Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

BACKGROUND: The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. PATIENTS AND METHODS: A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. RESULTS: Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. CONCLUSIONS: Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.

GEP-NET radiomics: a systematic review and radiomics quality score assessment.

OBJECTIVE: The number of radiomics studies in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is rapidly increasing. This systematic review aims to provide an overview of the available evidence of radiomics for clinical outcome measures in GEP-NETs, to understand which applications hold the most promise and which areas lack evidence. METHODS: PubMed, Embase, and Wiley/Cochrane Library databases were searched and a forward and backward reference check of the identified studies was executed. Inclusion criteria were (1) patients with GEP-NETs and (2) radiomics analysis on CT, MRI or PET. Two reviewers independently agreed on eligibility and assessed methodological quality with the radiomics quality score (RQS) and extracted outcome data. RESULTS: In total, 1364 unique studies were identified and 45 were included for analysis. Most studies focused on GEP-NET grade and differential diagnosis of GEP-NETs from other neoplasms, while only a minority analysed treatment response or long-term outcomes. Several studies were able to predict tumour grade or to differentiate GEP-NETs from other lesions with a good performance (AUCs 0.74-0.96 and AUCs 0.80-0.99, respectively). Only one study developed a model to predict recurrence in pancreas NETs (AUC 0.77). The included studies reached a mean RQS of 18%. CONCLUSION: Although radiomics for GEP-NETs is still a relatively new area, some promising models have been developed. Future research should focus on developing robust models for clinically relevant aims such as prediction of response or long-term outcome in GEP-NET, since evidence for these aims is still scarce. KEY POINTS: • The majority of radiomics studies in gastroenteropancreatic neuroendocrine tumours is of low quality. • Most evidence for radiomics is available for the identification of tumour grade or differentiation of gastroenteropancreatic neuroendocrine tumours from other neoplasms. • Radiomics for the prediction of response or long-term outcome in gastroenteropancreatic neuroendocrine tumours warrants further research.

Real-world comparison of healthcare resource utilization and costs of [177Lu]Lu-DOTA-TATE in patients with progressive neuroendocrine tumors in England: a matched cohort analysis using data from the hospital episode statistics dataset.

OBJECTIVE: To explore the healthcare resource utilization (HCRU) and costs for patients with progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with [177Lu]Lu-DOTA-TATE and matched patients treated with somatostatin analogs (SSAs), chemotherapy, or targeted therapies. METHODS: Hospital Episode Statistics (HES) dataset 2016-2018 was used to compare HCRU and costs between the two cohorts. The [177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET, a procedure code for imaging or SSAs, and a subsequent code for radionuclide therapy. The non-[177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET who had an increased frequency of SSAs or switched from SSAs to chemotherapy or targeted therapies. Cohorts were matched on propensity scores with sex, age at disease progression, and Charlson Comorbidity Index as parameters. Healthcare Resource Group codes were used for costing. RESULTS: A total of 199 matched patients were included. The [177Lu]Lu-DOTA-TATE cohort had lower overall costs (£1,882,028 vs. £3,016,321; p < .0001), non-elective inpatient spells (289 vs. 611 days) and costs (£849,569 vs. £1,707,109; p < .0001 for both), Accident & Emergency costs (£41,978 vs. £62,480; p = .0013), and average length of stay for overall inpatient spells (14.2 vs. 23.3 days; p = .1092) compared with the non-[177Lu]Lu-DOTA-TATE cohort. CONCLUSIONS: These analyses indicate significantly lower overall costs and HCRU for progressive GEP-NET patients treated with [177Lu]Lu-DOTA-TATE. Current research reveals that future real-world analyses would further benefit from using additional databases linked to the HES dataset such as the Clinical Practice Research Datalink and/or National Cancer Registration and Analysis Service database.

