Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. METHODS: To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. RESULTS: Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated.

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma.

INTRODUCTION: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.

Translational research in neuroendocrine tumors: pitfalls and opportunities.

Interest in research on neuroendocrine tumors (NETs) has grown in the past 10 years, coinciding with improvements in our understanding of the molecular pathogenesis of NETs. In addition, NETs have become one of the most exciting settings for drug development. Two targeted agents for the management of advanced pancreatic NETs have been approved, but the development of targeted agents for NETs is limited by problems with both patient selection and demonstration of activity. In this review, we analyze these limitations and discuss ways to increase the predictive value of preclinical models for target discovery and drug development. The role of translational research and 'omics' methodologies is emphasized, with the final aim of developing personalized medicine. Because NETs usually grow slowly and metastatic tumors are found at easily accessible locations, and owing to improvements in techniques for liquid biopsies, NETs provide a unique opportunity to obtain tumor samples at all stages of the evolution of the disease and to adapt treatment to changes in tumor biology. Combining clinical and translational research is essential to achieve progress in the NET field. Slow growth and genetic stability limit and challenge both the availability and further development of preclinical models of NETs, one of the most crucial unmet research needs in the field. Finally, we suggest some useful approaches for improving clinical drug development for NETs: moving from classical RECIST-based response end points to survival parameters; searching for different criteria to define response rates (for example, antiangiogenic effects and metabolic responses); implementing randomized phase II studies to avoid single-arm phase II studies that produce limited data on drug efficacy; and using predictive biomarkers for patient selection.

Safety of long-term treatment with Pegvisomant: analysis of Spanish patients included in global ACROSTUDY.

PURPOSE: To evaluate the long-term safety of Pegvisomant (PEG) in the Spanish cohort of ACROSTUDY. METHODS: As of July 2013, 199 Spanish patients were included in ACROSTUDY, a global non interventional safety PEG surveillance study. Patients were observed for safety, biochemical outcome and magnetic resonance imaging evaluations. RESULTS: PEG was administered during an average period of 6.7 ± 2.1 years and a mean daily dose of 15.5 ± 7.5 mg. 48.2% of patients received PEG monotherapy. 90.9% of patients had received other medical treatment before PEG start. 195 adverse events (AEs) were reported in 88 patients (44.2%), and serious AEs were described in 31 patients (15.6%). There were no cases of liver tests >10 ULN, or permanent liver damage. Tumor size changes were locally reported in 61 cases (33.5%), with increases observed in 11 patients (6%). In acromegalic patients with diabetes mellitus a decrease in fasting serum glucose value was reported, reaching statistical significance after 1 and 4 years of treatment (-24.6 and -25.9 mg/dl, p = 0.04). After 60 months, normal or lower limit of normal (LLN) IGF-I levels were found in 67.9% of patients. 85.5% of patients showed an IGF-I normal or

Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population.

Influence of the length of progestagen treatment and the time of oestradiol benzoate application on the ovulatory follicle size and ovulation time in anoestrous and cyclic beef cows.

