Publications by authors named "Agnieszka Kolasińska-Ćwikła"

23 Publications

  • Page 1 of 1

Radiological and Clinical Efficacy of Intra-Arterial Y-DOTATATE in Patients with Unresectable, Progressive, Liver Dominant Neuroendocrine Neoplasms.

J Clin Med 2021 Apr 20;10(8). Epub 2021 Apr 20.

Department of Cardiology and Internal Medicine, School of Medicine, University of Warmia and Mazury, Warszawska 30, 10-082 Olsztyn, Poland.

This study was performed to determine if intra-arterial (i.a.) administration of Y DOTATATE can provide an effective and safe alternative to the accepted standard for i.v. of peptide receptor radionuclide therapy (PRRT) in liver-dominant metastases of gastrointestinal pancreatic neuroendocrine neoplasm (GEP-NEN). A single site, prospective, preliminary case series study included 39 patients with histologically proven liver-dominant NEN. PRRT in the form of 1.15GBq Y DOTATATE was given selectively into the liver via radiological catheterization of the hepatic artery, up to four times. The endpoint was radiological response (RECIST). Secondary endpoints assessed clinical well-being post-treatment, progression-free survival (PFS), overall survival (OS), and toxicity. Partial response (PR) was noted in 13% of subjects six weeks post-therapy, increasing to 24% at six months and dropping to 13% at 36 months. Disease progression (DP) was not seen at six weeks, was 5% at six months, and 47% at 36 months. Clinical response based on PS seen in 74% of patients at six weeks, 69% at six months, and 39% at 36 months had PFS and OS, respectively, of 22.7 months and 38.2 months. There was no difference in OS/PFS between those with RECIST PR and SD. One patient had significant toxicity (3%). Use of i.a. PRRT appears to be safe and effective in treating patients with liver-dominant NEN. In addition, the best OS (51 vs. 22 months) was seen when i.a. was used as an upfront treatment of bulky GEP-NEN liver metastases and not after i.v. Y DOTATATE. The use of i.a. Y DOTATATE PRRT appears to be safe and effective in treating patients with liver-dominant NEN.
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http://dx.doi.org/10.3390/jcm10081794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074370PMC
April 2021

Outcomes of Patients with Pulmonary Large Cell Neuroendocrine Carcinoma in I-IV Stage.

Medicina (Kaunas) 2021 Jan 28;57(2). Epub 2021 Jan 28.

Department of Cardiology and Internal Medicine Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.

: Large cell neuroendocrine cancer is characterised by poor prognosis. The standard of treatment is still not established. The aim of this study was to assess the predictive factors of overall survival (OS) and progression-free survival (PFS) of pulmonary large cell neuroendocrine carcinoma (LCNEC) and combined LCNEC. : All patients had confirmed pathology stage I-IV disease recorded between period 2002-2018. Survival curves were estimated by Kaplan-Meier method. Uni- and multivariable analysis was conducted using Cox-regression analysis. : A total of 132 patients with LCNEC and combined LCNEC were included. Half of them had clinical stage IIIB/C-IV. Patients were treated with radical ( = 67, including surgery alone; resection with neo-adjuvant or adjuvant chemotherapy, radiochemotherapy, or adjuvant radiotherapy; patients treated with radiochemotherapy alone), palliative ( = 41) or symptomatic ( = 24) intention. Seventeen patients were treated with resection margin R1 or R2. Non-small cell carcinoma (NSCLC) chemotherapy (platinum-vinorelbine; PN schedule) and small-cell lung carcinoma (SCLC) chemotherapy approaches (platinum/carboplatinum-etoposide; PE/KE schedule) were administered in 20 and in 55 patients, respectively. The median (95% Confidence Interval (CI)) OS and PFS were 17 months (9.0-36.2 months) and 7 months (3.0-15.0 months), respectively. Patients treated with negative resection margin, with lower clinical stage, without lymph node metastasis, and with size of primary tumour ≤4 cm showed significantly better OS and PFS. The main risk factors with an adverse effect on survival were advanced CS and positive resection margin. : Patients with LCNEC characterized poor prognosis. Independent prognostic factors influencing PFS were initial clinical stage and resection margin R0 vs. R1-2.
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http://dx.doi.org/10.3390/medicina57020118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911070PMC
January 2021

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Oncologist 2021 04 29;26(4):294-301. Epub 2020 Dec 29.

