Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients.

INTRODUCTION: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. METHODS: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. RESULTS: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2-40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8-30.4) having a serious infection and 7 (6.3%; 95% CI 2.6-12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02-1.60; p = 0.03) as an independent risk factor for serious infection. CONCLUSION: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

Tumor Growth Rate to Predict the Outcome of Patients with Neuroendocrine Tumors: Performance and Sources of Variability.

INTRODUCTION: Tumor growth rate (TGR), percentage of change in tumor volume/month, has been previously identified as an early radiological biomarker for treatment monitoring in neuroendocrine tumor (NET) patients. We assessed the performance and reproducibility of TGR at 3 months (TGR3m) as a predictor factor of progression-free survival (PFS), including the impact of imaging method and reader variability. METHODS: Baseline and 3-month (±1 month) CT/MRI images from patients with advanced, grade 1-2 NETs were retrospectively reviewed by 2 readers. Influence of number of targets, tumor burden, and location of lesion on the performance of TGR3m to predict PFS was assessed by uni/multivariable Cox regression analysis. Agreement between readers was assessed by Lin's concordance coefficient (LCC) and kappa coefficient (KC). RESULTS: A total of 790 lesions were measured in 222 patients. Median PFS was 22.9 months. On univariable analysis, number of lesions (

Morphostructural and histochemical dynamics of Euterpe precatoria (Arecaceae) germination.

The fruits of Euterpe precatoria, popularly known as açaí palm, have been commercially exploited for use in food and beverages because of their medicinal and energetic properties. However, despite the growing demand, little is known about the seeds germination, until now, its main form of propagation. In this context, we have characterized the structure of the zygotic embryo and described temporally the germination process of E. precatoria with emphasis on the morpho-anatomical and histochemical aspects. For this end, we have collected and analyzed zygotic embryo and seedlings samples before sowing and at different periods after sowing-2, 4, 6, 8, 10, 15, 20, 30, 40, 50, and 60 days. The embryo has an oblique embryonic axis and mainly protein reserves. Seed germination is classified as cryptocotyledonar, hypogeal, and adjacent ligular and we observed seedlings at 20 days after sowing (33.3%), although anatomical evidence of the beginning of the germination process have been observed at 15 days. The day-20 was histologically marked by the expansion of the ligule, beginning of second eophyll differentiation, and complete root protrusion. This stage was characterized by the total consumption of protein reserves and increased starch grains. The occurrence of 100% of root and ligula emission was verified at day-60, which characterizes a slow and heterogeneous process. The morphological marker of the E. precatoria germination is the exit of the proximal region (cotyledonary petiole) of the embryo from within the seed by the lifting of the operculum and the species has some peculiarities, such as the presence of high concentrations of phenolic compounds and idioblasts before and throughout the germination process, and starch grains located on the embryonic axis. We can verify that the consumption of protein reserves of the embryo is related to the energy supply necessary for root protrusion.

Genetic structure and diversity of native Guadua species (Poaceae: Bambusoideae) in natural populations of the Brazilian Amazon rainforest.

The Southwestern Region of the Brazilian Amazon is formed by forests dominated by bamboos. The genus Guadua is endemic to the Americas, and little is known about the genetic diversity and structure of species of this genus. This study aimed to evaluate the genetic diversity and structure of two native Guadua species in natural populations in the Southwestern region of the Brazilian Amazon. Therefore, the genetic diversity and structure of Guadua aff. chaparensis and Guadua aff. lynnclarkiae were evaluated with the use of microsatellite molecular markers (SSR). It was verified that the average genetic diversity for the populations studied was considered high ( H ^ e =0.5) compared to other species of bamboo. All populations had rare and private alleles, and none of them presented significant values of inbreeding. The populations were divergent ( G ^ ST = 0.46), resulting in a low apparent gene flow. The Bayesian analysis showed that among the 350 individuals analyzed, five groups (K=5) were formed, with little similarity among the groups (Populations), although two of them presented clonal individuals. According to the results obtained, it can be conclude that populations should be treated as having unique characteristics, mainly when accessed for management and for in situ and ex situ conservation studies.

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET)-The GREPONET Study.

INTRODUCTION: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications. MATERIALS AND METHODS: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m). RESULTS: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS. CONCLUSION: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up. IMPLICATIONS FOR PRACTICE: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

Unmet Needs in Appendiceal Neuroendocrine Neoplasms.

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted "grey areas".

Interleukin-23 promotes intestinal T helper type17 immunity and ameliorates obesity-associated metabolic syndrome in a murine high-fat diet model.