Previous research from our laboratory in beef cattle suggests that the pre-ovulatory follicle size, maturity and subsequent susceptibility to gonadotropin are influenced by the length of progestagen treatment in artificial insemination programme in beef cows. To test this hypothesis, two experiments were conducted. In experiment 1, 35 anoestrous beef cows received an intravaginal sponge containing 200 mg of medroxyprogesterone acetate. The treatment lasted for 7 (n = 12), 8 (n = 11) or 9 (n = 12) days. Half of the animals in each group were injected with 0.7 mg of oestradiol benzoate (EB) at device removal (0 h) and the other half 24 h later. In experiment 2, 38 cycling beef cows were treated with the same protocols as in experiment 1. Ultrasound examinations were performed to determine the follicular diameter at device removal (dominant follicle), interval to ovulation and ovulatory follicle diameter. The dominant follicle of anoestrous cows with progestagen for 7 days (8.4 ± 1.6 mm) resulted smaller (p < 0.05) than the cows treated for 8 (10.5 ± 1.6 mm) and 9 days (10.6 ± 1.2 mm). However, regardless of the length of the treatments, ovulation time after device removal was longer (p < 0.05) when EB was injected 24 h after withdrawal than at 0 h in anoestrous cows (EB0 = 52.7 ± 4.0 h; EB24 = 70.8 ± 6.2 h) and in cyclic cows (EB0 = 50.0 ± 21.0 h; EB24 = 73.0 ± 20.0 h). In anoestrous cows, the treatment with progestagen for 9 days and EB at 24 h increased the diameter of the ovarian follicle (p = 0.033) but did not affect the diameter of the ovulatory follicle in cyclic cows. In conclusion, increasing the length of progestagen treatment for 8 or 9 days compared to 7 days increased the diameter of the dominant follicle, in anoestrous and cyclic beef cows. Oestradiol benzoate administered at device removal resulted in a shorter interval from device removal to ovulation compared with EB injection 24 h after the end of a progestagen treatment.

Effect of estradiol benzoate used at the start of a progestagen treatment on superovulatory response and embryo yield in lactating and non-lactating llamas.

Two experiments were conducted to determine the effect of estradiol benzoate (EB) and intravaginal progestagen treatment on ovarian follicular dynamics and superstimulatory response in eCG-treated llamas. The purpose of Experiment 1 was to evaluate the effect of EB and progestagen treatment starting at different phases of dominant follicle (DF1) development on regression pattern and subsequent follicle wave emergence (WE2) in lactating and non-lactating llamas. Early lactating (n=24, 30+/-4 days postpartum) and non-lactating (n=24) females were assigned in equal numbers (n=8) to one of three groups according to the phase of DF1 (growing, static or regressing) determined by ultrasonography from day -3 to day 0. At day 0, llamas received an intravaginal sponge (MPA, 150 mg) and 5mg of MPA (i.m.). Half of the females (n=4) of each group were injected with 2mg (i.m.) of EB and half were not (control group). A 2 x 2 x 3 (lactational status, EB treatment and follicular phases) factorial design was used. Each sponge was removed 8 days later. Ovaries were monitored from day 0 to day 12. Daily blood samples were taken to determine 17beta-estradiol (E(2)) profiles from day 0 to day 8. The DF1 regression pattern was not affected (P>0.05) by the phase of follicle wave at the start of the treatment or any interactions among main effects. Follicle wave emergence in EB-treated llamas was delayed (P<0.05) by 2.3 days compared with non-treated llamas. Following EB treatment, plasma concentrations of E(2) were greater (P<0.05) from day 1 to day 5 in the treated than in non-treated females, but not from day 6 onward (P>0.05). Experiment 2 was designed to evaluate the effect of this treatment on the ovarian superovulatory response and embryo yield following eCG treatment administered on day of follicular wave emergence as determined in the Experiment 1. The same lactating (n=18, 61+/-4 days postpartum) and non-lactating (n=18) llamas at random stages of follicle wave were treated as those in Experiment 1 and received 1200IU of eCG at the time of WE2 (EB-treated=day 6.5 and non-treated=day 4.5). Llamas were mated 5 days after sponge withdrawal. A second mating was allowed 24h later. Embryos were collected between 7 and 8 days after the first mating and blood samples were taken to determine progesterone (P(4)) concentrations. The mean number of follicles on day of mating and the number of CL on day of embryo collection were not affected by lactational status, EB treatment or their interactions (P>0.05). Ovulation rate and mean (+/-SEM) number of recovered embryos for EB treatment group (67.5% and 2.4+/-0.4) were greater (P<0.05) than for no EB treatment (51.1% and 1.1+/-0.4). Plasma P(4) concentrations and number of CL per llama were correlated (r=0.49; P=0.014). In conclusion, progestagen plus EB treatment facilitates the prediction of the emergence of a new follicular wave approximately 6 days after treatment and resulted in a higher ovulation rate and embryo production in ovarian superstimulated llamas regardless of lactational status.

