Radioligand therapy, vascular deprivation and surgical resection as a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass 

Radioligand therapy, vascular deprivation and surgical resection as a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Radioligand therapy, vascular deprivation and surgical resection as a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass Giacomo Deiro, Marsia Tancredi, Campra Donata, Andrea Discalzi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6579873/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 26 You are reading this latest preprint version Abstract Background Surgery for symptomatic non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) represents the only definitive curative treatment option and improves the overall survival rate. The new frontier in locally advanced NF-PanNETs treatment is Radioligand therapy (RLT) in a neoadjuvant setting. Acute gastrointestinal bleeding is a rare complication that requires immediate treatment with a multidisciplinary approach. Case presentation We present a case of a 36-year-old male diagnosed with locally advanced non-functioning PanNET in the pancreatic body-tail diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). RLT, proposed to reduce mass dimension in the planning of surgical resection, was performed to obtain a downstaging tumor and enabling access to radical surgery. For the acute onset of hemorrhagic shock caused by lower gastrointestinal bleeding, tumor endovascular embolization was performed using microspheres and gelatin sponge. On vascular deprivation day 4, a posterior radical antegrade modular pancreatosplenectomy (P-RAMPS), left lateral duodenectomy (III and IV portion) and resection of the left colic flexure were performed. Reconstruction of intestinal continuity was ensured by isoperistaltic side-to-side duodeno-jejuno and colo-colic anastomosis. The patient had a short hospital stay with quick recovery and a good outcome at 6 months follow-up after the surgery. Conclusions Symptomatic non-functioning PanNETs are infrequent slow-growing tumors and some of them may present in advanced stages with local involvement of surrounding structures. Our case suggests that a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass is mandatory and aggressive surgical management is a mainstay. Pancreatic neuroendocrine tumors Radioligand therapy Artery embolization Radical antegrade modular pancreatosplenectomy Figures Figure 1 Figure 2 Figure 3 Background Non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) represent a heterogeneous group of primary neoplasms of the pancreas. Symptomatic NF-PanNETs are diagnosed in most cases following mass effects symptoms. 12 Prognosis takes into account tumor size, tumor site, and local invasiveness. 3 4 Surgery is recommended for resectable tumors in young patients and is required for cases with signs of local invasiveness, such as main pancreatic duct dilation, jaundice, or suspected nodal involvement. 5 Standard pancreatectomy with lymphadenectomy is mandatory for symptomatic NF-PanNETs, regardless of tumor size. 6 In the case of advanced or metastatic NF-PanNETs, the goals of treatment include extending survival, enhancing quality of life, and managing both tumor growth and symptoms. To obtain these results, in addition to the surgical approach, many therapies are currently available, including somatostatin analogues (SSA), tyrosine kinase inhibitors (e.g. Sunitinib), mTOR inhibitors (e.g. everolimus), chemotherapy and radioligand therapy, which have become mainstays of advanced PanNETs treatment. 7 8 9 10 Herein, we present the case of locally advanced NF-PanNET of the pancreatic body and tail with left colon and adrenal gland involvement. This report is the first to describe a multistep approach for spontaneous lower gastrointestinal bleeding due to tumor infiltration of the colonic wall seven days after the first administration of RLT. Preoperative vascular artery embolization and posterior radical antegrade modular pancreatosplenectomy (RAMPS) were performed. Case presentation A 36-year-old man presented to our emergency department with abdominal pain, profuse diarrhea, and an 8 kg weight loss. A mass was present in the upper left abdominal quadrant on examination. Subsequent computed tomography (CT) showed a well-demarcated, enhanced lesion located on the pancreatic body and tail, measuring 90 x 80 mm in diameter, with colic left flexure and left adrenal gland infiltration and obstruction of the splenic vein due to either thrombosis formation and neighboring mass effect resulted in left-sided portal hypertension (LSPH) (Fig. 1 A and 1 B). In addition to the splenic artery, the lesions demonstrated aberrant vascularization by branches of the superior mesenteric artery (SMA), left branch of middle colic artery (MCA ) , left colic artery (LCA) and inferior mesenteric artery (IMA) (Fig. 1 D). An endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) was planned and confirmed the presence of a hypoechoic, well-defined pancreatic mass (93x85 mm), with a sign of Treitz's ligament infiltration and lymphadenopathy. Histological examination revealed a grade 2 (G2) non-functioning pancreatic neuroendocrine tumor (NF-PanNET) according to the World Health Organization (WHO) Classification of Tumors of the Digestive System. 