Department of Endocrine Oncology University Medical Center Utrecht, The Netherlands.

Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited.

Materials And Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints.

Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea.

Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%.

Implications For Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.
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http://dx.doi.org/10.1002/onco.13633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018333PMC
April 2021

Outcomes of Patients with Clinical Stage I-IIIA Large-Cell Neuroendocrine Lung Cancer Treated with Resection.

J Clin Med 2020 May 7;9(5). Epub 2020 May 7.

Department of Pulmonology, School of Medicine, University of Warmia and Mazury in Olsztyn, Jagiellonska 78, 11-041 Olsztyn, Poland.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare malignancy with poor prognosis. The rationale of the study was to determine the survival of LCNEC patients in I-IIIA clinical stages who underwent resection. A total of 53 LCNEC (89%) and combined LCNEC (11%) patients in stages I-IIIA who underwent surgery with radical intent between 2002-2018 were included in the current study. Overall survival (OS) and time to recurrence (TTR) were estimated. Uni- and multivariable analyses were conducted using Cox-regression model. Patients were treated with surgery alone (51%), surgery with radiochemotherapy (4%), with radiotherapy (2%), with adjuvant chemotherapy (41%), or with neoadjuvant chemotherapy (2%). The median (95% Confidence Interval (CI)) OS and TTR was 52 months (20.1-102.1 months) and 20 months (7.0-75.6 months), respectively. Patients treated in clinical stage I showed better OS than patients in stages II-IIIA ( = 0.008). Patients with R0 resection margin (negative margin, no tumor at the margin) and without lymph node metastasis had significantly better TTR. In the multivariate analysis, age was an independent factor influencing OS. Recurrence within 1 year was noted in more than half cases of LCNEC. R0 resection margin and N0 status (no lymph node metastasis) were factors improving TTR. Age >64 years was observed as a main independent factor influencing OS.
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http://dx.doi.org/10.3390/jcm9051370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290504PMC
May 2020

Monitoring the response to neoadjuvant chemotherapy in patients with breast cancer using ultrasound scattering coefficient: A preliminary report.

J Ultrason 2019 28;19(77):89-97. Epub 2019 Jun 28.

Ultrasound Department , Institute of Fundamental Technological Research , Polish Academy of Sciences , Warsaw , Poland.

Neoadjuvant chemotherapy was initially used in locally advanced breast cancer, and currently it is recommended for patients with Stage 3 and with early-stage disease with human epidermal growth factor receptors positive or triple-negative breast cancer. Ultrasound imaging in combination with a quantitative ultrasound method is a novel diagnostic approach. The aim of this study was to analyze the variability of the integrated backscatter coefficient, and to evaluate their use to predict the effectiveness of treatment and compare to ultrasound examination results. Ten patients (mean age 52.9) with 13 breast tumors (mean dimension 41 mm) were selected for neoadjuvant chemotherapy. Ultrasound was performed before the treatment and one week after each course of neoadjuvant chemotherapy. The dimensions were assessed adopting the RECIST criteria. Tissue responses were classified as pathological response into the following categories: not responded to the treatment (G1, cell reduction by ≤9%) and responded to the treatment partially: G2, G3, G4, cell reduction by 10-29% (G2), 30-90% (G3), >90% (G4), respectively, and completely. In B-mode examination partial response was observed in 9/13 cases (completely, G1, G3, G4), and stable disease was demonstrated in 3/13 cases (completely, G1, G4). Complete response was found in 1/13 cases. As for backscatter coefficient, 10/13 tumors (completely, and G2, G3, and G4) were characterized by an increased mean value of 153%. Three tumors 3/13 (G1) displayed a decreased mean value of 31%. The variability of backscatter coefficient, could be associated with alterations in the structure of the tumor tissue during neoadjuvant chemotherapy. There were unequivocal differences between responded and non-responded patients. The backscatter coefficient analysis correlated better with the results of histopathological verification than with the B-mode RECIST criteria.

