Evaluation of treatment delays in hepatopancreatico-biliary surgery during the first COVID-19 wave.

INTRODUCTION: The COVID-19 pandemic has caused oncological services worldwide to face unprecedented challenges resulting in treatment disruption for surgical patients. Hepatopancreatico-biliary (HPB) cancers are characterised by rapid disease progression. This study aims to assess delays in receiving surgery for this patient cohort during the first COVID-19 wave. METHODS: Patients undergoing surgery between April and July 2020 (COVID-19 period) were compared with a control group from the preceding year. Delay in receiving surgery was defined as more than 50 days between referral and surgery date. Statistical analysis was carried out to evaluate predictors of delay and short-term outcomes. RESULTS: During the COVID-19 and pre-COVID-19 periods, 94 and 115 patients underwent surgery, respectively. No patients contracted COVID-19 postoperatively. Some 118 patients waited more than 50 days for surgery versus 91 who received surgery within 50 days from referral. Independent predictors for surgical delay were undergoing surgery in the COVID-19 era (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.2-4.1; p=0.015), referral pathway (OR 35.1, 95% CI 4.2-296; p=0.001) and presenting pathology (OR 8.3, 95% CI 1.2-56.1; p=0.03). Short-term outcomes were comparable between groups. CONCLUSIONS: Patient referral pathway and presenting pathology may contribute to delays in undergoing HPB cancer surgery during COVID-19 outbreaks. It is hoped that a better understanding of these factors will aid in designing shifts in healthcare policy during future pandemic outbreaks.

Evaluating cost-effectiveness in the management of neuroendocrine neoplasms.

The rapid evolution of novel, costly therapies for neuroendocrine neoplasia (NEN) warrants formal high-quality cost-effectiveness evaluation. Costs of individual investigations and therapies are high; and examples are presented. We aimed to review the last ten years of standalone health economic evaluations in NEN. Comparing to published standards, EMBASE, Cochrane library, Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database and the Health Technology Assessment (HTA) Database were searched for health economic evaluations (HEEs) in NEN published between 2010 and October 2019. Of 12 economic evaluations, 11 considered exclusively pharmacological treatment (3 studies of SSAs, 7 studies of sunitinib, everolimus and/or 177Lu-DOTATATE and 1 study of telotristat ethyl) and 1 compared surgery with intraarterial therapy. 7 studies of pharmacological treatment had placebo or best supportive care as the only comparator. There remains a paucity of economic evaluations in NEN with the majority industry funded. Most HEEs reviewed did not meet published health economic criteria used to assess quality. Lack of cost data collected from patient populations remains a significant factor in HEEs where clinical expert opinion is still often substituted. Further research utilizing high-quality effectiveness data and rigorous applied health economic analysis is needed.

Timing of peptide receptor radiotargeted therapy in relation to cardiac valve surgery for carcinoid heart disease in patients with neuroendocrine metastases and cardiac syndrome. A single-centre study from a centre of excellence.

INTRODUCTION: Perioperative mortality of patients who undergo heart valve surgery for carcinoid heart valve disease has been observed to be high (5%-10%). We investigated whether peptide receptor radiotherapy with lutetium-177 dotatate can be used safely in patients with neuroendocrine neoplasm carcinoid heart valve disease and if there is associated survival advantage by reducing overall exposure of the valves to high doses of vasoactive peptides. METHOD: Retrospective case notes review was performed on 18 neuroendocrine neoplasm patients (mean 60 years), who underwent heart valve surgery between 2003 and 2017 for carcinoid heart valve disease, 9 of whom received peptide receptor radiotherapy in addition to surgery. RESULTS: All patients were treated with somatostatin receptor antagonists and underwent cardiac valvular surgery (mean two valves replaced) and three benefitted from additional coronary bypass grafting. Nine patients underwent surgery alone: in this group, the time from surgery to progression was 14 months (mean; SD 13.5 months). Nine were treated with peptide receptor radiotherapy in addition to surgery. Six underwent surgery with peptide receptor radiotherapy on progression. Time to progression from surgery to first peptide receptor radiotherapy was mean 25.1 months (SD 23.6 months). No patients developed peritreatment cardiac complications. There were no deaths within the 30-day postoperative period. Average time from surgery to last follow-up/death was 41 months (6-79) in the surgery + lutetium group and in the surgery only group 17 months (1-24). Nine patients died, five in the surgery + lutetium group and four in the surgery only group, all at greater than 1-year postsurgery. DISCUSSION: Peptide receptor radiotherapy is safe in the setting of Carcinoid valvular heart disease in patients with controlled heart failure, PPRT can be use in the pre- and post-valve surgery period. There appears to be a survival benefit of having peptide receptor radiotherapy. Further evidence for peptide receptor radiotherapy in the neoadjuvant setting prior to cardiothoracic surgery is required.