11 [18F]F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and [68Ga]Ga-DOTA-TOC-positron emission tomography (DOTATOC-PET) were performed. In FDG-PET the mass showed a moderate increase in glucose metabolism (SUVmax of 8.7) while it showed an intense uptake on DOTATOC-PET (SUVmax 58.2) (Fig. 1 C and 1 D). During the diagnostic framework, for the occurrence of occasional episodes of hematochezia without anemia, the patient performed martial supplementation and colonoscopy examination that showed an ab-extrinsic compression of the colonic wall without mucosal infiltration. After a multidisciplinary discussion, we proposed a Radioligand therapy (RLT) as a neoadjuvant treatment and a subsequent Distal Pancreatectomy (DP). The patient performed the first of four administrations of RLT with Lutetium (177Lu) oxodotreotide (Lutathera→), without early complication (no hematological or renal toxicity occurred and no aggravation of preexisting hematochezia). On post-RLT day 7, the patient was admitted to our emergency department for acute onset of lower gastrointestinal bleeding and initial hemodynamic instability treated with blood transfusions. Since stabilization was promptly reached, a CT scan angiography was performed that showed active bleeding. Therefore, a preoperative endovascular embolization of peripheral aberrant branches of the SMA, MCA, LCA, IMA and left gastroepiploic artery (LGEA) was performed using a mixture of microspheres (HydroPearl 400 micron, Terumo, Japan) and gelatin sponge (Embocube 2.5 mm, Merit, USA) (Fig. 2 ). CT scans taken 3 days after embolization confirmed successful outcome of the procedure without intraluminal blushing. On post-embolization day 4, a posterior radical antegrade modular pancreatosplenectomy (P-RAMPS), left lateral duodenectomy (III and IV portion), and resection of the left colic flexure was performed (Fig. 3 A and 3 B). Reconstruction of intestinal continuity was ensured by isoperistaltic side-to-side duodeno-jejuno and colo-colic anastomosis. The postoperative course was characterized by a grade A chyle fistula. Histological examination confirmed a ypT4N1 (4/21) - G2 PanNET. 6-month follow-up was regular (Fig. 3 D). Discussion and Conclusions Symptomatic non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) usually present with signs related to mass effects, pancreatitis, and distant metastases. 12 To our knowledge, very few case reports are available in the literature on spontaneous bleeding NF-PanNETs. 12 , 11 The discussion of this complex clinical case consists of three main topics, which treated in sequence provide an understanding of the step-by-step clinical management of NF-PanNET mass-forming determined hemorrhagic shock. In pancreatic neuroendocrine tumors, surgery represents the only definitive curative treatment option. The 5-year survival rate is more than 60% in resectable tumors, whereas it drops to less than 30% in unresectable lesions. 13 The role of debulking surgery in advanced Pan-NETs is unclear. It is recommended for alleviating symptoms of carcinoid syndrome or mass compression symptoms. The new frontier in NET treatment is represented by the RLT in the neoadjuvant setting to obtain downstaging of the tumor, enabling access to radical surgery. In fact, the intensification of therapy improves outcomes for patients with locally advanced NF-Pan NETs. 7 RLT is a tumor-directed systemic treatment exploiting the abundance of SSTRs, especially sst2, on the cell membrane of well-differentiated NETs. 14 Usually, it represents a second line of treatment, introduced after inefficiency or no possibility of primary therapy, and with disease progression 15 16 . The advantage of RLT is based on the fact that its proven efficacy has few, mostly non-serious side effects such as nausea, vomiting, and fatigue, while more serious side effects, e.g. rectal bleeding, are generally uncommon. In the NETTER-1 trial, a randomized phase 3 trial, RLT was shown to significantly improve progression-free survival (PFS) in patients with midgut NETs and was not correlated to major hematologic or renal toxicity in any patient 7 17 . Following this trial, other studies demonstrate the same efficacy even in Pan-NET- and, recently, the NETTER-2 study demonstrated that RLT with Lutetium ( 177 Lu) oxodotreotide (Lutathera → ) should be considered the first-line therapy in locally advanced NF-PanNETs 9 8 . The use of RLT as a neoadjuvant for NF-PanNET is desirable and to be evaluated, as in the case we presented, in young patients with a good prognosis. In addition, recent evidence demonstrates the efficacy of RLT as neoadjuvant therapy in resectable PanNETs to induce intratumoral changes that result in the facilitation of subsequent surgery, hypothetically also in locally advanced/unresectable NF-Pan NETs with vascular involvement or lymph node invasion 18 19 17 20 . Here, we reported a case of major bleeding of NF-PanNETs that occurred seven days after the first administration of RLT. The patient presented acute onset of rectal bleeding due to aberrant irroration associated with ab-extrinsic erosion and massive full-thickness infiltration of the left colic flexure. Considering the initial hemodynamic stability, preoperative embolization was performed, following the WSES guidelines for acute gastrointestinal bleeding. The recommended first-line treatment for pancreatic bleeding is transcatheter arterial embolization (TAE), with success rates of 67–97% and mortality rates of 4–19%. 