Neuroendocrine neoplasms (NENs) are uncommon cancers involving the body's neuroendocrine cells. One type of NEN that is less aggressive with more favorable characteristics and prognosis is known as neuroendocrine tumor (NET). Somatostatin receptors (SSTR) are expressed by most NETs and are important treatment targets. Two-thirds of NETs originate in the body's gastroenteropancreatic system (GEP-NETs). GEP-NET is typically treated in the first instance with somatostatin analogs (SSAs), while other treatments such as chemotherapy, biologic targeted therapy, or Radio Ligand Therapy (RLT), can be offered to patients who have progressed. [¹⁷⁷Lu]Lu-DOTA-TATE is a form of RLT that has recently been approved for use in England, Wales, and Scotland.The purpose of this study is to analyze the utilization of healthcare resources and the costs associated with the management of GEP-NETs patients who have progressed on SSAs. This study is based on hospital data from England as available in the Hospital Episode Statistics dataset 2016­2018.The utilization and costs of healthcare resources were compared between two groups of patients. Following progression, one group received [¹⁷⁷Lu]Lu-DOTA-TATE, while the other group received other therapies (chemotherapy, biologic targeted therapy, or SSA with escalated or more frequent dosing). Statistical techniques were applied to enhance the comparability of analyzed groups of patients.The results revealed that the [¹⁷⁷Lu]Lu-DOTA-TATE group had lower inpatient admissions, outpatient appointments, and Accident & Emergency attendances compared with the non-[¹⁷⁷Lu]Lu-DOTA-TATE group. Furthermore, the overall costs in the [¹⁷⁷Lu]Lu-DOTA-TATE group were lower by 37.6%. This study indicated that patients and hospitals in England and other parts of the United Kingdom may benefit from the use of [¹⁷⁷Lu]Lu-DOTA-TATE. Further research is foreseen involving additional and linked databases, including further clinical outcomes as well.

Survival of Patients With Gastroenteropancreatic Neuroendocrine Tumors and Diabetes Mellitus.

OBJECTIVES: Diabetes mellitus (DM) is associated with an increased risk of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the association between DM and GEP-NET survival is unknown. We evaluated disease characteristics and survival in individuals with DM and GEP-NETs. METHODS: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare (SEER-Medicare) claims database, we examined sociodemographics, GEP-NET characteristics, and treatment in patients with and without DM before GEP-NET diagnosis. We compared survival using univariate and multivariate analyses. RESULTS: We identified 1858 individuals with GEP-NETs: 478 (25.7%) with DM and 1380 (74.3%) without. Significant differences in race (P = 0.002) were found between the DM and non-DM groups. Compared with individuals without DM, those with DM had more gastric (9.7% vs 14.9%), duodenal (6.5% vs 10.0%), and pancreatic (17.0% vs 21.8%), and less jejunal/ileal (18.1% vs 12.8%) NETs (P < 0.0001). Patients with DM had earlier stages (stage I, 37.0%; stage IV, 30.8%) than those without (stage I, 30.6%; stage IV, 36.4%; P = 0.0012). We found no difference in survival (multivariate hazard ratio, 0.97; 95% confidence interval, 0.76-1.23) between groups. CONCLUSIONS: Among patients with and without DM before GEP-NET diagnosis, we found differences in tumor location and stage, but not survival.

Insurance-based Disparities in Gastro-Entero-Pancreatic Neuroendocrine Tumor Patients.

In the United States, uninsurance remains a major barrier in accessing health care for many citizens and residents. Studies have shown that uninsured patients with many cancers and chronic diseases have worse survival than insured patients. A recent study similarly showed that uninsured patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) have significantly shortened survival. While GEP-NETs are indolent tumors with generally favorable prognosis, comprehensive care involves years of surveillance, imaging, and treatment following resection, all of which carry a large financial burden. In this commentary, we expand on these findings as they relate to insurance-based disparities as well as management and policy implications.

Socioeconomic disparities in cancer incidence and mortality in England and the impact of age-at-diagnosis on cancer mortality.