Ileocolonic neuroendocrine tumours identified in the English bowel cancer screening programme.

AIM: Ileocolonic neuroendocrine tumours (NETs) are diagnosed as part of bowel cancer screening programmes (BCSPs). The aim of this study was to identify and characterize NETs diagnosed within the English BCSP, a double-screen programme that uses guaic faecal occult blood test (gFOBT) screening and colonoscopy, by interrogating the national colorectal screening database and validating the findings with individual BCSP centres. METHOD: The Exeter database was interrogated by running queries to identify participants with coded NETs (from the start of the programme in July 2006 - 1 December 2014). A written proforma was sent to the responsible BCSP clinician for validation and characterization. RESULTS: During this period, 13 061 716 participants were adequately screened using gFOBTs, and 259 765 participants had definitively abnormal results. There were 146 unique participants with NET-related codes from 216 707 BCSP colonoscopies. The diagnosis rates per 100 000 colonoscopies were 29 rectal, 18 colonic and 11 ileal NETs. The majority of rectal NETs had Grade 1 (80%) and Stage T1 (85.1%) disease. Over half of ileal NETs (53.6%) in this study had invasive disease, with 85.2% having nodal and 36.1% having metastastatic disease. CONCLUSION: The current study highlights the rate of colorectal NETs diagnosed in the English BCSP. These data highlight a higher-than-anticipated incidence, and the potential additional benefit of BCSPs in identifying occult NETs.

Review article: the investigation and management of rectal neuroendocrine tumours.

BACKGROUND: Rectal neuroendocrine tumours (NETs) are increasingly identified at endoscopy possibly as a result of bowel cancer screening programmes. AIM: To present a review of the literature to aid clinicians in the diagnosis and management of rectal neuroendocrine tumours. METHODS: A literature search was conducted through MEDLINE using search terms: rectal, rectum, carcinoid, NET, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review with reference lists reviewed for additional articles. RESULTS: The incidence of rectal neuroendocrine tumours is approximately 1 per 100 000 population per year with the majority (80-90%) being <1 cm and localised to the submucosa. Metastatic disease is infrequent (<20%) with risk factors including size, atypical appearance, grade and depth of invasion. The primary resection modality influences complete resection rates and the need for secondary therapy. A thorough pre-resection diagnostic work up is required for lesions that are at higher risk of invasion and metastasis. Device-assisted endoscopic mucosal resection and endoscopic submucosal dissection are used to resect localised rectal neuroendocrine tumours <2 cm. Transanal surgery is also used to resect localised 1-2 cm rectal neuroendocrine tumours. Oncological surgical resection is used for rectal neuroendocrine tumours that are >2 cm or with invasion and regional disease. The treatment of advanced disease is multimodal. CONCLUSIONS: The long-term tumour biology of small rectal neuroendocrine tumours remains unclear. There is uncertain impact from bowel cancer screening programmes on rectal neuroendocrine tumour incidence, morbidity and mortality. Referral to neuroendocrine tumour centres for patients with locally advanced disease or metastatic disease is recommended.

Review article: the investigation and management of gastric neuroendocrine tumours.