Transvaginal follicular aspiration and embryo development in superstimulated early postpartum beef cows and subsequent fertility after artificial insemination.

This study was conducted to investigate in early postpartum suckled beef cows with and without FSH pre-stimulation: (i) the influence of the postpartum period on the number and quality of oocytes recovered by ovum pick-up (OPU), (ii) the overall efficiency of the OPU/IVP embryos from days 30 to 80 postpartum and (iii) if repeated OPU negatively affect fertility following a fixed-time artificial insemination protocol. After parturition suckled Angus cows (n = 30) were divided in three groups (n = 10 group(-1)). All cows were anestrous at the commencement of experimental treatments (30.0 +/- 3.2 days postpartum, mean +/- SD; range 25-34 days). Group 1 treatments included: dominant follicle ablation (DFA), FSH treatment and OPU procedure 5 days after DFA. A total of 9 mg FSH (Ovagen) was administered s.c. once a day over 2 days at equal doses (4.5 + 4.5mg). For fertility test the cows received an intravaginal progesterone treatment from Days 78 to 86 postpartum and were fixed-time artificially inseminated (FTAI) at 56 and 72 h after device removal. Group 2: as cited for Group 1 with no FSH treatment. In both groups, OPU was repeated four times (Days 35, 49, 63 and 77 postpartum) and the collected oocytes classified as viable were in vitro matured, fertilized and presumptive embryos cultured for 8 days. Group 3 (Control FTAI): cows that had not previously aspirations were FTAI as Groups 1 and 2. Pregnancy was diagnosed by means ultrasonography 39 days after FTAI. The numbers (mean +/- SEM) of follicles visible and aspirated at the time of OPU in FSH-treated cows were greater (P < 0.05) than in non-treated cows (10.6 +/- 0.6 and 8.4 +/- 0.4 vs. 8.0 +/- 0.5 and 4.6 +/- 0.3, respectively). Following FSH treatment, the number (mean +/- SEM) of recovered oocytes per cow per OPU session and percentage of viable oocytes were greater in the treated (P < 0.05) than in non-treated animals (3.0 +/- 0.1 and 39.5% vs. 1.5 +/- 0.1 and 30.0%). The cleavage and embryo development rates were similar (P > 0.05) for both groups (14.8 and 6.4% vs. 16.6 and 5.5%). After FTAI the pregnancy rates were not different (P > 0.05) among groups (70, 60 and 90% for Groups 1, 2 and 3, respectively). We can conclude that (1) FSH-treated suckled postpartum cows can be a source of oocytes for in vitro fertilization and (2) repeated DFA/OPU applied during postpartum period did not affect the subsequent fertility following FTAI.

Effect of progesterone administration on the ovarian response to superovulatory treatments in cattle.

To evaluate ovarian response in Angus cows previously treated with progesterone (P4), animals were randomly assigned to two groups: T600 group (n=14), 600 mg of P4/day. P4 was injected from days 3 to 7 of the estrous cycle. On day 7, superovulatory treatments began. The control group (n=12) was given vehicle only. The superovulatory treatments in the control group began on days 7-9 of the estrous cycle. The superovulatory total treatment dose of 400mg NIH FSH P1 was given twice a day over a 4-day period. Ultrasonography of the ovaries was conducted 3 days preceding the initiation of superovulatory treatment, every 24h. In both groups, an additional ultrasonographic evaluation was made at 24h after the end of superovulatory treatment. Blood samples were collected 4 days preceding the initiation of superovulatory treatment, every 24h. Additional samples were taken from the P600 group for 12 day after of initiation of superovulatory treatment every 24h, except on the fifth day after the initiation of superovulatory treatment. In the P600 group, P4 concentrations were greater than in the control group (P<0.01) and remained over 1 ng/ml up to day 11 after beginning of superovulatory treatment. The diameter of the dominant follicle was larger in the animals of the control group (P<0.01). Cows of the P600 group had a greater number of Class I (3-4mm) follicles (P<0.01). A significant day and treatment effect (P<0.01) were observed in Class II (5-9 mm) follicles. Effects due to treatment on the number of Class III follicles (P<0.05) were observed. In the P600 group, no estrous post-superovulatory was observed and there were no ovulations that occurred. Conversely, 100% of the cows of the control group showed estrous. In the P600 group, there were a greater number of Class III follicles (P<0.01) and a lesser number of Class II follicles (P<0.05) at 24h after the end of superovulatory. In the control group, 66.7% of the cows responded to superovulatory treatments. In conclusion, the daily administration of 600 mg of P4, from days 3 to 7 of the estrous cycle, produces an increase of plasma concentrations of this hormone from day 4, resulting in changes in follicular dynamics (absence of follicles greater than 10mm of diameter and an increase of the population of Class I follicles). As to the ovarian stimulation using Folltropin V in animals receiving a daily injection of 600 mg of P4 from days 3 to 7 of the estrous cycle, a greater population of follicles>or=10mm developed by 24h after superovulatory treatments were completed.