We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice.

Identifying Prognostic Factors for Well-Differentiated Metastatic Pancreatic Neuroendocrine Tumours: A Retrospective International Multicentre Cohort Study.

Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status ≥2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkaline-phosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status ≥2, synchronous metastases, Ki-67 ≥10%, and high alkaline-phosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.

Interactive virtual assistance for mental health promotion and self-care management in elderly with type 2 diabetes (IVAM-ED): study protocol and statistical analysis plan for a randomized controlled trial.

BACKGROUND: With one in five individuals aged 65 or older living with type 2 diabetes worldwide, it is crucial to acknowledge and address the challenges faced by this population. In this context, our study aims to evaluate the efficacy of a behavioral intervention model delivered through a smart speaker on mental health and diabetes self-care in the elderly with diabetes. METHODS: This is a single-center, pragmatic, parallel two-arm open randomized clinical trial involving elderly patients with type 2 diabetes. We plan to enroll a total of 112 individuals who will be randomized 1:1 to receive the Smart Speaker EchoDot 3rd Gen device (Amazon Echo®) for home use (intervention arm) or to maintain usual care (control arm). The primary outcome is mental distress, assessed using the 20-item Self Reporting Questionnaire (SRQ-20) after a 12-week intervention period. Secondary outcomes include quality of life, adherence to diabetes self-care behaviors, perception of stress, glycemic control, blood pressure, and lipid profile. Analysis of covariance (ANCOVA) will be used to evaluate the effects of the intervention on the outcomes. DISCUSSION: This study assesses the effectiveness of an interactive virtual assistance system for enhancing mental health and glycemic control among elderly individuals with type 2 diabetes. The findings may introduce smart speakers as a valuable tool for promoting diabetes-related self-care in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05329376. Registered on 15 April 2022. Enrollment began on 20 June 2023 and the last update of protocol was on 13 December 2023.

Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies.

In the past century, there have been many attempts to treat cancer with low levels of electric and magnetic fields. We have developed noninvasive biofeedback examination devices and techniques and discovered that patients with the same tumor type exhibit biofeedback responses to the same, precise frequencies. Intrabuccal administration of 27.12 MHz radiofrequency (RF) electromagnetic fields (EMF), which are amplitude-modulated at tumor-specific frequencies, results in long-term objective responses in patients with cancer and is not associated with any significant adverse effects. Intrabuccal administration allows for therapeutic delivery of very low and safe levels of EMF throughout the body as exemplified by responses observed in the femur, liver, adrenal glands, and lungs. In vitro studies have demonstrated that tumor-specific frequencies identified in patients with various forms of cancer are capable of blocking the growth of tumor cells in a tissue- and tumor-specific fashion. Current experimental evidence suggests that tumor-specific modulation frequencies regulate the expression of genes involved in migration and invasion and disrupt the mitotic spindle. This novel targeted treatment approach is emerging as an appealing therapeutic option for patients with advanced cancer given its excellent tolerability. Dissection of the molecular mechanisms accounting for the anti-cancer effects of tumor-specific modulation frequencies is likely to lead to the discovery of novel pathways in cancer.

Systemic treatment in patients with Child-Pugh B liver dysfunction and advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno-oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child-Pugh-Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3-5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.

Association Between Knee Extension Strength and Functional Capacity After Intensive Care Unit Discharge: A 6-Mo Prospective Cohort Study.

INTRODUCTION: Assessing functional improvement after intensive care unit discharge is particularly challenging. The aim of this study was to measure the association between (1) changes in knee extension muscle strength or quadriceps femoris and rectus femoris muscle thickness and (2) changes in functionality/function-related measurements in post-intensive care unit patients. METHODS: This prospective cohort study included adult patients without previous disability, consecutively selected after intensive care unit discharge. Some parameters, such as Short-Form 36, 6-min walking test, 1-min sit-to-stand, and Short Physical Performance Battery, were measured at baseline and 3 and 6 mos after discharge. Correlations were assessed and regression models were built to assess the association between evolution in knee extension strength or muscle thickness and evolution in functional tests. RESULTS: Thirty patients completed the follow-up. Moderate correlation was found between knee extension strength change and Short-Form 36 physical functioning (correlation coefficient [ ρ ] = 0.53), 6-min walking test ( ρ = 0.38), 1-min sit-to-stand ( ρ = 0.52), and Short Physical Performance Battery ( ρ = 0.38). Baseline values and changes in knee extension strength moderately predicted evolution in Short-Form 36 physical functioning ( r2 = 0.32, P = 0.006). Changes in muscle thickness were overall not associated with changes in functional variables. CONCLUSION: Changes in knee extension muscle strength may inform on functional progression over time after intensive care unit discharge, although confirmatory studies are needed.