BACKGROUND: Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6-2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007. AIM: To review the literature and assist clinicians in managing patients with GCs. METHODS: A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. RESULTS: There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal. CONCLUSIONS: Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research.

Lymphogranuloma venereum proctitis masquerading as inflammatory bowel disease in 12 homosexual men.

BACKGROUND: Lymphogranuloma venereum (LGV) is a recognized cause of proctitis. Symptoms, endoscopy and histology findings are similar in IBD and LGV proctitis. AIMS: To characterize the clinical, endoscopic and histological features seen in men diagnosed initially with IBD and subsequently with LGV proctitis, and to attempt isolation of Chlamydia trachomatis DNA from the stored rectal biopsy specimens of these patients using real-time PCR. METHODS: Clinical data were collated from confirmed or suspected cases of LGV proctitis where endoscopy and biopsy had been performed as part of the investigation of clinical symptoms. LGV was confirmed by the detection of LGV-specific DNA from rectal swab specimens, with supportive evidence from Chlamydial serology. Stored histological specimens from rectal biopsies were analysed retrospectively for LGV-specific DNA with molecular techniques. RESULTS: Rectal biopsies had been obtained from twelve cases of LGV proctitis. Mucosal ulcers, cryptitis, crypt abscesses and granulomas were common histological findings. Extraction of LGV-specific DNA from rectal biopsy specimens enabled confirmation of three suspected cases. CONCLUSIONS: During the recent LGV proctitis epidemic among UK men who have sex with men, it has become apparent that this infection may closely resemble IBD. Gastroenterologists should remain alert to LGV as a cause of proctitis in this group.

The Glasgow Blatchford scoring system enables accurate risk stratification of patients with upper gastrointestinal haemorrhage.

BACKGROUND: Upper gastrointestinal (UGI) haemorrhage is a frequent cause of hospital admission. Scoring systems have been devised to identify those at risk of adverse outcomes. We evaluated the Glasgow Blatchford score's (GBS) ability to identify the need for clinical and endoscopic intervention in patients with UGI haemorrhage. METHODS: A retrospective observational study was performed in all patients who attended the A&E department with UGI haemorrhage during a 12-month period. Patients were separated into low and high risk categories. High risk encompassed patients who required blood transfusions, operative or endoscopic interventions, management on high dependency or intensive care units, and those who re-bled, represented with further bleeding, or who died. RESULTS: A total of 174 patients were seen with UGI bleeding. Eight of them self-discharged and were excluded. Of the remaining 166, 94 had a 'low risk' bleed, and 72 'high risk'. The GBS was significantly higher in the high risk (median = 10) than in the low risk group (median 1, p < 0.001). To assess the validity of the GBS at separating low and high risk groups, receiver-operator characteristic (ROC) curves were plotted. The GBS had an area under ROC curve of 0.96 (95% CI 0.95-1.00). When a cut-off value of > or = 3 was used, sensitivity and specificity of GBS for identifying high risk bleeds was 100% and 68%. Thus at a cut-off value of < or = 2 the GBS is useful for distinguishing those patients with a low risk UGI bleed. CONCLUSIONS: The GBS accurately identifies low risk patients who could be managed safely as outpatients.

Long-term results of patients with malignant carcinoid syndrome receiving octreotide LAR.

BACKGROUND: Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. AIM: To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome. METHODS: A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria. RESULTS: Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted. CONCLUSIONS: Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.

Circulating angiopoietin-2 is elevated in patients with neuroendocrine tumours and correlates with disease burden and prognosis.