Neoadjuvant chemotherapy was initially used in locally advanced breast cancer, and currently it is recommended for patients with Stage 3 and with early-stage disease with human epidermal growth factor receptors positive or triple-negative breast cancer. Ultrasound imaging in combination with a quantitative ultrasound method is a novel diagnostic approach. The aim of this study was to analyze the variability of the integrated backscatter coefficient, and to evaluate their use to predict the effectiveness of treatment and compare to ultrasound examination results. Ten patients (mean age 52.9) with 13 breast tumors (mean dimension 41 mm) were selected for neoadjuvant chemotherapy. Ultrasound was performed before the treatment and one week after each course of neoadjuvant chemotherapy. The dimensions were assessed adopting the RECIST criteria. Tissue responses were classified as pathological response into the following categories: not responded to the treatment (G1, cell reduction by ≤9%) and responded to the treatment partially: G2, G3, G4, cell reduction by 10–29% (G2), 30–90% (G3), >90% (G4), respectively, and completely. In B-mode examination partial response was observed in 9/13 cases (completely, G1, G3, G4), and stable disease was demonstrated in 3/13 cases (completely, G1, G4). Complete response was found in 1/13 cases. As for backscatter coefficient, 10/13 tumors (completely, and G2, G3, and G4) were characterized by an increased mean value of 153%. Three tumors 3/13 (G1) displayed a decreased mean value of 31%. The variability of backscatter coefficient, could be associated with alterations in the structure of the tumor tissue during neoadjuvant chemotherapy. There were unequivocal differences between responded and non-responded patients. The backscatter coefficient analysis correlated better with the results of histopathological verification than with the B-mode RECIST criteria.
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http://dx.doi.org/10.15557/JoU.2019.0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750328PMC
June 2019

A Clinical Efficacy of PRRT in Patients with Advanced, Nonresectable, Paraganglioma-Pheochromocytoma, Related to SDHx Gene Mutation.

J Clin Med 2019 Jun 30;8(7). Epub 2019 Jun 30.

Department of Hypertension and Department of Radiology Institute of Cardiology, 04-628 Warsaw, Poland.

Paragangliomas and pheochromytomas (PPGLs) exhibit variable malignancy, advanced/hormonally active/progressive need therapy. PRRT (Peptide Receptor Radionuclide Therapy) could be an option for these patients. To evaluate the effectiveness of PRRT (90Y DOTATATE), based on overall survival (OS) and progression-free survival (PFS), in patients with PPGLs, related to SDHx gene mutation, we conducted a prospective open-label, single-center, phase II study. Thirteen patients were observed, eight PGL1 and five PGL4, all with advanced, non-resectable tumors, and eight had metastases. All were treated with 90Y DOTATATE. Efficacy was based on OS and PFS, and radiological response was based on RECIST. Hormonal activity was evaluated using serum-fractionated free catecholamines. Eight subjects had a clinical response, three were stable, and two exhibited disease progression. Among four patients with hormonally-active PPGLs, three showed a reduction and one showed normalization. OS for all was 68.0 months; PFS was 35.0 months. OS in PGL4 = 25.0 vs. N.R. (not reached) in PGL1. PFS in PGL4 = 12.0 vs. N.R. in PGL1. A difference was seen in the OS and PFS in patients who did not respond clinically, compared to those who did, OS = 22.0 vs. N.R. PFS = 7.0 vs. N.R. A difference in the OS and PFS was noted in patients with liver and bone involvement compared to those without. PRRT is an effective therapy in selected population of patients with SDHx, in those with locally-advanced, non-resectable tumors. Furthermore, it is effective regardless of the secretory status.
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http://dx.doi.org/10.3390/jcm8070952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678858PMC
June 2019

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms.

Neuroendocrinology 2020 16;110(3-4):185-197. Epub 2019 Apr 16.

Gastroenterological and Endoscopic Surgery, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN.

Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study.

Material And Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica).

Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression).

Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.
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http://dx.doi.org/10.1159/000500202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472424PMC
February 2021

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease.

Neuroendocrinology 2019 17;108(3):219-231. Epub 2019 Jan 17.