15 Surgery is indicated only if TAE fails or is not feasible since it leads to higher morbidity and mortality in urgent settings and re-operations are needed in up to one-third of the patients. 21 After urgent pancreatic surgery, abdominal sepsis, diffuse bleeding, and ischemic complications turn out to be frequently fatal. 22 23 Vascular deprivation, shifting the setting from urgent to elective, allows one to perform an oncological radical surgery. Embolization allows to stop of severe coagulopathy development and massive transfusion multiorgan injuries. In addition, organs with extensive collateral circulation like the pancreas, tolerate well relatively large areas of embolization, minimizing ischaemic risks. In the present case, vascular deprivation of the hemorrhagic NF-PanNet allowed patient stabilization, avoided pancreatitis, like in the trauma setting, and offered to the patient the best available treatment, a planned (semi-urgent) oncologic radical intervention. A P-RAMPS, partial duodenectomy and resection of the left colic flexure were performed. The advantages of P-RAMPS include improved exposure of the pancreaticoduodenal region, better lymph node dissection, and reduced risk of positive surgical margins compared to traditional methods. 16 RAMPS was described in 2003 by Strasberg to achieve negative posterior resection margins. Oncologic safety with R0 was obtained in more than 85% of case series. 24 25 Lymph node metastasis, an independent prognostic factor in NF-PanNETs, is detected significantly more in the RAMPS procedure than in the standard procedure. In fact, celiac (n° 9) and left side of SMA (n°14) lymph nodes are removed in addiction of n°10, 11 and 18 according to Japanese classification. In conclusion, symptomatic non-functioning pancreatic neuroendocrine tumors are infrequent slow-growing tumors and some of them may present in advanced stages with local involvement of surrounding structures. This case represents a good example of a multidisciplinary therapeutic approach in NF-PanNET with even innovative aspects such as the use of RLT for neoadjuvant purposes followed by the surgical approach, as suggested by recent scientific evidence. Rarely, during preparatory phases, as in the neoadjuvant treatment course, they can present acute gastrointestinal bleeding. In case of this occurrence, a step-up-approach can manage the bleeding without compromising the surgical plan. Abbreviations NF-PanNETs: non-functioning pancreatic neuroendocrine tumors RLT: radioligand therapy EUS-FNA: endoscopic ultrasound-guided fine needle aspiration P-RAMPS: posterior radical antegrade modular pancreatosplenectomy SSA: somatostatin analogues CT: computed tomography LSPH: left-sided portal hypertension SMA: superior mesenteric artery MCA: middle colic artery LCA: left colic artery IMA: inferior mesenteric artery G2: grade 2 WHO: World Health Organization 18 FDG-PET [18F] F-Fluorodeoxyglucose positron emission tomography 68 Ga DOTATOC-PET: [68Ga] Ga-DOTA-TOC-positron emission tomography SUV: standardized uptake value DP: distal pancreatectomy LGEA: left gastroepiploic artery TAE: transcatheter arterial embolization Declarations Statement of Ethics The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study was approved by the institutional review board. Consent Statement Written informed consent was obtained from the patient for the publication of this case report. Sources of funding Sources of funding for your research: none. Availability of data and material The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Author Contributions All authors contributed equally to this work: G. D. and M. T.: wrote the manuscript, drafting the work; critical revision for important intellectual content. G. D., A. N., M. B., R. T. and A. D. supervised the paper and made definitive changes on final version. All Authors approved the final version of the manuscript. Conflict of interest No conflict of interest to disclose. References Achilli P, Chiarelli M, Giustizieri U, et al. Spontaneous rupture of a non-functioning pancreatic neuroendocrine tumor A case report of a rare cause of acute abdomen. Ann Ital Chir. 2020;91:88–92. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6579873","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":454843251,"identity":"15dd1ccd-ea8d-41be-8b67-50ca7265a641","order_by":0,"name":"Giacomo 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Turin","correspondingAuthor":false,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Santarelli","suffix":""}],"badges":[],"createdAt":"2025-05-02 16:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6579873/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6579873/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82618166,"identity":"9283b2bd-e0dc-45ee-b36e-aede864b4fcd","added_by":"auto","created_at":"2025-05-13 11:58:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":203562,"visible":true,"origin":"","legend":"\u003cp\u003eA and B: computed tomography (CT) showed a well-demarcated, enhanced lesion located on the pancreatic body and tail, measuring 90 x 80 mm in diameter. C: [68Ga]Ga-DOTA-TOC-positron emission tomography (DOTATOC-PET). D: aberrant vascularization by branches of the superior mesenteric artery (SMA), left branch of middle colic artery (MCA), left colic artery (LCA) and inferior mesenteric artery (IMA).E: an intense uptake on DOTATOC-PET (SUVmax 58.2).\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6579873/v1/930f1764c68a51641caa7baa.jpg"},{"id":82618172,"identity":"392259ba-7745-4e6f-8e80-fe431f9d53cb","added_by":"auto","created_at":"2025-05-13 11:58:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":184066,"visible":true,"origin":"","legend":"\u003cp\u003eA: computed tomography (CT) scan angiography showed aberrant branches of the inferior mesenteric artery (IMA) (1), angiography before (2) and after (3) endovascular embolization. B: computed tomography (CT) scan angiography showed aberrant branches of the left gastroepiploic artery (LGEA) (1), angiography before (2) and after (3) endovascular embolization. C: computed tomography (CT) scan angiography showed aberrant branches of the superior mesenteric artery (SMA), left branch of middle colic artery (MCA) (1), angiography before (2) and after (3) endovascular embolization.\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6579873/v1/32347bc905e82b64d88d8ae0.jpg"},{"id":82618164,"identity":"bb6f4677-5eb0-47f1-9893-a1ad46ec6550","added_by":"auto","created_at":"2025-05-13 11:58:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":244839,"visible":true,"origin":"","legend":"\u003cp\u003eA and B: Posterior radical antegrade modular pancreatosplenectomy (P-RAMPS), left lateral duodenectomy (III and IV portion) and resection of the left colic flexure. C: computed tomography (CT) before surgery. D: computed tomography (CT) 6-month after surgery.\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6579873/v1/29c08d19a0188a9ab13388ed.jpg"},{"id":82618813,"identity":"765121ce-8e48-4b38-8d2e-b4dc59508e10","added_by":"auto","created_at":"2025-05-13 12:06:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1091840,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6579873/v1/1ac1f480-d143-4518-afbd-c41616ff6e05.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Radioligand therapy, vascular deprivation and surgical resection as a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass ","fulltext":[{"header":"Background","content":"\u003cp\u003eNon-functioning pancreatic neuroendocrine tumors (NF-PanNETs) represent a heterogeneous group of primary neoplasms of the pancreas. Symptomatic NF-PanNETs are diagnosed in most cases following mass effects symptoms.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Prognosis takes into account tumor size, tumor site, and local invasiveness.\u003csup\u003e3 4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSurgery is recommended for resectable tumors in young patients and is required for cases with signs of local invasiveness, such as main pancreatic duct dilation, jaundice, or suspected nodal involvement.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Standard pancreatectomy with lymphadenectomy is mandatory for symptomatic NF-PanNETs, regardless of tumor size. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the case of advanced or metastatic NF-PanNETs, the goals of treatment include extending survival, enhancing quality of life, and managing both tumor growth and symptoms. To obtain these results, in addition to the surgical approach, many therapies are currently available, including somatostatin analogues (SSA), tyrosine kinase inhibitors (e.g. Sunitinib), mTOR inhibitors (e.g. everolimus), chemotherapy and radioligand therapy, which have become mainstays of advanced PanNETs treatment. \u003csup\u003e7 8 9 10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHerein, we present the case of locally advanced NF-PanNET of the pancreatic body and tail with left colon and adrenal gland involvement. This report is the first to describe a multistep approach for spontaneous lower gastrointestinal bleeding due to tumor infiltration of the colonic wall seven days after the first administration of RLT. Preoperative vascular artery embolization and posterior radical antegrade modular pancreatosplenectomy (RAMPS) were performed.