Angiogenesis is an essential process in the development and growth of tumours. There are a large number of angiogenic mediators including the angiopoietin (Ang) family and vascular endothelial growth factor, which play an important role in both physiological and pathological angiogenesis. This study examines serum levels of Ang-1 and Ang-2 in patients with neuroendocrine tumour (NET) compared healthy controls. ELISA for Ang-1 and Ang-2 was performed in 47 patients with histologically proven NETs and 44 healthy controls. Immunohistochemical staining for Ang-2 was performed in patients to demonstrate cellular location of Ang-2. Serum Ang-2 levels were significantly elevated in patients compared controls (median 4756 vs 2495 pg/ml, P<0.001), while there was no significant difference in Ang-1 levels. The ratio of Ang-2:Ang-1 was significantly elevated in patients compared controls (0.13 vs 0.066, P<0.001). Serum Ang-2 levels were significantly elevated in patients with distant metastases compared with those without metastasis (median 5080 vs 3360 pg/ml, P=0.01). There was also a significant increase between Ang-2 levels and volume of liver metastases (P=0.014). Time to disease progression was worse in patients with serum Ang-2 levels >4756 pg/ml (P=0.04). Serum Ang-2 but not Ang-1 is elevated in NET patients. Ang-2 may be a useful serum marker for monitoring and assessment of prognosis in patients with NETs.

Review article: future therapies for management of metastatic gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are relatively uncommon tumours that occur anywhere within the gastrointestinal tract. The prevalence of GEP NETs is estimated to be 35 per 100 000 population. Patients often present with metastatic disease and consequently, palliative treatments form the mainstay of therapy. AIM: To review the current and novel therapeutic options for management of GEP NETs. METHODS: Searches for all studies related to GEP NETs, NETs and carcinoid tumours in Medline and abstracts from international meetings. RESULTS: Somatostatin analogues remain the first line therapy for management of symptoms of GEP NETs and may have anti-proliferative action. New somatostatin analogues with different somatostatin receptor affinity have been developed. Radionuclide peptide receptor therapy is established in patients with positive somatostatin scintigraphy. A number of new agents and targeted therapies are currently being evaluated in a phase I and II studies and these include angiogenic inhibitors, mammalian target of rapamycin inhibitors and immune therapies. CONCLUSIONS: A number of nonsurgical therapies are available for management of gastroenteropancreatic neuroendocrine tumours. It is hoped, the development of some of these promising novel therapies will expand the therapeutic armamentarium.

Expression of somatostatin and dopamine 2 receptors in neuroendocrine tumours and the potential role for new biotherapies.

INTRODUCTION: Somatostatin and dopamine receptors are both G-protein-coupled receptors. Somatostatin receptor (SSTR) expression in neuroendocrine tumours has been well characterised, and there is evidence of dopamine receptor expression in neuroendocrine tumours. In this study, we examined expression of D2R, SSTR-2 and SSTR-5 using immunohistochemistry in patients with neuroendocrine tumours. METHODS: Consecutive samples of formalin-fixed paraffin-embedded tumour tissue were available from 56 patients with a histologically confirmed diagnosis of neuroendocrine tumour (NET). The study population was divided into low-grade (n = 29), intermediate-grade (n = 18) and high-grade NET (n = 9). Immunohistochemical evaluation was performed for the expression of SSTR-2a, SSTR-5 and D2 receptors (D2R). RESULTS: Both SSTR-2 and SSTR-5 were expressed in 100% of low-grade, 94.4% of intermediate-grade and 66.7% of high-grade NET. D2R was expressed in 93.1% of low-grade, 77.8% of intermediate-grade and 44.4% of high-grade tumours. Co-expression of all 3 receptors was present in 93.1% of low-grade tumours. There was an inverse correlation of SSTR-2 (r = -0.380, p < 0.005) and SSTR-5 (r = -0.472, p < 0.0001) with tumour grade. D2R was positively correlated with SSTR-2 (r = 0.269, p = 0.041) and SSTR-5 (r = 0.267, p = 0.045). Also, D2R expression was inversely correlated with grade of tumour (r = 0.395, p = 0.006). Octreoscan correlated with SSTR-2, SSTR-5 and D2R expression. CONCLUSION: D2R is expressed in the majority of low and intermediate grade tumours. It is co-expressed with SSTR-2 and SSTR-5 in the majority of cases. The advent of new chimeric molecules that bind both somatostatin and dopamine receptors may provide a new therapeutic option in the management of neuroendocrine patients.

Surgical management and palliative treatment in bronchial neuroendocrine tumours: a clinical study of 45 patients.