BACKGROUND: We identify socioeconomic disparities by region in cancer morbidity and mortality in England for all-cancer and type-specific cancers, and use incidence data to quantify the impact of cancer diagnosis delays on cancer deaths between 2001-2016. METHODS AND FINDINGS: We obtain population cancer morbidity and mortality rates at various age, year, gender, deprivation, and region levels based on a Bayesian approach. A significant increase in type-specific cancer deaths, which can also vary among regions, is shown as a result of delay in cancer diagnoses. Our analysis suggests increase of 7.75% (7.42% to 8.25%) in female lung cancer mortality in London, as an impact of 12-month delay in cancer diagnosis, and a 3.39% (3.29% to 3.48%) increase in male lung cancer mortality across all regions. The same delay can cause a 23.56% (23.09% to 24.30%) increase in male bowel cancer mortality. Furthermore, for all-cancer mortality, the highest increase in deprivation gap happened in the East Midlands, from 199 (186 to 212) in 2001, to 239 (224 to 252) in 2016 for males, and from 114 (107 to 121) to 163 (155 to 171) for females. Also, for female lung cancer, the deprivation gap has widened with the highest change in the North West, e.g. for incidence from 180 (172 to 188) to 272 (261 to 282), whereas it has narrowed for prostate cancer incidence with the biggest reduction in the South West from 165 (139 to 190) in 2001 to 95 (72 to 117) in 2016. CONCLUSIONS: The analysis reveals considerable disparities in all-cancer and some type-specific cancers with respect to socioeconomic status. Furthermore, a significant increase in cancer deaths is shown as a result of delays in cancer diagnoses which can be linked to concerns about the effect of delay in cancer screening and diagnosis during the COVID-19 pandemic. Public health interventions at regional and deprivation level can contribute to prevention of cancer deaths.

Initiation of Somatostatin analogues for neuroendocrine tumor patients: a cost-effectiveness analysis.

BACKGROUND & AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known. METHODS: A decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty. RESULTS: Our model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY. CONCLUSIONS: Our modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.

Colonic Strictures in Inflammatory Bowel Disease: Epidemiology, Complications, and Management.

The management of colorectal stricture complicating inflammatory bowel disease [IBD] remains a challenging condition. Stricture raises concern about neoplastic complications, which cannot be fully ruled out by negative endoscopic biopsies. Also, impassable strictures restrict the endoscopic monitoring of upstream disease activity and dysplasia. Surgery remains the 'gold standard' treatment for colonic strictures but is associated with high morbidity. Over the past few decades, our therapeutic arsenal for IBD has been reinforced by biologics and therapeutic endoscopy. Few studies have focused on colonic strictures, and so current therapeutic strategies are based on a low level of evidence and applied by analogy with the treatment of ileal strictures. With a view to facilitating the decision making process in clinical practice, we reviewed the literature on the epidemiology, natural history, and management of colonic strictures in IBD.

Ki-67 Proliferation Index Assessment in Gastroenteropancreatic Neuroendocrine Tumors by Digital Image Analysis With Stringent Case and Hotspot Level Concordance Requirements.

OBJECTIVES: The Ki-67 proliferation index is integral to gastroenteropancreatic neuroendocrine tumor (GEP-NET) assessment. Automated Ki-67 measurement would aid clinical workflows, but adoption has lagged owing to concerns of nonequivalency. We sought to address this concern by comparing 2 digital image analysis (DIA) platforms to manual counting with same-case/different-hotspot and same-hotspot/different-methodology concordance assessment. METHODS: We assembled a cohort of GEP-NETs (n = 20) from 16 patients. Two sets of Ki-67 hotspots were manually counted by three observers and by two DIA platforms, QuantCenter and HALO. Concordance between methods and observers was assessed using intraclass correlation coefficient (ICC) measures. For each comparison pair, the number of cases within ±0.2xKi-67 of its comparator was assessed. RESULTS: DIA Ki-67 showed excellent correlation with manual counting, and ICC was excellent in both within-hotspot and case-level assessments. In expert-vs-DIA, DIA-vs-DIA, or expert-vs-expert comparisons, the best-performing was DIA Ki-67 by QuantCenter, which showed 65% cases within ±0.2xKi-67 of manual counting. CONCLUSIONS: Ki-67 measurement by DIA is highly correlated with expert-assessed values. However, close concordance by strict criteria (>80% within ±0.2xKi-67) is not seen with DIA-vs-expert or expert-vs-expert comparisons. The results show analytic noninferiority and support widespread adoption of carefully optimized and validated DIA Ki-67.