University of Warmia and Mazury, Olsztyn, Poland.

Background: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status.

Aim: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study.

Material And Methods: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD.

Results: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31).

Conclusions: Elevated -NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.
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http://dx.doi.org/10.1159/000497037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472425PMC
December 2019

The Value of Somatostatin Receptor Scintigraphy (SRS) in Patients with NETG1/G2 Pancreatic Neuroendocrine Neoplasms (p-NENs).

Nucl Med Rev Cent East Eur 2019 2;22(1):1-7. Epub 2018 Oct 2.

School of Medicine, University of Warmia and Mazury, Olsztyn, Poland, Aleja Warszawska 30,, 11-082 Olsztyn, Poland.

Background: Neuroendocrine neoplasms of the pancreas (p-NEN) are common gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). The aim of this retrospective study was to review the of value of Somatostatin Receptor Scintigraphy (SRS) in initial detection of p-NEN, evaluation of tumour extent and as imaging follow-up after radical surgery in patients with confirmed well (NETG1) or moderate (NETG2) differentiated p-NEN based on pathological WHO 2017 classification.

Material And Methods: Overall 281 patients with confirmed p-NEN were enrolled. The SRS was performed to evaluation of primary p-NEN, also to assess clinical stage of disease, based on current World Health Organization (WHO) classification and during clinical follow-up. A total of 829 examinations were performed over time in these 281 patients using 99mTc HYNICTOC. Images were acquired between 1 - 3 h after i.v. injection of radiotracer. Initially whole body WB-SPECT and then WB-SPECT/CT, with standard iterative reconstruction were used.

Results: There were 159 patients with NETG1 (57%) and 122 subjects with NETG2 (43%). The female to male ratio was 1.1:1. In 68 patients (22%) with NETG1/G2 eight-seven SRS (10%) were performed to confirm initial diagnosis. SRS results were as follow: true positive (TP) = 84 (97%), false negative (FN) = 3 (3%), no true negative (TN) or false positive (FP) results of SRS examination (sensitivity of SRS per patient was 96%). In 198 subjects (66%) SRS was used in evaluation and re-evaluation of the clinical stage, A total of 661 (80%) examinations were carried out in these patients. There were TP=514 (77%), TN=136 (21%), FN=7 (1%) and FP=4 (1%) results. The sensitivity and specificity per patient were: 96% and 95%. The sensitivity and specificity per study: 98% and 97%. In 35 patients (12%) SRS was used as imaging follow-up after radical surgery, there were overall 81 examination (10%) which were performed. There were 76 (91%) TN results of examinations of SRS and in 4 patients we identified recurrence (TP). In total, which consists of initial diagnosis/staging and follow-up patients, the sensitivity of SRS was 96% and specificity 97% per patient and per study sensitivity and specificity was 98%.

Conclusions: SRS using 99mTc HYNICTOC acquired in WB-SPECT or WB-SPECT/CT techniques is an excellent imaging modality in detection of primary NETG1/G2 p-NEN. Our study confirms that SRS has high sensitivity and specificity, as a result has tremendous value as an examination method to assess clinical stage of disease and as an imaging follow-up after radical treatment.
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http://dx.doi.org/10.5603/NMR.a2018.0032DOI Listing
April 2020

Right and left-sided carcinoid heart disease.

Cardiol J 2018 ;25(3):417

Department of Radiology, Institute of Cardiology,, Alpejska 42, 04-628 WARSAW, Poland.

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http://dx.doi.org/10.5603/CJ.2018.0061DOI Listing
December 2018

Peptide Receptor Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors - from oncology perspective.

Nucl Med Rev Cent East Eur 2018 ;21(2)

Maria Sklodowska-Curie Memorial Cancer Center and Institiute of Oncology, Wawelska 15, 02-034 Warszawa, Poland.

