Respiratory responses to chemical stimulation of the parabrachial nuclear complex in the rabbit

The respiratory role of the parabrachial nuclear complex (PNC) was investigated in α-chloralose–urethane anesthetized, vagotomized, paralysed and artificially ventilated rabbits by means of unilateral microinjections (10–20 nl) of 20 mM -homocysteic acid. Chemical stimulation elicited three main types of site-specific respiratory effects: excitatory, apneustic and inhibitory responses. The results suggest that the PNC plays a complex role in the control of breathing.     

A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial,infratentorial, and spinal cord ependymoma

BackgroundNo standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O⁶-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas.MethodsPatients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI–Spine Tumor modules were collected.ResultsThe 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients.ConclusionsThis treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.     

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.     

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.     

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.     

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.First developed as anticancer agents in the 1950s, microtubule targeting agents (MTAs) are used in the treatment of a wide variety of malignancies and until now have been thought to kill cells by arresting them in mitosis (1, 2). Although this explanation applies to rapidly dividing cells in preclinical models, it cannot explain the activity of these agents in tumors in humans because these cells divide much more slowly. For the latter situtation, a different paradigm must explain the activity of MTAs, and we have proposed that interfering with microtubule (MT) trafficking in interphase cells is the principal mechanism of MTA action (3–5). In breast, ovarian, lung, and head and neck cancers, as well as in most lymphomas, combination regimens that include a MTA and a DNA-damaging agent (DDA) are preferred (Table S1). Although the frequency with which these combinations are used might be fortuitous, it is likely there is a mechanistic basis for this outcome. We hypothesized that by hampering the trafficking of essential DNA repair proteins, MTAs synergize with DDAs, augmenting their toxicity. To explore this theory further we studied the effects of combining a MTA and a DDA in a number of cell models and examined the distribution and biology of nine different proteins involved in DNA repair. We have confirmed the hypothesis and report our findings.