Association between somatostatin analogues and diabetes mellitus in gastroenteropancreatic neuroendocrine tumor patients: A Surveillance, Epidemiology, and End Results-Medicare analysis of 5235 patients.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are increasingly common malignancies and tend to have favorable long-term prognoses. Somatostatin analogues (SSA) are a first-line treatment for many NETs. Short-term experiments suggest an association between SSAs and hyperglycemia. However, it is unknown whether there is a relationship between SSAs and clinically significant hyperglycemia causing development of diabetes mellitus (DM), a chronic condition with significant morbidity and mortality. AIM: In this study, we aimed to compare risk of developing DM in patients treated with SSA vs no SSA treatment. METHODS AND RESULTS: Using the Surveillance, Epidemiology, and End Results (SEER) database and linked Medicare claims (1991-2016), we identified patients age 65+ with no prior DM diagnosis and a GEP-NET in the stomach, small intestine, appendix, colon, rectum, or pancreas. We used χ2 tests to compare SSA-treated and SSA-untreated patients and multivariable Cox regression to assess risk factors for developing DM. Among 8464 GEP-NET patients, 5235 patients had no prior DM and were included for analysis. Of these, 784 (15%) patients received SSAs. In multivariable analysis, the hazard ratio of developing DM with SSA treatment was 1.19, which was not statistically significant (95% CI 0.95-1.49). Significant risk factors for DM included black race, Hispanic ethnicity, prior pancreatic surgery, prior chemotherapy, tumor size >2 cm, pancreas tumors, and higher Charlson scores. CONCLUSION: DM was very common in GEP-NET patients, affecting 53% of our cohort. Despite prior studies suggesting an association between SSAs and hyperglycemia, our analysis found similar risk of DM in SSA-treated and SSA-untreated GEP-NET patients. Further studies are needed to better understand this relationship. As NET patients have increasingly prolonged survival, it is crucial to identify chronic conditions such as DM that these patients may be at elevated risk for.

Lutetium oxodotreotide (177Lu-Dotatate) for the treatment of unresectable or metastatic progressive gastroenteropancreatic neuroendocrine tumors: a cost-effectiveness analysis for Scotland.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland. METHODS: Cost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes. RESULTS: For unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus. CONCLUSIONS: Cost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Resection of Primary Gastrointestinal Neuroendocrine Tumor Among Patients with Non-Resected Metastases Is Associated with Improved Survival: A SEER-Medicare Analysis.

BACKGROUND: The objective of this study was to analyze whether primary tumor resection (PTR) among patients with stage IV gastrointestinal neuroendocrine tumor (GI-NET) and unresected metastases was associated with improved outcomes. METHODS: Patients diagnosed with stage IV GI-NETs were identified in the linked SEER-Medicare database from 2004 to 2015. Overall survival (OS) of patients who did versus did not undergo PTR was examined using bivariate and multivariable cox regression analysis as well as propensity score matching (PSM). RESULTS: Among 2219 patients with metastatic GI-NETs, 632 (28.5%) underwent PTR, whereas 1587 (71.5%) did not. The majority of individuals had a NET in the pancreas (n = 969, 43.6%); the most common site of metastatic disease was the liver (n = 1064, 47.9%). Patients with stage IV small intestinal NETs most frequently underwent PTR (62.6%) followed by individuals with colon NETs (56.5%). After adjusting for all competing factors, PTR remained independently associated with improved OS (HR = 0.65, 95% CI: 0.56-0.76). Following PSM (n = 236 per group), patients who underwent PTR had improved OS (median OS: 1.3 years vs 0.8 years, p = 0.016). While PTR of NETs originating from stomach, small intestine, colon, and pancreas was associated with improved OS, PTR of rectal NET did not yield a survival benefit. CONCLUSION: Primary GI-NET resection was associated with a survival benefit among individuals presenting with metastatic GI-NET with unresected metastases. Resection of primary GI-NET among patients with stage IV disease and unresected metastases should only be performed in selected cases following multi-disciplinary evaluation.

