Novel Tumor Growth Rate Analysis in the Randomized CLARINET Study Establishes the Efficacy of Lanreotide Depot/Autogel 120 mg with Prolonged Administration in Indolent Neuroendocrine Tumors

IntroductionTumor quantity while receiving cancer therapy is the sum of simultaneous regression of treatment‐sensitive and growth of treatment‐resistant fractions at constant rates. Exponential rate constants for tumor regression/decay (d) and growth (g) can be estimated. Previous studies established g as a biomarker for overall survival; g increases after treatment cessation, can estimate doubling times, and can assess treatment effectiveness in small cohorts by benchmarking to large reference data sets. Using this approach, we analyzed data from the clinical trial CLARINET, evaluating lanreotide depot/autogel 120 mg/4 weeks (LAN) for treatment of neuroendocrine tumors (NETs).Methods and MaterialsComputed tomography imaging data from 97 LAN‐ and 101 placebo‐treated patients from CLARINET were analyzed to estimate g and d.ResultsData from 92% of LAN‐ and 94% of placebo‐treated patients could be fit to one of the equations to derive g and d (p < .001 in most data sets). LAN‐treated patients demonstrated significantly slower g than placebo recipients (p = .00315), a difference of 389 days in doubling times. No significant difference was observed in d. Over periods of LAN administration up to 700 days, g did not change appreciably. Simulated analysis with g as the endpoint showed a sample size of 48 sufficient to detect a difference in median g with 80% power.ConclusionAlthough treatment of NETs with LAN can affect tumor shrinkage, LAN primarily slows tumor growth rather than accelerates tumor regression. Evidence of LAN efficacy across tumors was identified. The growth‐retarding effect achieved with LAN was sustained for a prolonged period of time.Implications for PracticeThe only curative treatment for neuroendocrine tumors (NETs) is surgical resection; however, because of frequent late diagnosis, this is often impossible. Because of this, treatment of NETs is challenging and often aims to reduce tumor burden and delay progression. A novel method of analysis was used to examine data from the CLARINET trial, confirming lanreotide depot/autogel is effective at slowing tumor growth and extending progression‐free survival. By providing the expected rate and doubling time of tumor growth early in the course of treatment, this method of analysis has the potential to guide physicians in their management of patients with NETs.     

Validation study of the Chinese version of the Brief Fatigue Inventory (BFI-C)

A cross-sectional study was conducted among 249 Chinese cancer patients with multiple diagnoses to validate a Chinese version of the Brief Fatigue Inventory (BFI-C). Cronbach's coefficient alpha was 0.92 for fatigue severity items and 0.90 for fatigue interference items. Construct validity was explored by principal factor analysis and suggested a two-factor solution: fatigue severity and fatigue interference. Internal consistency reliability was excellent. Convergent validity was examined by correlating the BFI-C with 2 subscales and 2 component scores of the MOS 36-Item Short-Form Health Survey (coefficients ranged between -0.44 and -0.71, P<0.001). Known-group validity was examined by comparing fatigue severity in patients having different scores on the Eastern Cooperative Oncology Group Performance Status Scale. Approximately 60% of patients experienced moderate to severe fatigue (4 or greater on the 0-10 scale of the BFI-C "fatigue worst" item). The BFI-C is a valid, reliable instrument to measure the severity and impact of cancer-related fatigue among Chinese patients.     

Integration of a Low‐Cost Introductory Ultrasound Curriculum Into Existing Procedural Skills Education for Preclinical Medical Students

We evaluated integration of an introductory ultrasound curriculum into our existing mandatory procedural skills program for preclinical medical students. Phantoms consisting of olives, pimento olives, and grapes embedded in opaque gelatin were developed. Four classes encouraged progressive refinement of phantom‐scanning and object identification skills. Students improved their ability to identify hidden objects, although each object type achieved a statistically significant improvement in correct identification at different time points. The total phantom cost per student was $0.76. Our results suggest that short repeated experiences scanning simple, low‐cost ultrasound phantoms confer basic ultrasound skills.     