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 36-year-old man presented to our emergency department with abdominal pain, profuse diarrhea, and an 8 kg weight loss. A mass was present in the upper left abdominal quadrant on examination. Subsequent computed tomography (CT) showed a well-demarcated, enhanced lesion located on the pancreatic body and tail, measuring 90 x 80 mm in diameter, with colic left flexure and left adrenal gland infiltration and obstruction of the splenic vein due to either thrombosis formation and neighboring mass effect resulted in left-sided portal hypertension (LSPH) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). In addition to the splenic artery, the lesions demonstrated aberrant vascularization by branches of the superior mesenteric artery (SMA), left branch of middle colic artery (MCA\u003cem\u003e)\u003c/em\u003e, left colic artery (LCA) and inferior mesenteric artery (IMA) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). An endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) was planned and confirmed the presence of a hypoechoic, well-defined pancreatic mass (93x85 mm), with a sign of Treitz's ligament infiltration and lymphadenopathy. Histological examination revealed a grade 2 (G2) non-functioning pancreatic neuroendocrine tumor (NF-PanNET) according to the World Health Organization (WHO) Classification of Tumors of the Digestive System.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e [18F]F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and [68Ga]Ga-DOTA-TOC-positron emission tomography (DOTATOC-PET) were performed. In FDG-PET the mass showed a moderate increase in glucose metabolism (SUVmax of 8.7) while it showed an intense uptake on DOTATOC-PET (SUVmax 58.2) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). During the diagnostic framework, for the occurrence of occasional episodes of hematochezia without anemia, the patient performed martial supplementation and colonoscopy examination that showed an ab-extrinsic compression of the colonic wall without mucosal infiltration.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter a multidisciplinary discussion, we proposed a Radioligand therapy (RLT) as a neoadjuvant treatment and a subsequent Distal Pancreatectomy (DP). The patient performed the first of four administrations of RLT with Lutetium (177Lu) oxodotreotide (Lutathera→), without early complication (no hematological or renal toxicity occurred and no aggravation of preexisting hematochezia).\u003c/p\u003e \u003cp\u003eOn post-RLT day 7, the patient was admitted to our emergency department for acute onset of lower gastrointestinal bleeding and initial hemodynamic instability treated with blood transfusions. Since stabilization was promptly reached, a CT scan angiography was performed that showed active bleeding. Therefore, a preoperative endovascular embolization of peripheral aberrant branches of the SMA, MCA, LCA, IMA and left gastroepiploic artery (LGEA) was performed using a mixture of microspheres (HydroPearl 400 micron, Terumo, Japan) and gelatin sponge (Embocube 2.5 mm, Merit, USA) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). CT scans taken 3 days after embolization confirmed successful outcome of the procedure without intraluminal blushing. On post-embolization day 4, a posterior radical antegrade modular pancreatosplenectomy (P-RAMPS), left lateral duodenectomy (III and IV portion), and resection of the left colic flexure was performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Reconstruction of intestinal continuity was ensured by isoperistaltic side-to-side duodeno-jejuno and colo-colic anastomosis. The postoperative course was characterized by a grade A chyle fistula. Histological examination confirmed a ypT4N1 (4/21) - G2 PanNET. 6-month follow-up was regular (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cp\u003eSymptomatic non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) usually present with signs related to mass effects, pancreatitis, and distant metastases.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e To our knowledge, very few case reports are available in the literature on spontaneous bleeding NF-PanNETs.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e,\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe discussion of this complex clinical case consists of three main topics, which treated in sequence provide an understanding of the step-by-step clinical management of NF-PanNET mass-forming determined hemorrhagic shock.\u003c/p\u003e\u003cp\u003eIn pancreatic neuroendocrine tumors, surgery represents the only definitive curative treatment option. The 5-year survival rate is more than 60% in resectable tumors, whereas it drops to less than 30% in unresectable lesions.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The role of debulking surgery in advanced Pan-NETs is unclear. It is recommended for alleviating symptoms of carcinoid syndrome or mass compression symptoms.\u003c/p\u003e\u003cp\u003eThe new frontier in NET treatment is represented by the RLT in the neoadjuvant setting to obtain downstaging of the tumor, enabling access to radical surgery. In fact, the intensification of therapy improves outcomes for patients with locally advanced NF-Pan NETs.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eRLT is a tumor-directed systemic treatment exploiting the abundance of SSTRs, especially sst2, on the cell membrane of well-differentiated NETs.