Peptide Receptor Radionuclide Therapy (PRRT) is a form of molecular targeted therapy which is performed by using a small peptide (somatostatin analogue - SSA) that is coupled with a radionuclide beta emitting radiation. PRRT is a nuclear medicine for the systemic treatment of non-resectable, metastasized well/moderately differentiated, neuroendocrine tumours (NET) with overexpression of somatostatin receptor. These types of tumours include gastroenteropancreatic neoplasm (GEP-NENs), e.g. arising from the small bowel (often called carcinoid tumours), the pancreas, duodenum or stomach, but also from the large bowel or the lung and many other tissues (so called diffuse neuroendocrine system). The goal of PRRT is irradiation of tumour cells, via direct binding into specific receptor, somatostatin receptors (SSTR) family, overexpressed on the cell membrane of the primary tumours as well as on the metastasis. Over many years of clinical use of PRRT with ⁹⁰Y and current with ¹⁷⁷Lu DOTA conjugated somatostatin analogues proved to be efficient therapy option for NETs, with tumour responses, base on radiological evaluation. Also, a clinical response with symptoms relief and improvement in quality of life based on standard EORTC questioners is seen. Additional, common NET biomarker reduction and, ultimately, an impact on overall survival (OS) of patients with advanced non-resectable often progressive NEN can be expected. PRRT with ⁹⁰Y or ¹⁷⁷Lu-labelled peptides is generally well tolerated by most of the patients. The acute side effects (Adverse Events - AEs) are usually mild; most of them are related to the co-administration of amino acids (AA), such as nausea and vomiting. Others are related to the radioisotopes, such as fatigue or the exacerbation of endocrine syndromes, which are very rarely and they occurs, only in patients with functional tumours and large tumours burden. Chronic and permanent damage has an effect on target organs, particularly the kidneys and the bone marrow, which are generally mild. Currently, when ¹⁷⁷Lu DOTATATE is used, the potential risk to kidney damage is significantly reduced, compared to the previous usage of ⁹⁰Y labelled analogues. Up to now, kidney and bone marrow toxicity limits the dose of radioactivity of PRRT.
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http://dx.doi.org/10.5603/NMR.2018.0019DOI Listing
September 2018

Prognostic value of chromogranin A in patients with GET/NEN in the pancreas and the small intestine.

Endocr Connect 2018 Jun 3;7(6):803-810. Epub 2018 May 3.

Department of Pathology and Laboratory DiagnosticsLaboratory of Tumor Markers, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.

The aim of this study was to evaluate the clinical usefulness of the chromogranin A (CgA) determination in patients with neuroendocrine neoplasms (NENs) of the digestive system and to analyse the association between concentration of the marker and progression-free survival (PFS) and overall survival (OS). Serum concentrations of CgA were determined before the treatment in 131 patients with NENs, including patients with tumours located in the pancreas, the small intestine, caecum, appendix and in the colon. No significant associations were identified in CgA concentrations between the control group and patients with NENs in appendix and colon. In patients with NENs of the pancreas and NENs of the small intestine and caecum, increased CgA levels were associated with lymph node involvement, distant metastases and a baseline liver involvement. Analyses revealed significantly higher CgA concentrations in patients with active disease compared to those without symptoms of NEN. In patients with NENs of the pancreas, CgA concentration was correlated with tumour grade and Ki67. Significantly higher CgA levels were also found in patients who died compared to those who lived. Analyses of PFS and OS revealed that CgA concentration was not a prognostic factor in patients with NENs of the pancreas. In patients with NENs of the small intestine and caecum, increased CgA concentrations are independent, poor prognostic factors for both PFS and OS. In conclusion, in patients with NENs in pancreas, CgA levels are associated with disease progression, while in patients with NENs in small intestine and caecum, its concentration is a predictive indicator for PFS and OS.
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http://dx.doi.org/10.1530/EC-18-0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987360PMC
June 2018

The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression.

Eur J Cardiothorac Surg 2018 03;53(3):631-639

Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.

Objectives: The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection.

Methods: (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post-surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal < 14%) and compared with chromogranin A (enzyme-linked immunosorbent assay; normal <109 ng/ml).

