Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN).

PURPOSE OF REVIEW: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.

Appendicular neoplasms and consequences in patients undergoing surgery for suspected acute appendicitis.

INTRODUCTION: In patients treated with an appendectomy for acute appendicitis, the specimen is generally sent for histological evaluation. In an era of increasing non-operative treatment for acute appendicitis, it is important to know the incidence, the diagnostic accuracy, and treatment consequences of appendicular neoplasms that are found in acute appendicitis. We hypothesize that pre- and intra-operative parameters might predict an appendicular neoplasm. METHODS: Data was used from our previous prospective observational cohort study. All patients undergoing surgery for suspected acute appendicitis were included. The primary outcome was the incidence of appendicular neoplasms in patients operated for acute appendicitis. Secondary outcomes were pre-operative diagnostics and imaging outcomes, intra-operative surgical judgment, and postoperative management and outcome. Possible predictors of an appendicular neoplasm were identified and used in multivariable logistic regression. Patients with an appendicular neoplasm were followed for 3 years after initial appendectomy. RESULTS: A total of 1975 patients underwent surgery for suspected acute appendicitis and in 98.3% (1941/1975) the appendix was removed. In 1.5% (30/1941) of these patients, an appendicular neoplasm was found. Among the malignant neoplasms, the majority were grade 1 neuroendocrine tumors (NET) in 65% (13/20). On pre-operative imaging, there was no suspicion of malignancy. In three cases, there was an intra-operative suspicion of malignancy. Multivariable analysis showed only age as an independent predictor for appendicular neoplasms. No recurrent or new malignancy was found during follow-up. DISCUSSION: The incidence of appendicular neoplasm in patients undergoing an acute appendectomy is very low and clinical risk factors could not be identified.

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma.

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

Giant dilatation of pancreatic duct associated with congenital anomaly of the pancreatic ductal system and small neuroendocrine tumor.

Dilatation of the main pancreatic duct (MPD) ˃50 mm is a rare phenomenon. We present the case of successful surgical treatment a 63-year-old female patient who presented epigastric pain and weight loss of 10 kg in 6 months. Based on preoperative examination, the dilatation of MPD was 75 mm. The preliminary diagnosis was main duct intraductal papillary mucinous neoplasm. Extended pylorus-preserving pancreatoduodenectomy with resection of the body of the pancreas was performed. According to the results of pathological and immunohistochemical studies, performed by independent experts, the final diagnosis of congenital anomaly of the ductal system and neuroendocrine tumor of the accessory pancreatic duct was made.

Case report: Rare case of a preoperatively diagnosed spermatic cord paraganglioma and literature review.

Paraganglioma (PGL) is rare, and PGL that arises from the urogenital system is even rarer. Here we report a case of PGL in spermatic cord and review the relevant literatures. We encountered a 15-year-old boy with a history of hypertension for almost 2 years, accompanied with headache and palpitations. His serum and urine catecholamines were elevated, but no adrenal lesions were detected, suggesting the existence of PGL. Upon physical examination, a painless nodule adherent to the spermatic cord in the right scrotum was found. A systemic Ga68 DOTATATE PET-CT was then performed, and it revealed a mass with high DOTATATE uptake in the right scrotum. The CT, MRI, and ultrasound images showed the abundant blood supply to the tumor. Based on the above-mentioned imaging and biochemical information, a diagnosis of PGL was made prior to surgery. After 2 weeks of preparation with Cardura, an open surgery was performed to remove the tumor together with the right testis and right epididymis. The blood pressure increased to 180/100 mmHg when the tumor was touched intraoperatively and decreased to 90/55 mmHg after the tumor was removed. Post-operative pathology confirmed our diagnosis of PGL originating from the spermatic cord. Immunohistochemical (IHC) staining showed SDHB (+), CgA (+), synaptophysin (+), GATA3 (+), CD56 (+), sertoli cells S-100 (+), and Ki67 (5%). Genetic testing revealed a missense mutation in the SDHA gene. Only 16 cases of spermatic cord PGL have been reported to date. Although it is easy to diagnose by histology and IHC examinations, preoperative diagnosis is quite important as it can actually reduce intraoperative complications.

Targeting neuroendocrine tumors with octreotide and lanreotide: Key points for clinical practice from NET specialists.