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Usually, it represents a second line of treatment, introduced after inefficiency or no possibility of primary therapy, and with disease progression\u003csup\u003e15 16\u003c/sup\u003e. The advantage of RLT is based on the fact that its proven efficacy has few, mostly non-serious side effects such as nausea, vomiting, and fatigue, while more serious side effects, e.g. rectal bleeding, are generally uncommon. In the NETTER-1 trial, a randomized phase 3 trial, RLT was shown to significantly improve progression-free survival (PFS) in patients with midgut NETs and was not correlated to major hematologic or renal toxicity in any patient \u003csup\u003e7 17\u003c/sup\u003e. Following this trial, other studies demonstrate the same efficacy even in Pan-NET- and, recently, the NETTER-2 study demonstrated that RLT with Lutetium (\u003csup\u003e177\u003c/sup\u003eLu) oxodotreotide (Lutathera\u003csup\u003e→\u003c/sup\u003e) should be considered the first-line therapy in locally advanced NF-PanNETs \u003csup\u003e9 8\u003c/sup\u003e. The use of RLT as a neoadjuvant for NF-PanNET is desirable and to be evaluated, as in the case we presented, in young patients with a good prognosis.\u003c/p\u003e\u003cp\u003eIn addition, recent evidence demonstrates the efficacy of RLT as neoadjuvant therapy in resectable PanNETs to induce intratumoral changes that result in the facilitation of subsequent surgery, hypothetically also in locally advanced/unresectable NF-Pan NETs with vascular involvement or lymph node invasion \u003csup\u003e18 19 17 20\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eHere, we reported a case of major bleeding of NF-PanNETs that occurred seven days after the first administration of RLT. The patient presented acute onset of rectal bleeding due to aberrant irroration associated with ab-extrinsic erosion and massive full-thickness infiltration of the left colic flexure. Considering the initial hemodynamic stability, preoperative embolization was performed, following the WSES guidelines for acute gastrointestinal bleeding. The recommended first-line treatment for pancreatic bleeding is transcatheter arterial embolization (TAE), with success rates of 67–97% and mortality rates of 4–19%.\u003csup\u003e15\u003c/sup\u003e Surgery is indicated only if TAE fails or is not feasible since it leads to higher morbidity and mortality in urgent settings and re-operations are needed in up to one-third of the patients. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e After urgent pancreatic surgery, abdominal sepsis, diffuse bleeding, and ischemic complications turn out to be frequently fatal. \u003csup\u003e22 23\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eVascular deprivation, shifting the setting from urgent to elective, allows one to perform an oncological radical surgery.\u003c/p\u003e\u003cp\u003eEmbolization allows to stop of severe coagulopathy development and massive transfusion multiorgan injuries. In addition, organs with extensive collateral circulation like the pancreas, tolerate well relatively large areas of embolization, minimizing ischaemic risks. In the present case, vascular deprivation of the hemorrhagic NF-PanNet allowed patient stabilization, avoided pancreatitis, like in the trauma setting, and offered to the patient the best available treatment, a planned (semi-urgent) oncologic radical intervention. A P-RAMPS, partial duodenectomy and resection of the left colic flexure were performed. The advantages of P-RAMPS include improved exposure of the pancreaticoduodenal region, better lymph node dissection, and reduced risk of positive surgical margins compared to traditional methods.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e RAMPS was described in 2003 by Strasberg to achieve negative posterior resection margins. Oncologic safety with R0 was obtained in more than 85% of case series.\u003csup\u003e24 25\u003c/sup\u003e Lymph node metastasis, an independent prognostic factor in NF-PanNETs, is detected significantly more in the RAMPS procedure than in the standard procedure. In fact, celiac (n° 9) and left side of SMA (n°14) lymph nodes are removed in addiction of n°10, 11 and 18 according to Japanese classification. In conclusion, symptomatic non-functioning pancreatic neuroendocrine tumors are infrequent slow-growing tumors and some of them may present in advanced stages with local involvement of surrounding structures.\u003c/p\u003e\u003cp\u003eThis case represents a good example of a multidisciplinary therapeutic approach in NF-PanNET with even innovative aspects such as the use of RLT for neoadjuvant purposes followed by the surgical approach, as suggested by recent scientific evidence. Rarely, during preparatory phases, as in the neoadjuvant treatment course, they can present acute gastrointestinal bleeding. In case of this occurrence, a step-up-approach can manage the bleeding without compromising the surgical plan.