Results: NETest was significantly elevated in carcinoids (48.7 ± 27%) versus controls (6 ± 6%, P < 0.001) with metrics: sensitivity 93%, specificity 89%, positive predictive value 92% and negative predictive value 91%. NETest differentiated progressive disease (73 ± 22%) from stable disease (36 ± 19%, P < 0.001) and R0 resections (10 ± 5%, P < 0.001, area under the curve: 0.98). Levels in chronic obstructive pulmonary disease and lung cancers were 18-24% while elevated in small-cell lung carcinoma/large-cell neuroendocrine carcinoma (59 ± 10%). In BPNETs on postoperative Day 30, NETest decreased by 60% (P < 0.001). Chromogranin A was elevated in only 40% of carcinoids and not altered by surgery.

Conclusions: Blood NET gene levels accurately identified BPNETs (100%) and differentiated these from controls, benign and malignant lung disease. Progressive disease could be identified and surgical resection verified. Chromogranin A had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumour and identifying progressive disease.
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http://dx.doi.org/10.1093/ejcts/ezx386DOI Listing
March 2018

Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):79-110

Klinika Endokrynologii i Nowotworów Neuroendokrynnych, Katedra Patofizjologii i Endokrynologii, Śląski Uniwersytet Medyczny.

Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechów near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.
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http://dx.doi.org/10.5603/EP.2017.0015DOI Listing
July 2017

Colorectal neuroendocrine neoplasms - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):250-260

Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer-tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358-368.
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http://dx.doi.org/10.5603/EP.2017.0019DOI Listing
July 2017

Neuroendocrine neoplasms of the small intestine and appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):223-236

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered.
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http://dx.doi.org/10.5603/EP.2017.0018DOI Listing
July 2017

Pancreatic neuroendocrine neoplasms - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):169-197

This article presents updated diagnostic and therapeutic guidelines for the management of pancreatic neuroendocrine tumours (PNEN), proposed by the Polish Network of Neuroendocrine Tumours. The guidelines contain new data received in the years 2013-2016, which confirm previous recommendations, and have led to modification of previous guidelines or have resulted in the formulation of new guidelines. Biochemical and imaging (anatomical and functional) tests are of great importance in diagnostics, as well as histopathological diagnosis to determine the management of PNEN patients, but they must be confirmed by an immunohistochemical examination. PNEN therapy requires collaboration among the members a multidisciplinary team of specialists experienced in the management of these neoplasms. Surgery is the basic form of treatment in many cases. Further therapy requires a multidirectional procedure; therefore, the rules of biotherapy, peptide receptor radionuclide therapy, molecular targeted therapy, and chemotherapy are discussed.
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http://dx.doi.org/10.5603/EP.2017.2016DOI Listing
July 2017

Gastroduodenal neuroendocrine neoplasms, including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

Endokrynol Pol 2017 ;68(2):138-153

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.
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http://dx.doi.org/10.5603/EP.2017.0016DOI Listing
July 2017

Disseminated Pancreatic Neuroendocrine Neoplasm (NEN) with an Uncommon Localisation in the Central Nervous System. A Case Report.

Pol J Radiol 2017 1;82:120-125. Epub 2017 Mar 1.

Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland; Department of Radiology, Clinical University Hospital in Olsztyn, Olsztyn, Poland.

Background: Neuroendocrine neoplasms (NEN) are rare neoplasms that originate from neuroendocrine cells and are characterized by the potential of hormonal activity. Approximately 70% of these tumours are located in the gastrointestinal system (GI), followed by the bronchi, endocrine glands-like C cells of the thyroid (medullary carcinoma), the parasympathetic and sympathetic system (paragangliomas, pheochromocytoma) and other very rare locations. The prevalence of cerebral metastases in neuroendocrine tumours is estimated by various authors to be approximately 1.5-5%. When the primary tumour is located in the pancreas, it is associated with a risk of cerebral metastases lower than 2%.

Case Report: We describe a patient with a disseminated pancreatic NEN that presented with an isolated lesion in the brain. We gathered the important data via medical history,, observation, analysis of medical records, imaging and others diagnostic tests. Despite the fairly rare prevalence of cerebral metastases in NENs, a neurological work-up should be performed. This should include neuroimaging of the brain, preferably with MR, together with the somatostatin receptor scintigraphy (SRS), in each clinically suspicious case. A histopathological examination of the CNS tumour can confirm a dedifferentiation of NEN in the direction of a neuroendocrine carcinoma (NEC - neuroednocrine carcinoma) with a poor prognosis.