Octreotide and lanreotide are the two somatostatin analogs (SSA) currently available in clinical practice. They have been approved first to control the clinical syndrome (mainly carcinoid syndrome) associated with functioning neuroendocrine tumors (NET) and later for tumor growth control in advanced low/intermediate grade NET. Although evidence regarding their role, especially as antiproliferative therapy, has been increasing over the years some clinical indications remain controversial. Solicited by AIOM (Italian Association of Medical Oncology) a group of clinicians from various specialties, including medical oncology, endocrinology, and gastroenterology, deeply involved in NET for their clinical and research activity, addressed eight open questions, critically reviewing evidence and guidelines and sharing clinical take-home messages. The questions regarded the use of long-acting octreotide and lanreotide in the following settings: functioning and non-functioning NET refractory to label dose, first-line metastatic pulmonary NET, combination with other therapy with an antiproliferative intent, maintenance in NET responding to other therapies, adjuvant treatment, Ki-67-related cut-off, somatostatin receptor imaging, safety, and feasibility. The level of evidence is not absolute for the majority of these clinical contexts, so it is recommended to distinguish routine versus sporadic utilization in very selected cases. Mention of such specific issues by the main European guidelines (ENETS, European Neuroendocrine Tumor Society, and ESMO, European Society for Medical Oncology) was explored and their position reported. However, different clinical decisions on single patients could be made if the case is carefully discussed within a NET-dedicated multidisciplinary team.

Ten-Fold Elevation of Chromogranin A Level Unrelated to a Neuroendocrine Tumor: A Case Report of the Diagnostic Interference of Proton Pump Inhibitors.

Chromogranin A (CgA) is a well-known biomarker for neuroendocrine tumors (NETs). However, due to its non-specificity, a proper assessment of CgA test results requires a detailed knowledge of the factors, conditions, and medications influencing its serum concentration. We describe a case of a 61-year-old patient presenting with a mass suspicious of a gastrointestinal NET and an exceedingly high level of serum CgA persistent after mass resection. Following a thorough review of patient's medical history and clinical presentation, along with radiographic and pathological findings, no evidence of a NET was detected. A trial of proton-pump inhibitor (PPI) withdrawal led to a dramatic normalization of CgA level, marking it as the culprit causing this tumor marker elevation. This case highlights the significant impact of PPI use on CgA level, and should incentivize clinicians to provide proper education to patients prior to testing.

Hedinger Syndrome-Lessons Learnt: A Single-Center Experience.

BACKGROUND: Hedinger syndrome (HS) or carcinoid heart disease (CD) is a rare and challenging manifestation of malignant neuroendocrine tumours (NETs) involving the heart. We aimed to report our experience with surgical strategies and midterm results in HS patients. METHODS: Eleven patients (58 ± 11 (range 41 to 79 years); 5 females) with HS who underwent cardiac surgery in our department between 07/2005 and 05/2023 were analysed. RESULTS: All patients showed a New York Heart Association (NYHA) class III-IV and in all the tricuspid valve (TV) was involved. Four patients received a TV replacement, and three TV reconstruction. Recently, to preserve the geometry and function of the compromised right ventricle (RV), we have applied the TV "bio-prosthesis in native-valve" implantation technique with the preservation of the valve apparatus (tricuspid valve implantation: TVI) in four cases. Concomitant procedures included pulmonary valve replacement in four, pulmonary implantation in one, and aortic valve replacement in three cases. To treat RV failure, we adapted a combined TandemHeart®-CytoSorb® haemoperfusion strategy in Patient #10 and venoarterial extracorporeal membrane oxygenation (V-A ECMO) support avoidance, after experiencing an ECMO-induced carcinoid-storm-related death in Patient #8. Mortality at 30 days was 18% (2/11). The median follow up was 2 ± 2.1 years (range 1 month to 6 years) with an overall mortality during the follow-up period of 72.7% (8/11). CONCLUSIONS: HS surgery, despite being a high-risk procedure, can efficiently prolong survival, and represents a safe and feasible procedure. However, patient selection seems to be crucial. Further follow up and larger cohorts are needed.

EML4-ALK rearrangement of lung large cell neuroendocrine carcinoma: a case report.

