Oncological outcomes after pancreatoduodenectomy for pancreatic ductal adenocarcinoma in octogenarians: case-control study.

BACKGROUND: By the end of this decade, 70 per cent of all diagnosed pancreatic ductal adenocarcinomas will be in the elderly. Surgical resection is the only curative option. In the elderly perioperative mortality is higher, while controversy still exists as to whether aggressive treatment offers any survival benefit. This study aimed to assess the oncological benefit of pancreatoduodenectomy in octogenarians with pancreatic ductal adenocarcinoma. METHOD: Retrospective multicentre case-control study of octogenarians and younger controls who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 2008 and 2017. The primary endpoint was overall survival and the secondary endpoint was disease-free survival. RESULTS: Overall, 220 patients were included. Although the Charlson co-morbidity index was higher in octogenerians, Eastern Cooperative Oncology Group performance status, ASA and pathological parameters were comparable. Adjuvant therapy was more frequently delivered in the younger group (n = 80, 73 per cent versus n = 58, 53 per cent, P = 0.006). There was no significant difference between octogenarians and controls in overall survival (20 versus 29 months, P = 0.095) or disease-free survival (19 versus 22 months, P = 0.742). On multivariable analysis, age was not an independent predictor of either oncological outcome measured. CONCLUSION: Octogenarians with pancreatic ductal adenocarcinoma of the head and uncinate process may benefit from comparable oncological outcomes to younger patients with surgical treatment. Due to the age- and disease-related frailty and co-morbidities, careful preoperative assessment and patient selection is of paramount importance.

Diagnostic features and management options for duodenal neuroendocrine neoplasms: a retrospective, multi-centre study.

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32-87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9-130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54-13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56-29.5) (p < 0.05) in the multivariate analysis. Lesions 11-20 mm in size had OR 11.1 (1.16-106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81-0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.

Human Immunocompetent Model of Neuroendocrine Liver Metastases Recapitulates Patient-Specific Tumour Microenvironment.

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies.

Minimizing the risk of small-for-size syndrome after liver surgery.

BACKGROUND: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant (FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-for-size syndrome (SFSS). DATA SOURCES: This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specific modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. RESULTS: Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. CONCLUSIONS: With those techniques the indications of radical treatment for patients with liver tumors have significantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modification of interventions and the right timing of surgery.

Short-term outcomes after pancreatoduodenectomy in octogenarians: multicentre case-control study.

BACKGROUND: Pancreatoduodenectomy (PD) is frequently the surgical treatment indicated for a number of pathologies. Elderly patients may be denied surgery because of concerns over poor perioperative outcomes. The aim of this study was to evaluate postoperative clinical outcomes and provide evidence on current UK practice in the elderly population after PD. METHODS: This was a multicentre retrospective case-control study of octogenarians undergoing PD between January 2008 and December 2017, matched with younger controls from seven specialist centres in the UK. The primary endpoint was 90-day mortality. Secondary endpoints were index admission mortality, postoperative complications, and 30-day readmission rates. RESULTS: In total, 235 octogenarians (median age 81 (range 80-90) years) and 235 controls (age 67 (31-79) years) were included in the study. Eastern Cooperative Oncology Group performance status (median 0 (range 0-3) versus 0 (0-2); P = 0.010) and Charlson Co-morbidity Index score (7 (6-11) versus 5 (2-9); P = 0.001) were higher for octogenarians than controls. Postoperative complication and 30-day readmission rates were comparable. The 90-day mortality rate was higher among octogenarians (9 versus 3 per cent; P = 0.030). Index admission mortality rates were comparable (4 versus 2 per cent; P = 0.160), indicating that the difference in mortality was related to deaths after hospital discharge. Despite the higher 90-day mortality rate in the octogenarian population, multivariable Cox regression analysis did not identify age as an independent predictor of postoperative mortality. CONCLUSION: Despite careful patient selection and comparable index admission mortality, 90-day and, particularly, out-of-hospital mortality rates were higher in octogenarians.

The Impact of 68Gallium DOTA PET/CT in Managing Patients With Sporadic and Familial Pancreatic Neuroendocrine Tumours.