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNF-PanNETs: non-functioning pancreatic neuroendocrine tumors\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRLT: radioligand therapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEUS-FNA: endoscopic ultrasound-guided fine needle aspiration\u003c/p\u003e\n\u003cp\u003eP-RAMPS: posterior radical antegrade modular pancreatosplenectomy\u003c/p\u003e\n\u003cp\u003eSSA: somatostatin analogues\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u003c/p\u003e\n\u003cp\u003eLSPH: left-sided portal hypertension\u003c/p\u003e\n\u003cp\u003eSMA: superior mesenteric artery\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMCA: middle colic artery\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eLCA: left colic artery\u003c/p\u003e\n\u003cp\u003eIMA: inferior mesenteric artery\u003c/p\u003e\n\u003cp\u003eG2: grade 2\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e18\u003c/sup\u003eFDG-PET [18F] F-Fluorodeoxyglucose positron emission tomography\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGa DOTATOC-PET: [68Ga] Ga-DOTA-TOC-positron emission tomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSUV: standardized uptake value\u003c/p\u003e\n\u003cp\u003eDP: distal pancreatectomy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLGEA: left\u0026nbsp;gastroepiploic\u0026nbsp;artery\u003c/p\u003e\n\u003cp\u003eTAE: transcatheter arterial embolization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study was approved by the institutional review board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSources of funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSources of funding for your research: none.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed equally to this work:\u003c/p\u003e\n\u003cp\u003eG. D. and M. T.: wrote the manuscript, drafting the work; critical revision for important intellectual content.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eG. D., A. N., M. B., R. T. and A. D. supervised the paper and made definitive changes on final version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll Authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAchilli P, Chiarelli M, Giustizieri U, et al. Spontaneous rupture of a non-functioning pancreatic neuroendocrine tumor A case report of a rare cause of acute abdomen. Ann Ital Chir. 2020;91:88\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSch\u0026uuml;tte K, Bornschein J, Kuester D, Wieners G, Malfertheiner P. 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J Am Coll Surg. 2007;204(2):244\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jamcollsurg.2006.11.002\u003c/span\u003e\u003cspan address=\"10.1016/j.jamcollsurg.2006.11.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pancreatic neuroendocrine tumors, Radioligand therapy, Artery embolization, Radical antegrade modular pancreatosplenectomy","lastPublishedDoi":"10.21203/rs.3.rs-6579873/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6579873/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSurgery for symptomatic non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) represents the only definitive curative treatment option and improves the overall survival rate. The new frontier in locally advanced NF-PanNETs treatment is Radioligand therapy (RLT) in a neoadjuvant setting. Acute gastrointestinal bleeding is a rare complication that requires immediate treatment with a multidisciplinary approach.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe present a case of a 36-year-old male diagnosed with locally advanced non-functioning PanNET in the pancreatic body-tail diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). RLT, proposed to reduce mass dimension in the planning of surgical resection, was performed to obtain a downstaging tumor and enabling access to radical surgery. For the acute onset of hemorrhagic shock caused by lower gastrointestinal bleeding, tumor endovascular embolization was performed using microspheres and gelatin sponge. On vascular deprivation day 4, a posterior radical antegrade modular pancreatosplenectomy (P-RAMPS), left lateral duodenectomy (III and IV portion) and resection of the left colic flexure were performed. Reconstruction of intestinal continuity was ensured by isoperistaltic side-to-side duodeno-jejuno and colo-colic anastomosis. The patient had a short hospital stay with quick recovery and a good outcome at 6 months follow-up after the surgery.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSymptomatic non-functioning PanNETs are infrequent slow-growing tumors and some of them may present in advanced stages with local involvement of surrounding structures. Our case suggests that a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass is mandatory and aggressive surgical management is a mainstay.\u003c/p\u003e","manuscriptTitle":"Radioligand therapy, vascular deprivation and surgical resection as a step-up-approach for locally advanced pancreatic neuroendocrine bleeding mass ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 11:58:39","doi":"10.21203/rs.3.rs-6579873/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision 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