Assessment of Mechanistic Data for Hexavalent Chromium-Induced Rodent Intestinal Cancer Using the Key Characteristics of Carcinogens.

Oral exposure to hexavalent chromium (Cr[VI]) induces intestinal tumors in mice. Mutagenic and nonmutagenic modes of action (MOAs) have been accepted by different regulatory bodies globally, the latter involving cytotoxicity-induced regenerative cell proliferation. However, concerns persist that all possible MOAs have not been fully considered. To address the potential for alternative MOAs, mechanistic data not represented in the existing two MOAs were evaluated. Relevant data were identified and organized by key characteristics of carcinogens (KCCs); literature related to epigenetics, immunosuppression, receptor-mediated effects, and immortalization were reviewed to identify potential key events associated with an alternative MOA. Over 200 references were screened for these four KCCs and further prioritized based on relevance to the research objective (ie, in vivo, oral exposure, gastrointestinal tissue). Minimal data were available specific to the intestine for these KCCs, and there was no evidence of any underlying mechanisms or key events that are not already represented in the two proposed MOAs. For example, while epigenetic dysregulation of DNA repair genes has been demonstrated, epigenetic effects were not measured in intestinal tissue, and it has been shown that Cr(VI) does not cause DNA damage in intestinal tissue. High-throughput screening data related to the KCCs were also evaluated, with activity generally limited to the two recognized MOAs. Collectively, no plausible alternative MOAs (or key events) were identified in addition to those previously proposed for Cr(VI) small intestine tumors.

Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection.

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Assessment of biomarkers influencing treatment success on small intestinal lymphoma in dogs.

This study aimed to determine a reliable therapeutic biomarker for localized small intestinal lymphoma (SIL) in dogs based on clinical and histopathological features. We retrospectively investigated 84 dogs with localized SIL, including 36 dogs receiving surgery and 48 dogs receiving chemotherapy. The dogs receiving surgery were divided into two subgroups: 18 dogs (group 1) with overall survival (OS) <120 days (median OS) and 18 dogs (group 2) with OS ≥120 days. Correspondingly, the dogs receiving chemotherapy were divided into 24 dogs (group 3) with OS <98 days (median OS) and 24 dogs (group 4) with OS ≥98 days. Clinical, haematological, histopathological and immunohistochemical analyses were comparatively evaluated among the four subgroups. There was no significant difference in OS between the surgery and chemotherapy groups. In dogs receiving surgery, the rate of Ki67-positive cells was significantly increased in group 1 compared to group 2 and showed no significant difference between groups 3 and 4. In dogs receiving chemotherapy, the rate of O6-methylguanine-DNA methyltransferase (MGMT) was significantly higher in group 3 than in group 4 and showed no significant difference between groups 1 and 2. Additionally, our data showed that OS in dogs with higher Ki67 expression might be significantly increased by chemotherapy than by surgery, that of those with higher MGMT expression might be significantly increased by surgery than by chemotherapy, and Ki67 and MGMT were independent of each other. Indices of Ki67 and MGMT are suggested therapeutic biomarkers to determine the optimal first-line treatment for localized SIL in dogs.

Clinical Assessment of 177Lu-DOTATATE Quantification by Comparison of SUV-Based Parameters Measured on Both Post-PRRT SPECT/CT and 68Ga-DOTATOC PET/CT in Patients With Neuroendocrine Tumors: A Feasibility Study.