Survival and Response Outcomes for Gastrointestinal Neuroendocrine Tumor (GEP-NETs) Patients Treated with Lutetium-177-DOTATATE in a Brazilian Reference Center: A Six-Year Follow-Up Experience.

BACKGROUND: PRRT can be an option for all-grade GEP-NETs, but selecting patients is challenging. In this scenario, clinical-pathological and radiological characteristics, such as pre-treatment Ga-68 DOTA PET/CT, might have the potential to help. METHODS: A retrospective chart review was conducted on advanced GEP-NETs treated with at least one PRRT dose. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Krenning Score (KS), and the maximum standardized uptake value (SUVmax) were derived from the pre-treatment scans. A maximally selected rank statistics test was used for SUVmax simple cut point estimate. RESULTS: Among 36 patients, 19 had primary pancreatic tumors. The numbers of G1, G2, and G3 tumors were 10, 18, and 7, respectively. During a median follow-up of 90.5 months, 4 patients died. Median OS was not reached for G1 and G2 tumors, and it was 30 months for G3 (p = 0.001). Median PFS was 23 months, with G3 showing lower PFS compared to G1 [7 versus 30 months; HR 8.41 (95%CI 2.2-31.0; p = 0.001)]. CONCLUSIONS: PRRT provides long-term PFS in patients with G1/G2 GEP-NETs independent of clinical characteristics and primary site. G3 has worse survival, but selected patients may experience long OS after PRRT treatment.

Low-energy amplitude-modulated electromagnetic field exposure: Feasibility study in patients with hepatocellular carcinoma.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) and poor liver function lack effective systemic therapies. Low-energy electromagnetic fields (EMFs) can influence cell biological processes via non-thermal effects and may represent a new treatment option. METHODS: This single-site feasibility trial enrolled patients with advanced HCC, Child-Pugh A and B, Eastern Cooperative Oncology Group 0-2. Patients underwent 90-min amplitude-modulated EMF exposure procedures every 2-4 weeks, using the AutEMdev (Autem Therapeutics). Patients could also receive standard care. The primary endpoints were safety and the identification of hemodynamic variability patterns. Exploratory endpoints included health-related quality of life (HRQoL), overall survival (OS). and objective response rate (ORR) using RECIST v1.1. RESULTS: Sixty-six patients with advanced HCC received 539 AutEMdev procedures (median follow-up, 30 months). No serious adverse events occurred during procedures. Self-limiting grade 1 somnolence occurred in 78.7% of patients. Hemodynamic variability during EMF exposure was associated with specific amplitude-modulation frequencies. HRQoL was maintained or improved among patients remaining on treatment. Median OS was 11.3 months (95% confidence interval [CI]: 6.0, 16.6) overall (16.0 months [95% CI: 4.4, 27.6] and 12.0 months [6.4, 17.6] for combination therapy and monotherapy, respectively). ORR was 24.3% (32% and 17% for combination therapy and monotherapy, respectively). CONCLUSION: AutEMdev EMF exposure has an excellent safety profile in patients with advanced HCC. Hemodynamic alterations at personalized frequencies may represent a surrogate of anti-tumor efficacy. NCT01686412.

Whole body diffusion for metastatic disease assessment in neuroendocrine carcinomas: comparison with OctreoScan® in two cases.

Neuroendocrine tumor (NET) patients must be adequately staged in order to improve a multidisciplinary approach and optimal management for metastatic disease. Currently available imaging studies include somatostatin receptor scintigraphy, like OctreoScan®, computed tomography (CT), scans and magnetic resonance imaging (MRI), which analyze vascular concentration and intravenous contrast enhancement for anatomic tumor localization. However, these techniques require high degree of expertise for interpretation and are limited by their availability, cost, reproducibility, and follow-up imaging comparisons. NETs significantly reduce water diffusion as compared to normal tissue. Diffusion-weighted imaging (DWI) in MRI has an advantageous contrast difference: the tumor is represented with high signal over a black normal surrounding background. The whole-body diffusion (WBD) technique has been suggested to be a useful test for detecting metastasis from various anatomic sites. In this article we report the use of DWI in MRI and WBD in two cases of metastatic pulmonary NET staging in comparison with OctreoScan® in order to illustrate the potential advantage of DWI and WBD in staging NETs.