Bronchial neuroendocrine tumours account for 1-2% of all lung cancers; they are thought to arise from the neuroendocrine cells located in the bronchial mucosa. The majority of the literature available comprises surgical series and there is a scarcity of data available for the management of patients with inoperable disease. We present a series of 45 patients referred to our institution from 1998 to 2006, with a mean follow-up of 54 months. Histological diagnosis from our department was available for 39 patients, with the remainder having had histological assessment performed previously. Typical carcinoid was present in 25 cases, atypical in 9 cases, large cell neuroendocrine carcinoma in 4 and 1 case of small cell lung carcinoma. All patients were staged at time of initial diagnosis with CT scan, in addition Octreoscans were performed when appropriate. Twenty-six of these 45 cases had unresectable disease, whilst the remainder were treated with surgical resection. Initial therapy with surgical resection was performed in 19 patients, 2 of whom had undergone neo-adjuvant chemotherapy. Recurrence occurred in 7 (36.8%), average duration of disease-free survival post-surgery was 61 months. Chemotherapy was first line therapy in five cases, four achieved disease stabilization and one case had progressive disease. Somatostatin analogues were used as first line therapy in six patients, for symptom control and anti-tumour effect. Peptide receptor radionuclide therapy, with Yttrium-90 DOTA-Octreotate, was given in two cases, both of whom achieved disease stabilization for 9-12 months respectively. There was a significant difference between Stage 4 and Stage 1 disease at presentation and survival. In conclusion curative surgical resection is treatment of choice, however, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy offers palliation improving both symptoms and mortality.

Alpha-fetoprotein and human chorionic gonadotrophin-beta as prognostic markers in neuroendocrine tumour patients.

Serum chromogranin A is the most useful general and prognostic tumour marker available for neuroendocrine tumour (NET) patients. The role of other tumour markers is less clear. In order to determine the diagnostic and prognostic value of serum alpha-fetoprotein (AFP) and human chorionic gonadotrophin-beta (hCGbeta) in NETs, a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using Statistical Package for the Social Sciences, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCGbeta. Alpha-fetoprotein and hCGbeta were raised in 9.5 and 12.3% of patients respectively and jointly raised in 9.1% of patients in whom it was measured. Alpha-fetoprotein levels associated strongly and positively with tumour grade, serum CgA and hCGbeta levels, and worse survival. Human chorionic gonadotrophin-beta levels also associated strongly and positively with serum CgA and AFP levels, and worsening survival. Alpha-fetoprotein and hCGbeta are elevated in high-grade NETs, with a rapidly progressive course and poorer survival. They also correlate with chromogranin-A, which is known to be a marker of tumour burden and to have prognostic value. Thus AFP and hCGbeta are clinically important in NETs and when elevated are poor prognostic markers.

A review of thymic tumours.

Tumours of the thymus are uncommon and are generally regarded as being indolent. Whilst this is often true of thymomas; thymic adenocarcinoma and thymic neuroendocrine cancer can be aggressive and have a poor prognosis. Understanding the biology of these tumours is important for prognosis and management. The pathological features of these tumours are examined in detail. Imaging modalities for aiding in diagnosis and staging of these tumours are described; this includes CT and MRI, plus more recent advances including the use of FDG-PET and Indium-111 Octreotide scintigraphy. The treatment options available including curative surgery, debulking surgery, chemotherapy, somatostatin analogues and peptide receptor radionuclide therapy are discussed. The optimal chemotherapy regimens are still unclear, although promising results have been obtained with platinum-based chemotherapy. The role for adjuvant therapy in both thymic carcinoma and thymoma is unclear except, in patients with stage I thymomas. There is a high expression of somatostatin receptors in thymic tumours and anti-tumour benefit has been reported in patients treated with somatostatin analogues. A new development is the role of peptide receptor radionuclide therapy. This has become an established therapy in management of gastroenteropancreatic neuroendocrine tumours and its use has been recently described in case reports in both thymoma and thymic carcinoma.