Conclusions: Cerebral metastases are diagnosed in 1.5-5% of patients with a neuroendocrine neoplasm. In each case suggestive of a dissemination into the central nervous system, MRI of the brain should be performed.
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http://dx.doi.org/10.12659/PJR.899007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344279PMC
March 2017

Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors.

Future Oncol 2017 May 18;13(12):1069-1079. Epub 2017 Jan 18.

Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland.

Aim: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with Y-[DOTA, D-Phe, Tyr]-octreotate.

Patients & Methods: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of Y-[DOTA, D-Phe, Tyr]-octreotate. The primary end point was overall survival.

Results: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression.

Conclusion: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.
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http://dx.doi.org/10.2217/fon-2016-0455DOI Listing
May 2017

Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy.

J Clin Endocrinol Metab 2015 Nov 8;100(11):E1437-45. Epub 2015 Sep 8.

Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405.

Context: Early and precise delineation of therapeutic responses are key issues in neuroendocrine neoplasm/tumor management. Imaging is currently used but exhibits limitations in sensitivity and specificity. The utility of biomarkers is unclear. objective, setting, and design: This prospective cohort study (11 mo) sought to determine whether measurements of circulating neuroendocrine tumor transcripts (NETest) predict responses to somatostatin analogs (SSAs).

Patients: The test set consisted of 35 SSA-treated gastroenteropancreatic-NETs (RECISTevaluated). The prospective set consisted of 28 SSA-treated Grade 1-Grade 2 GEP-NETs.

Intervention(s): Whole blood for transcript analysis (NETest) and plasma for Chromogranin A (CgA) (baseline), were collected every 4 weeks (prior to SSA injection). Morphologic (multidetector computed tomography/MRI) and functional imaging ((99m)Tc-[HYNIC, Tyr(3)]-Octreotide) was undertaken at entry and 6-month intervals until progression (RECIST 1.0).

Main Outcome Measure(s): Treatment response.

Results: Test set: NETest (≥80%; scale, 0-100%) differentiated stable (SD) and progressive (PD) disease (P < .0001). Prospective set: 28 patients (26/28 SD) undergoing standard SSA. Grading: 12 G1, 16 G2. SSA Response: progression-free survival: 315 days: 14 (50%) SD, 14 (50%) PD. NETest: Twenty had elevated (≥80%) values; 14 developed PD; six, SD. CgA: Twelve of 28 exhibited elevated baseline values and/or subsequent >25% increase; eight developed PD; four, SD. NETest (P = .002) and grade (P = .054) were the only factors associated with treatment response. Multiple regression analysis established that the NETest could predict disease progression (P = .0002). NETest changes occurred significantly earlier (146 d prior to progression vs 56 d CgA; P < .0001; χ(2) = 19) and in more patients (100 vs 57%; P < .02).

Conclusions: NETest values (80-100%) were more accurate and occurred at a significantly earlier time point than CgA and predicted SSA treatment response.
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http://dx.doi.org/10.1210/jc.2015-2792DOI Listing
November 2015

[Bilateral exudative retinal detachment as the first sign of breast cancer--case report].

Klin Oczna 2015 ;117(3):177-83

Metastatic choroidal tumours are the most common type of intraocular neoplasms in adults. Currently choroidal metastases are being diagnosed more frequently, generally due to the higher incidence of carcinomas, longer survival of cancer patients and better diagnostic possibilities. The most common primary cancers locations are breasts in women and lungs in men. These tumours are usually symptomatic and only in very rare cases metastases are the first symptom of carcinoma. We present such an atypical case of a 53-year-old female patient with bilateral exudative retinal detachment, which was the first symptom of a generalized malignancy originating in the mammary gland. Primary tumours and metastatic lesions both require a meticulous interdisciplinary examination, as well as the interdisciplinary treatment. Close liaison between oncologists and other specialists can result in faster diagnosis and improve treatment outcomes. Moreover, public health programs aimed at early detection of the most common tumours may help achieve better treatment results.
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May 2016