary embolism including either perfusion lung scan or contrast-enhanced spiral computed tomography, or both, and an imaging work-up for deep venous thrombosis including either venous color-coded duplex sonography or ascending phlebography, or both. A gadolinium-enhanced "one-stop shop'' magnetic resonance angiography was performed within 24 hours of completed diagnostic imaging work-up for pulmonary embolism and deep venous thrombosis in 20 patients. Results of pulmonary magnetic resonance angiography were concordant with perfusion lung scan and/or computed tomography in 90% of patients. Magnetic resonance angiography results of the deep lower venous system were concordant with venous duplex sonography and/or phlebography in 75% of patients and seemed to be more precise in 25% of patients. The "one-stop shop'' imaging procedure using gadolinium-enhanced magnetic resonance angiography was feasible and proved to offer a reliable and rapid diagnostic approach in thromboembolic disease, sparing patients' exposure to ionizing radiation and iodinated contrast media.

The value of FDG-PET in the diagnosis of thromboangiitis obliterans--a case series.

Thromboangiitis obliterans (TAO) is an inflammatory vascular disease affecting dominantly the vessels of the extremities and is etiologically strongly associated with tobacco consumption. Different imaging techniques are generally used to exclude potential differential diagnoses. We investigated the value of (18) F-flourodeoxyglucose positron emission tomography ([(18) F]FDG-PET) in the diagnosis of TAO. All consecutive patients with diagnosed TAO between Nov 2001 and Nov 2003 at our institution who underwent [(18) F]FDG-PET in the diagnostic workup were analyzed retrospectively. Whole-body scans were conducted after a fasting period of at least 6 h and blood glucose levels lower than 180 mg/dl. The primary endpoint was defined as significantly increased vascular FDG uptake. Tracer uptake was visually determined and, in accordance with strength, divided into grades 0 to 3. In total, ten patients were statistically evaluated. The median patient age at the date of the first [(18) F]FDG-PET was 41.5 years. Repetitive FDG-PET imaging was performed in seven out of ten patients (70 %). The endpoint was objectified in one of the initial examinations (10 %) and in another one out of seven follow-up scans (14.3 %). One positive [(18) F]FDG-PET was observed in the pelvic vessels and the other in the infrapopliteal arteries. Therefore, increased tracer uptake could be observed in two examinations on two different patients (both with grade 3 tracer uptake) out of 17 conducted [(18) F]FDG-PETs in total. The [(18) F]FDG-PET was not a suitable investigative procedure for the diagnosis of TAO in the present patient cohort.

Complete remission of a metastatic gastrointestinal stromal tumour with the tyrosine kinase inhibitor imatinib (STI 571): effect of low dosage in an advanced tumour with exon 11 mutation.

We report a 51-year-old man with an advanced malignant metastatic gastrointestinal stromal tumour, who showed a complete response after 5 months of treatment with imatinib at a dose of 400 mg per day. An early treatment response was demonstrated in an 18fluorodeoxyglucose positron emission tomography scan after 1 month of therapy. Complete remission was documented histologically by negative serial biopsies of residual tumour nodes after 5 months of therapy. No serious side effects were seen with imatinib. A 21 bp, exon 11, in-frame mutation of the c-kit gene was found by DNA sequence analysis of tumour tissue.

Determination of glycated hemoglobin in patients with advanced liver disease.

AIM: To evaluate the glycated hemoglobin (HbA(1c)) determination methods and to determine fructosamine in patients with chronic hepatitis, compensated cirrhosis and in patients with chronic hepatitis treated with ribavirin. METHODS: HbA(1c) values were determined in 15 patients with compensated liver cirrhosis and in 20 patients with chronic hepatitis using the ion-exchange high performance liquid chromatography and the immunoassay methods. Fructosamine was determined using nitroblue tetrazolium. RESULTS: Forty percent of patients with liver cirrhosis had HbA(1c) results below the non-diabetic reference range by at least one HbA(1c) method, while fructosamine results were either within the reference range or elevated. Twenty percent of patients with chronic hepatitis (hepatic fibrosis) had HbA(1c) results below the non-diabetic reference range by at least one HbA(1c) method. In patients with chronic hepatitis treated with ribavirin, 50% of HbA(1c) results were below the non-diabetic reference using at least one of the HbA(1c) methods. CONCLUSION: Only evaluated in context with all liver function parameters as well as a red blood count including reticulocytes, HbA(1c) results should be used in patients with advanced liver disease. HbA(1c) and fructosamine measurements should be used with caution when evaluating long-term glucose control in patients with hepatic cirrhosis or in patients with chronic hepatitis and ribavirin treatment.

Congenital familial vascular anomalies: a study of patients with an anomalous inferior vena cava, and of their first-degree relatives.

With magnetic resonance angiography and computed tomography, congenital anomalies of the inferior vena cava are diagnosed more frequently than they used to be. Accessory renal arteries identified by magnetic resonance angiography in a patient with an anomalous inferior vena cava indicated a combination of arterial and venous abnormalities. The study was initiated to screen consecutive patients with an anomalous inferior vena cava for concomitant abdominal and pelvic arterial abnormalities, and their first-degree relatives for congenital vascular anomalies. Magnetic resonance angiography identified in 2 of 5 patients with an anomalous inferior vena cava concomitant accessory renal arteries and in 5 of 11 first-degree relatives major abdominal vascular anomalies including accessory renal arteries, accessory renal veins, and anomalies of the hepatic artery. None of the relatives showed abnormalities of the inferior vena cava. The familial occurrence of vascular anomalies strongly suggests an underlying pathogenetic component in affected family members. In patients with a congenital anomaly of the inferior vena cava, concomitant arterial abnormalities should be considered. First-degree relatives may be at risk for congenital vascular anomalies.

[Determination of glycated hemoglobins (Hb A1c)]. / Uber die Bestimmung des glykierten Hämoglobins (HbA1c).

Glycated hemoglobin is measured as HbA1c and is the result of an irreversible non-enzymatic glycation of the beta chain of hemoglobin A. HbA1c is used routinely to assess long term glycemic control in patients with diabetes mellitus. There are more than 20 determination methods, the techniques used are cation-exchange chromatography, electrophoresis, affinity chromatography and immunoassays, although each of these techniques measures a different fraction of the glycated hemoglobin. In addition, genetic hemoglobin variants and chemically modified derivates of hemoglobin can affect the HbA1c measurement and thus can not be included in international attempts for standardization. This manuscript reviews the current information on glycation of hemoglobin, HbA1c determination methods, interferences and attempts for standardization. We aim at pointing out to the reader the current problems of glycated hemoglobin determination and to describe the necessary measures which need to be taken for proper measurement of HbA1c.