PATIENTS AND METHODS: Patients with WD-GEP-NET who benefited from a pretherapeutic 68Ga-DOTATOC PET/CT and a 177Lu-DOTATATE SPECT/CT after the cycle 1 of peptide receptor radionuclide therapy were prospectively included. SPECT/CT acquisitions were performed on a system calibrated with a conversion factor of 9.48 counts/MBq per second and were reconstructed with an iterative algorithm allowing quantification using the SPECTRA Quant software (MIM Software, Cleveland, OH). For each patient, different SUV parameters were recorded on both PET/CT (Ga parameters) and SPECT/CT (Lu parameters) for comparison: physiological uptakes (liver/spleen), tumor uptake (1-10/patient; SUVmax, SUVmean, SUVpeak, MTV), tumor-to-liver and tumor-to-spleen ratios according to liver/spleen SUVmax and SUVmean (TLRmax, TLRmean, TSRmax, and TSRmean, respectively). RESULTS: Ten patients (8 female; 2 male) aged from 50 to 83 years presenting with a metastatic progressive WD-GEP-NET (7 small intestine, 2 pancreas, 1 rectum) were included. Median values of lesional Lu-SUV were significantly lower than the corresponding Ga-SUV (P < 0.001), whereas median values of lesional Lu-MTV, Lu-TLR, and Lu-TSR were significantly higher than the corresponding Ga-MTV, Ga-TLR, and Ga-TSR (P < 0.02). Pearson correlation coefficients were strong for both SUV and MTV parameters (0.779-0.845), weak for TLR parameters (0.365-0.394), and moderate-to-strong for TSR parameters (0.676-0.750). CONCLUSIONS: Our results suggest the feasibility of 177Lu-DOTATATE SPECT/CT quantification in clinical practice and show a strong correlation of several SUV-based parameters with the corresponding in 68Ga-DOTATOC PET/CT.

Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2.

PURPOSE: Small intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature. METHODS: A retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT). RESULTS: Baseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82-5.56 and HR 1.47, 95% CI 1.16-1.86) and PFS (HR 3.08, 95% CI 1.86-5.10 and HR 1.37, 95% CI 1.11-1.68) for SSA, but not for PRRT. CONCLUSIONS: Baseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.

Cost-effectiveness of Lutetium [177Lu] oxodotreotide versus best supportive care with octreotide in patients with midgut neuroendocrine tumors in France.

BACKGROUND AND AIMS: In France, there are approximately 2,400 new cases of neuroendocrine tumors (NETs) annually. Peptide receptor radionuclide therapy with 177Lu-Dotatate plus long-acting repeatable [LAR] octreotide 30 mg has been shown to significantly improve progression-free survival and overall survival relative to high-dose octreotide LAR 60 mg in patients with unresectable or metastatic progressive midgut NETs. A long-term cost-effectiveness analysis was performed to assess whether 177Lu-Dotatate is a cost-effective option versus octreotide 60 mg for patients with unresectable/metastatic progressive midgut NETs from the perspective of French healthcare payer. METHODS: The analysis was performed using a three-state partitioned survival model. In the base case analysis 177Lu-Dotatate plus octreotide LAR 30 mg was compared with high-dose octreotide LAR 60 mg in patients with midgut NETs. Survival data were obtained from the phase III NETTER-1 trial in patients with metastatic midgut NETs. Future costs and clinical outcomes were discounted at 4% per annum. One-way deterministic and probabilistic sensitivity analyses were performed. RESULTS: In the base case analysis, for patients with midgut NETs, 177Lu-Dotatate treatment improved quality-adjusted life expectancy by 1.21 quality-adjusted life years (QALYs) relative to octreotide LAR 60 mg and the lifetime treatment costs were EUR 50,784 higher with 177Lu-Dotatate resulting in an incremental cost-effectiveness ratio (ICER) of EUR 42,106 per QALY gained versus octreotide LAR 60 mg. When compared with everolimus, 177Lu-Dotatate was associated with an ICER of EUR 59,769 per QALY gained. Sensitivity analyses showed that the results were sensitive to methods used to extrapolate survival data. CONCLUSIONS: For patients with advanced progressive midgut NETs 177Lu-Dotatate is likely to be considered a cost-effective option versus octreotide 60 mg from the perspective of the French healthcare payer.