Influence of different doses of progesterone treatments on ovarian follicle status in beef cows.

To determine a dose of progesterone (P4) that allow ovarian follicular wave control, Aberdeen Angus cows were randomly assigned into four groups: T600 (n=5), 600 mg of P4/day; T400 (n=5), 400 mg of P4/day; T200 (n=4), 200mg of P4/day and Control (n=4) (excipient only). Progesterone was injected from day 3 to 9 of estrous cycle. Ultrasonographies and blood sample collections were performed daily from day 2 to 10 and on day 15 of the estrous cycle. Additionally, an ultrasonographic study was conducted on day 13. Progesterone concentrations were different among all groups (P<0.01). The diameter of the dominant follicle was greater for control than for T200, T400 and T600 groups (P<0.01); there was no difference between T200 and T400 (P>0.05), but they had a greater diameter follicle than the T600 group (P<0.01). The growth rate of the dominant follicle between day 3 and 7 of estrous cycle was greater for control group (1.63+/-0.3 mmday(-1)) than for T200 (0.56+/-0.19 mmday(-1), P<0.05), T400 (0.6+/-0.23 mmday(-1), P<0.05) and T600 (0.11+/-0.13 mmday(-1), P<0.01) groups. The mean number of class I follicles (3-4mm) per day for the entire experimental period was less for the control group than for T200 (P<0.05), T400 and T600 (P<0.01) groups (3.7+/-1.3; 5.3+/-1.3; 6.6+/-1.8 and 8.1+/-1.9, respectively). The mean number for the T200 group was less than for T600 (P<0.05) and similar for T400 and T600 groups (P>0.05). The number of class III follicles was greater for control group than for the other groups (P<0.01). T200 and T400 groups had similar numbers of class III follicles (P>0.05) and both had greater numbers of follicles than the T600 group (P<0.05). The diameter of the corpus luteum of the T600 group (15.8+/-1.6 mm) was less than for control (21.0+/-2.5 mm, P<0.01), T200 (19.3+/-2.7 mm, P<0.01) and T400 (20.0+/-2.2 mm) groups (P<0.05). The mean diameter of corpus luteum of T200 was similar to T400 (P>0.05), but different from the control group (P<0.05). In conclusion, the daily intramuscular administration of 200mg or more of progesterone from day 3 to 9 of the estrous cycle indicates that plasma concentrations of progesterone can be used to modify the pattern of follicular development during the follicular wave. From day 5 of the estrous cycle, progesterone concentrations greater than 15 ng/ml (T600 group: 600 mg/day of progesterone from day 3 to 9 of the estrous cycle) inhibit dominant follicle development, increase the class I follicle populations (3-4 mm) and diminish the development of the corpus luteum.

Multiple endocrine neoplasia type 1 (MEN1): clinical heterogeneity in a large family with a nonsense mutation in the MEN1 gene (Trp471Stop).