Objective: Pancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of 68Gallium (68Ga)-DOTA PET/CT in managing patients with panNETs. Design: A retrospective study conducted across three tertiary UK NET referral centres. Methods: Demographic, clinical, biochemical, cross-sectional and functional imaging data were collected from patients who had undergone a 68Ga-DOTA PET/CT scan for a suspected panNET. Results: We collected data for 183 patients (97 male): median (SD) age 63 (14.9) years, 89.1 vs. 9.3% (n=163 vs. 17) alive vs. dead (3 data missing), 141 sporadic vs. 42 familial (MEN1, n=36; 85.7%) panNETs. Non-functional vs. functional tumours comprised 73.2 vs. 21.3% (n=134 vs. 39) (10 missing). Histological confirmation was available in 89% of individuals (n=163) but tumour grading (Ki67 classiifcation) was technically possible only in a smaller cohort (n=143): grade 1, 50.3% (n=72); grade 2, 46.2% (n=66) and grade 3, 3.5% (n=5) (40 histopathological classification either not technically feasible or biopsy not perfomed). 60.1% (n=110) were localised, 14.2% (n=26) locally advanced and 23.5% (n=43) metastatic (4 missing). 224 68Ga-DOTA PET/CT scans were performed in total for: diagnosis/staging 40% (n=88), post-operative assessment/clinical surveillance 53% (n=117) and consideration of peptide receptor radionuclide therapy (PRRT) 8% (n=17) (2 missing). PET/CT results confirmed other imaging findings (53%), identified new disease sites (28.5%) and excluded suspected disease (5%). Overall, 68Ga-DOTA PET/CT imaging findings provided additional information in 119 (54%) patients and influenced management in 85 (39%) cases. Conclusion: 68Ga-DOTA PET/CT imaging more accurately stages and guides treatment in patients with sporadic/familial panNETs with newly diagnosed/recurrent disease.

The effect of prophylactic surgery in survival and HRQoL in appendiceal NEN.

BACKGROUND/AIMS: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL). METHODS: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC. HRQoL EORTC-QLC-C30 questionnaires and cross-sectional imaging data were prospectively collected. Age- and sex-matched healthy controls were recruited for HRQoL analysis' validation. RESULTS: We included 166 patients (119 women [71.2%]: mean age at baseline: 31 ± 16 years). Mean follow-up was 50.9 ± 54 months. Most patients (152 [92%]) had tumors ≤20 mm in size. Fifty-eight patients (34.9%) underwent pRHC that in final analysis was regarded as an overtreatment in 38/58 (65.5%). In multivariable analysis, tumor size >20 mm was the only independent predictor for lymph node (LN) involvement (p = 0.002). No mortality was reported, whereas 2-, 5- and 10-year recurrence-free survival in patients subjected to postoperative cross-sectional imaging (n = 136) was 98.5%, 97.8%, and 97.8%, respectively. Global HRQoL was not significantly impaired in patients with WD-ANEN compared with age- and sex-matched healthy individuals (median scores 0.83[0.08-1] vs 0.83[0.4-1], respectively; p = 0.929). Among patients with WD-ANEN impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group. CONCLUSIONS: WD-ANEN is a low-malignant neoplasm with unconfirmed associated mortality, low recurrence rate, and overall preserved HRQoL. pRHC comes at a price of excessive surgery, functional HRQoL issues, and diarrhea. The value per se of a prophylactic surgical approach to patients with WD-ANENs <20 mm is challenged.

ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry.

BACKGROUND: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM. METHODS: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM. RESULTS: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively. CONCLUSIONS: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution.

The prognosis and management of neuroendocrine neoplasms-related metastatic bone disease: lessons from clinical practice.

PURPOSE: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). METHODS: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. RESULTS: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months. CONCLUSIONS: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance.

BACKGROUND/AIMS: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. METHODS: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. RESULTS: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p < 0.0001). CONCLUSION: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

Irreversible electroporation for the treatment of pancreatic neuroendocrine tumors.

BACKGROUNDS/AIMS: Resection or enucleation is currently the treatment of choice for small pancreatic neuroendocrine tumors (NETs). Irreversible electroporation is a novel ablative method that is used for locally advanced pancreatic adenocarcinoma, but little data exists for its use for pancreatic NETs. We report an early experience of IRE for early pancreatic NETs. METHODS: Between April 2014 and March 2015, 3 patients with small (<2 cm) pancreatic NETs were treated with percutaneous IRE. RESULTS: There were no adverse effects during the procedure. Mean hospital stay was 2.6 days. All patients remained disease free on 12-19 months follow up. One patient developed recurrent pancreatitis with pseudocyst formation. CONCLUSIONS: IRE for small tumors of the pancreas is practical and may offer advantages over other thermal ablative techniques, since it preserves vital structures such as blood vessels, bile and pancreatic ducts. Further data regarding the long term disease free interval is required to establish efficacy.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure for hepatocellular carcinoma with chronic liver disease: a case report and review of literature.

The incidence of complications after liver resection is closely related to functional future liver remnant (FLR). The standard approach to augment FLR is surgical or radiological occlusion of the artery or portal vein on the tumor side. Associated liver partition and portal vein ligation for staged hepatectomy (ALLPS) has been introduced as an alternative method to augment FLR. It offers rapid and effective hypertrophy for resecting liver metastases. However, data regarding its application in patients with hepatocellular carcinoma (HCC) with a background of chronic liver disease are limited. Here we describe the use of ALPPS procedure to manage a large solitary HCC with a background of chronic liver disease. The rising incidence of HCC has increased the number of surgical resections in patients with advanced stage liver disease not considered for liver transplantation. We reviewed reported experience of ALPPS in established chronic liver disease and current therapeutic modalities for HCC on a background of chronic liver disease in patients with potential liver insufficiency where tumor burden is beyond liver transplant criteria.