Using insulin as a drug rather than as a replacement hormone during acute illness: a new paradigm

The direct correlation between glucose levels and cardiovascular disease in individuals with type 2 diabetes can now be applied to individuals that share an abnormal metabolic milieu similar to that found in central obesity, the metabolic syndrome, and type 2 diabetes. Premature macrovascular complications with a very high morbidity and mortality rate can be found in these nondiabetic populations. The typical phenotype has visceral or central obesity, excess of free fatty acids, insulin resistance, increased insulin secretion, and hypertension. A more complex metabolic-cardiovascular syndrome develops that includes dyslipidemia, abnormal production of cytokines, chronic inflammatory state, and abnormal coagulation. The interplay of all these cardiovascular risk factors is responsible for the accelerated atherosclerotic process. The different terminologies used for populations sharing this common ground for premature cardiovascular disease now generally accepted as the metabolic syndrome, are also discussed. Aggressive insulin treatment during acute illness in individuals with the abnormal metabolic milieu is beneficial. Insulin treatment is changing from using insulin as a hormone to treat only severe hyperglycemia, to a new paradigm using insulin in high doses as a drug. Aggressive insulin regimens should be used to treat only minimal elevations of blood glucose or to prevent hyperglycemia. The newly observed properties of insulin are reviewed which include suppression of inflammatory cytokines and adhesion molecules, improved hemostasis, and other cardiac beneficial effects. The concomitant administration of intravenous glucose and insulin permits the administration of higher insulin doses that can result in improved outcome due to its nonglycemic-related benefits. The use of aggressive insulin therapy requires both better and more cost-effective algorithms to successfully treat this high-risk population during acute illness.     

Targeting the A2A adenosine receptor counteracts immunosuppression in vivo in a mouse model of chronic lymphocytic leukemia

Tumor immunosuppression is a major cause of treatment failure and disease relapse, both in solid tumors and leukemia. Local hypoxia is among the conditions that cause immunosuppression, acting at least in part through the upregulation of extracellular adenosine levels, which potently suppress T-cell responses and skew macrophages towards an M2 phenotype. Hence, there is intense investigation to identify drugs that target this axis. By using the TCL1 adoptive transfer chronic lymphocytic leukemia mouse model, we show that adenosine production and signaling are upregulated in the hypoxic lymphoid niches, where intense colonization of leukemic cells occurs. This leads to a progressive remodeling of the immune system towards tolerance, with expansion of T regulatory cells (Treg), loss of CD8⁺ T-cell cytotoxicity and differentiation of murine macrophages towards the patrolling (M2-like) subset. In vivo administration of {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304"}}SCH58261, an inhibitor of the A2A adenosine receptor, re-awakens T-cell responses, while limiting Treg expansion, and re-polarizes monocytes towards the inflammatory (M1-like) phenotype. These results show for the first time the in vivo contribution of adenosine signaling to immune tolerance in chronic lymphocytic leukemia, and the translational implication of drugs interrupting this pathway. Although the effects of {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304"}}SCH58261 on leukemic cells are limited, interfering with adenosine signaling may represent an appealing strategy for combination-based therapeutic approaches.     

Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1‐q44 duplication including the AKT3 gene

Somatic and germline duplications or activating mutations of AKT3 have been reported in patients with hemimegalencephaly and megalencephaly. We performed array comparative genomic hybridization on brain tissue and blood in 16 consecutive patients with symptomatic epilepsy due to focal or multilobar malformations of cortical development who underwent surgical treatment of epilepsy. One patient with infantile spasms and a dysplastic left frontal lobe harboured a somatic trisomy of the 1q21.1‐q44 chromosomal region, encompassing the AKT3 gene, in the dysplastic brain tissue but not in blood and saliva. Histopathology revealed severe cortical dyslamination, a thin cortex in the premotor area with microgyri and microsulci, immature neurons with disoriented dendrites and areas of cortical heterotopia in the sub‐cortical white matter. These cytoarchitectural changes are close to those defining type Ib focal cortical dysplasia. Immunohistochemistry in brain specimens showed hyperactivation of the PI3K/AKT/mTOR pathway. These findings indicate that AKT3 upregulation may cause focal malformations of cortical development. There appears to be an etiologic continuum between hemimegalencephaly and focal cortical dysplastic lesions. The extent of brain malformations due to AKT3 upregulation may be related to the embryonic stage when the post‐zygotic gene alteration occurs.     

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T‐cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long‐term disease control and the ability to retreat patients relapsing off‐therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third‐line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re‐initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics‐mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T‐cell lymphoma, but suggests a complex mechanism of action.