Background: Lung large cell neuroendocrine carcinoma (L-LCNEC) is a subtype of lung cancer with a low incidence and a high degree of malignancy. For early stage patients, surgical treatment is limited, and the risk of postoperative recurrence is high. For patients with unresectable or advanced disease, platinum-based chemotherapy is currently the mainstay of treatment, but its efficacy is unsatisfactory. L-LCNEC with the anaplastic lymphoma kinase (ALK) gene mutation is very rare and currently has no standard therapy. In this article, we report the case of a locally advanced L-LCNEC patient with ALK mutations who underwent first-line treatment with alectinib. Case Description: A previously healthy, 46-year-old, non-smoking woman was clinically diagnosed with unresectable locally advanced L-LCNEC. Next generation sequencing (NGS) of the patient's plasma and tumor specimen showed echinoderm microtubule-associated protein-like 4 (EML-4) (exon 13)-ALK (exon 20) fusion with a mutation frequency of 14.48% and 15.37%. The patient refused chemotherapy, and received first-line treatment with alectinib 600 mg, bis in die (bid), per day. After taking alectinib for 1 month, the patient's chest enhanced computed tomography (CT) scan showed a partial response (PR). After 12 months of treatment with alectinib, a radiological evaluation showed that the patient had maintained the PR. A grade 2-3 rash was observed at the beginning of the treatment. After symptomatic treatment, the rash disappeared, and the side effects were fully tolerated. At present, the patient can work normally, has a performance status of 0 and has not experience any major adverse events. Conclusions: Our case suggests that the first-line use of targeted therapy is also a good choice for L-LCNEC patients of stage III with gene mutations. The side effects are light, the patient can tolerate well, and the quality of life of can be improved.

Selected Parameters of Bone Turnover in Neuroendocrine Tumors-A Potential Clinical Use?

BACKGROUND: Currently, there are no effective markers to diagnose and monitor patients with neuroendocrine tumors (NETs). The aim of this study was to assess bone metabolism based on selected markers of bone turnover: OST, OPG, and IGFBP-3, in both the group of patients with NETs and the control group. Associations with selected sociodemographic, biochemical, and clinicopathological characteristics were examined. We also evaluated any potential associations between these markers and selected biochemical markers of NETs commonly used in clinical practice. METHODS: The study group included 60 patients with GEP-NETs and BP-NETs, while the control group comprised 62 healthy individuals. The serum concentrations of OST, OPG and IGFBP-3 were assessed using ELISA. RESULTS: OST and OPG levels were significantly higher in the study group compared to the control group. In the study group, we observed a significant correlation between OPG and the clinical stage and chromogranin A. Additionally, an association was found between OPG and histological grade, Ki-67, and metastasis in GEP-NET cases. CONCLUSIONS: Markers of bone turnover cannot be used in the routine diagnostics of neuroendocrine tumors. Nonetheless, these markers may help evaluate the skeletal system in patients with NETs. Further research is needed to determine the utility of osteocalcin (OST) and osteoprotegerin (OPG) as potential biomarkers for neuroendocrine tumors.

Outcome analysis in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with Lu-177-DOTATATE.

Background: Patients with neuroendocrine tumors (NET) of the gastroenteropancreatic tract (GEP-NET) were effectively treated with peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE in the NETTER-1 trial. The aim of this study was to assess the outcome of metastatic GEP-NET patients within a European Neuroendocrine Tumor Society (ENETS) certified center of excellence after this treatment. Methods: A total of 41 GEP-NET patients who received PRRT with Lu-177-DOTATATE between 2012 and 2017 at a single center were included in this analysis. Data on pre- and post-PRRT treatments [selective internal radiation therapy (SIRT), somatostatin analogue therapy (SSA), blood parameters, patient symptomatic burden and overall survival] was extracted from patient records. Results: Overall, PRRT was well tolerated and did not increase patient symptomatic burden. Blood parameters were not significantly affected by PRRT (means before and after therapy: hemoglobin: 125.4 vs. 122.3 mg/L, P=0.201; creatinine: 73.8 vs. 77.7 µmol/L, P=0.146), while leukocytes (6.6 vs. 5.6 G/L, P<0.01) and platelets (269.9 vs. 216.7 G/L, P<0.001) were significantly decreased yet without clinical significance in our study. Seven of 9 patients with SIRT treatment prior to PRRT were deceased (mortality odds ratio =4.083). The mortality odds ratio of patients with a pancreatic tumor and SIRT was 1.33 compared to patients with a different tumor origin. 6 of 15 patients (40%) with post-PRRT SSA were deceased (mortality odds ratio =0.429 without SSA after PRRT). Conclusions: Patients with advanced GEP-NET might benefit from PRRT with Lu-177-DOTATATE as it can provide a valuable treatment modality in advanced disease stages. Safety profiles of PRRT were manageable without increasing the symptomatic burden. SIRT before PRRT or lack of SSA after PRRT seem to impair the response and reduce survival.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review.

Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials have demonstrated efficacy benefits for new therapies in advanced NETs. Emerging long-term data from these trials have enabled clinicians to make more accurate risk-benefit assessments, particularly for patients receiving multiple lines of therapy. However, clinical data specifically regarding treatment sequencing are limited. In lieu of definitive data, treatment sequencing should be based on disease-related factors (e.g., site of tumor origin, volume of disease) and patient-related characteristics (e.g., comorbidities, patient preferences). Clinical decision-making in advanced NETs remains highly individualized and complex; important evidence gaps regarding treatment sequencing remain. Given this, advanced NET management should be a joint effort of multidisciplinary teams at referring and high-volume centers. Additional clinical trial and real-world evidence are needed to meet the challenge of understanding how to sequence available NET therapies. Until these trials are conducted, the best practices provided in this review may serve as a guide for clinicians making treatment sequencing decisions based on the available data.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

Theranostics in Oncology-Thriving, Now More than Ever.

Tracing its roots back to the 1940s, theranostics in nuclear oncology has proved successful mainly due to the beneficial effects of image-guided therapeutic concepts for patients afflicted with a variety of different cancers. The majority of these treatments are not only characterized by substantial prolongation of progression-free and overall survival, but are also generally safe, rendering theranostic agents as an attractive treatment option in various clinical scenarios in oncology. In this Special Issue Novel Theranostic Agents, nine original articles from around the globe provide further evidence on the use of the theranostic concept for neuroendocrine neoplasm (NEN), prostate cancer (PC), meningioma, and neuroblastoma. The investigated diagnostic and therapeutic radiotracers target not only established structures, such as somatostatin receptor, prostate-specific membrane antigen or norepinephrine transporter, but also recently emerging targets such as the C-X-C motif chemokine receptor 4. Moreover, the presented original articles also combine the concept of theranostics with in-depth read-out techniques such as radiomics or novel reconstruction algorithms on pretherapeutic scans, e.g., for outcome prediction. Even 80 years after its initial clinical introduction, theranostics in oncology continues to thrive, now more than ever.

Misleading clinical presentation of carcinoid syndrome.

Rare cases of carcinoid syndromes can develop from either gastrointestinal neuroendocrine tumors (NETs) without liver metastasis or large retroperitoneal involvement. We report a case of a patient with isolated flushing highly suggestive of carcinoid syndrome caused by an ileal NET with adjacent lymph node metastases but with no liver metastases. The final diagnose was delayed for this patient due to a combination of misleading clinical presentation and negative usual screening tests (urinary 5-HIAA and serum chromogranine A). Given its high sensitivity and specificity, 68Ga-DOTATATE PET/CT confirmed the diagnosis of neuroendocrine tumor. Therefore, this case reminds clinicians that carcinoid syndrome may manifest as flushing only and highlights that imaging is a major aspect of the evaluation and diagnosis of patients with suspected gastrointestinal NETs.

Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor-immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72-year-old man was diagnosed with an advanced pulmonary carcinoid tumor. CT-guided biopsies of lung and scapular tumors confirmed typical carcinoid (PD-L1, 1%-24%) and atypical carcinoid tumors (PD-L1, negative), respectively. Although the primary lung carcinoid tumor showed a partial response, the scapular tumor was significantly enlarged after two cycles of anti-PD-L1 antibody therapy in combination with carboplatin plus etoposide. We performed quantitative pathology imaging analysis with fluorescent multiplex immunohistochemistry. CD8+ T cell infiltration was detected in the PD-L1-positive primary lung tumor nest; however, it was mostly restrained in the stroma in a PD-L1-negative metastatic scapular tumor. Treg infiltrations into both tumor nests and stroma were detected in the lung tumor, which were not detected in the metastatic scapular tumor. This study provides the first evidence of coexistence of heterogeneous TIME within a single individual with a pulmonary carcinoid tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors.

Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward.