OBJECTIVE: Familial multiple endocrine neoplasia type 1 (MEN1) is an hereditary dominant trait characterized by tumours of the parathyroids, anterior pituitary and endocrine pancreatic glands, among others. The MEN1 gene has recently been cloned, and MEN1-mutations have been identified in several families as well as in a number of sporadic cases. The aim of this study was to search for mutations in a large MEN1-family in order to define the clinical heterogeneity among mutation-carriers. We also analysed DNA from several tumour tissues in order to test the 'two hit' model for inactivation of the MEN1 gene. PATIENTS AND METHODS: We searched for mutations in the MEN1-gene in members of a large MEN1-family. A total of 11 affected and 4 healthy at risk individuals were analysed. DNA was obtained and exons 1 to 10 of the MEN1-gene were PCR-amplified and subjected to automated-direct sequencing. In addition, we isolated DNA from parathyroid tumours of two family members, and compared this DNA with that of the normal tissue counterpart to define if the normal copy of the MEN1-gene was deleted. RESULTS: G to A change at nucleotide 7640 (exon 10) that would convert Trp to Stop at codon 471 was found. This mutation was identified in eleven affected individuals, as well as in four healthy (asymptomatic) family members. These patients showed a wide spectrum of clinical symptoms and ages of presentation. Comparison of normal and tumour DNAs showed the loss of the normal (non-mutated) copy of MEN1 gene in the tumour tissue. CONCLUSION: The different ages of disease presentation and the heterogeneity of symptoms among carriers of the Trp471Stop mutation, which would lead to the synthesis of a truncated non-functional protein, suggest that clinical heterogeneity is a characteristic of MEN1 independent of the type of mutation. Finally, the lack of amplification of the normal MEN1-allele on DNA from parathyroid tumours of two family members indicates that MEN1 is a tumour suppressor gene, the second hit that inactivates the normal copy in mutation carriers being a deletion.

Multiple endocrine neoplasia type 1 (MEN1): LOH studies in a affected family and in sporadic cases.

Multiple endocrine neoplasia (Menl) is an autosomai dominant hereditary trait characterized by tumors of endocrine tissues. The MEN1 gene maps to chromosome llql3, has been recently isolated, and encodes a protein termed menin that is ubiquitously expressed. This gene is likely to be a tumor suppressor gene, with tumors developing after the inactivation of both copies of the gene in a single cell. In agreement with this, 11q-deletions (loss of heterozygosity) are frequently found in neoplasms from MEN1 patients. In this study, DNA from family-members was extracted and analysed for 10 microsatellites flanking the MEN1-gene on chromosome 11q. SSCP was used to determine the presence of MEN1-mutations in several patients. DNA was extracted from paraffin blocks containing tissue from 10 parathyroid tumors (4 familial and 6 sporadic) and 2 gastrinomas (both from patients of the Men1-family). LOH was determined by comparing the autoradiographic patterns of several markers between the normal tissue and the malignant tissue counterpart. All the affected individuals in the MEN1-family shared one haplotype, not present in the healthy individuals. We searched for mutations at the MEN1 gene (SSCP-analysis) in several affected members. An SSCP-mobility shift was found at exon 9, and direct sequencing showed that this corresponded to a common polymorphism at codon 418 (GAC/GAT), LOH, a genetic alteration characteristic of genomic regions containing tumor suppressor genes, was found in all the parathyroid tumors, but not in two gastrinomas. SSCP-analysis of the MEN1-exon 9 polymorphism showed that LOH included the MEN1-gene in the informative parathyroid tumors. In conclusion, LOH at 11q is frequent in Menl-parathyroid tumors, either sporadic or familial, and the deletion involves the MEN1-gene. In contrast, the two gastrinomas did not show LOH, indicating the existence of a second mutation other than the MEN1-deletion in these tumors. Our data suggest that the mechanism that drives tumorigenesis in Menl either familial or sporadic, is influenced by the tissue context.