Peptide receptor radionuclide therapy (PRRT) is a highly effective anti-cancer treatment modality for patients with non-resectable, metastasized neuroendocrine tumors (NETs). During PRRT, specific receptors that are overexpressed on the cancer cells are targeted with a peptide labeled with a DNA-damaging radionuclide. Even though PRRT is a powerful treatment for metastasized NET patients, the majority still cannot be cured at this stage of the disease. Hence, many investigators focus on improving the therapeutic efficacy of this therapy. Improving PRRT can, for example, be achieved by using other radionuclides with different physical properties, by combining PRRT with radiosensitizing agents or by radiolabeling peptides with different characteristics. However, due to lack of extensive knowledge of radiobiological responses of cancer cells to PRRT, biological parameters that influence absorbed dose or that might even elicit insensitivity to therapy remain elusive and the context in which these improvements will be successful warrants further investigation. In this review, we will discuss the development of PRRT, its clinical merits in current treatment and future perspectives. We will highlight different radionuclides and their benefits and pitfalls, as well as different peptide-conjugates that hold these radionuclides. We will zoom in on the latest developments regarding combinatorial treatments and how investigators from different disciplines such as dosimetry and radiobiology are now joining forces to improve PRRT for NETs.

Outcomes and toxicity following Yttrium-90 radioembolization for hepatic metastases from neuroendocrine tumors-a single-institution experience.

BACKGROUND: The prognosis of patients with hepatic metastases from neuroendocrine tumors (NET) is generally good, and radioembolization with Yttrium-90 microspheres is a locoregional therapy that is used in efforts to improve hepatic disease control and survival. This study aims to describe the survival outcomes and toxicities associated with radioembolization for hepatic-predominant metastatic NET in a large single-institution cohort. METHODS: A total of 59 patients underwent radioembolization for metastatic NET with hepatic predominant disease at a single academic center. Patient outcomes were analyzed by Kaplan-Meier survival analysis and toxicities were detailed and described. Ten patients within the cohort underwent post-treatment dosimetric analysis using PET-MRI and normal liver dosimetry was correlated with hepatic fibrosis and toxicity. RESULTS: Median overall survival from time of radioembolization in the patient cohort was 31 months, and the 1- and 2-year overall survival was 80.4% and 65.6% respectively. Median hepatic progression-free survival and overall progression-free survival were 18 and 13 months, respectively. Three patients died of hepatic failure that was possibly therapy-related. Ten patients underwent evaluation of post-treatment dosimetry following radioembolization. In patients who did not develop hepatotoxicity or hepatic fibrosis, mean dose to normal liver was 25.4 Gy, while the mean liver dose in patients who experienced toxicity (hepatic fibrosis in n=2 and death from hepatic failure in n=1) was 59.1 Gy. CONCLUSIONS: Overall survival following radioembolization for hepatic metastases from NET is excellent; however, deaths that are potentially treatment-related have been observed. Preliminary data regarding dose to normal liver is suggestive of a relation between dosimetry and toxicity, however further work is required to further elucidate the mechanism, correlation with dosimetry, as well as additional patient and tumor factors that may predispose these patients to toxicity.

Hedinger syndrome: first experience and two-year follow-up in patients with carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) (Hedinger syndrome) is a rare manifestation, it has been described in up to 60% of patients with both neuroendocrine tumors (NETs) and carcinoid syndrome (CS) which, typically inducing right heart-sided abnormalities. METHODS: Between 07/15 and 10/18, six patients (mean age 63±12 years; 3 females) presented with manifested (NYHA III-IV) Hedinger syndrome's related valvular(s) lesion and were operated at our center. Clinical data, adverse events and patient outcomes were recorded. RESULTS: The tricuspid valve was involved in all patients. Tricuspid valve repair was possible in four patients and two needed replacement. In two patients, operation was performed on beating heart without cross-clamping. Concomitant pulmonary valve replacement in two patients and aortic valve replacement in another two patients. A mean cross-clamp time of 61±50 minutes was observed. One patient with severely impaired right ventricular function needed ECMO support, and died 3 days later due to neuroendocrine enzyme storm. At 13 months, one patient developed severe tricuspid stenosis and underwent re-operation with replacement. Another patient died 18 months after surgery related to the underlying tumour. At mean of 30 months follow-up, four patients were alive and asymptotic. CONCLUSIONS: Hedinger syndrome is a challenging entity in cardiac surgery characterized by aggressive valve lesions combined with metastatic neuroendocrine neoplasia affecting the systemic circulation. We advise a multidisciplinary collaboration to early diagnose cardiac involvement to offer an early and proper treatment regime.