A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1–9) intravenous infusions of 25 μg/m2bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis. © 2001 Cancer Research Campaign http://www.bjcancer.co

Aprepitant for cough in lung cancer: a randomised placebo-controlled trial and mechanistic insights

RATIONALE: Effective cough treatments are a significant unmet need in lung cancer patients. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of Neurokinin 1 (NK-1) receptors, a mechanism also implicated in cough. OBJECTIVE: To assess aprepitant in lung cancer patients with cough and evaluate mechanisms in vagal nerve tissue. METHODS: Randomised double-blind crossover trial of lung cancer patients with bothersome cough. They received three days of aprepitant or matched placebo; following a three day wash out, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease gap recording chambers, indicative of sensory nerve activation, was measured to evaluate mechanism. MEASUREMENTS AND MAIN RESULTS: Twenty lung cancer patients enrolled, mean age 66years (±7.7), 60% female, 80% non-small cell cancer, 50% advanced stage and 55% WHO performance status 1. Cough frequency improved with aprepitant, reducing by 22.2%(95%CI 2.8-37.7%) over placebo whilst awake (p=0.03), 30.3%(95%CI 12.7-44.3) over 24hours (p=0.002) and 59.8%(95%CI 15.1-86.0) during sleep (p=0.081). Patient-reported outcomes all significantly improved. Substance P depolarised both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P induced depolarisation by 78% in guinea pig (p=0.0145) and 94% in human vagus (p=0.0145). DISCUSSION: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as anti-tussive therapies. Clinical trial registration available at www.http://www.isrctn.com/, ID: ISRCTN16200035

Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition

A subset of lung adenocarcinomas is driven by the EML4‐ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on‐target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4‐ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti‐apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first‐, second‐ and third‐generation ALK inhibitors

EPAC-Lung:Pooled analysis of circulating tumor cells in advanced non-small cell lung cancer

Background: We assessed the clinical validity of circulating tumor cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a European pooled analysis of individual patient data. This is the largest study of its kind and the first to examine between-centre heterogeneity of CTC identification in NSCLC.Methods: Nine European NSCLC CTC centers were asked to provide reported/unreported anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 - March 2017. We used Cox regression models, stratified by centre, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinico-pathological models using likelihood ratio (LR) statistics and c-indices.Results: Seven out of nine eligible centers provided data for 550 eligible patients, including 209 patients whose prognostic information was previously unpublished. CTC counts of ≥ 2 and ≥5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: HR 1.72, p < 0·001; ≥5 CTCs: HR 2.21, p < 0·001) and overall survival (≥2 CTCs: HR 2·18, p < 0·001; ≥5 CTCs: HR 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinico-pathological models (log-transformed CTCs p < 0·0001; ≥2 CTCs p < 0·0001; ≥5 CTCs p < 0·0001), while more moderate improvements were observed with the use of c-index models. There was minor evidence of between-center heterogeneity in the effect on PFS, but not OS.No difference in CTC profile was observed between key NSCLC molecular subsets such as EGFR, ALK, and KRAS.Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC. CTC count improves prognostication when added to full clinico-pathological predictive models. ≥2 CTCs is an appropriate cutoff to move towards establishing clinical utility

Response to gefitinib and erlotinib in Non-small cell lung cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. Two tyrosine kinase inhibitors (TKIs) of EGFR, gefinitib and erlotinib, have been used with variable benefit.</p> <p>Methods</p> <p>We have analyzed outcome data of a population of NSCLC patients that received these TKIs to determine the benefit derived and to define the clinical and molecular parameters that correlate with response. Tumor tissue from a subgroup of these patients was analyzed by immunohistochemistry to measure the expression level of EGFR and four activated (phosphorylated) members of the pathway, pEGFR, pERK, pAKT, and pSTAT3.</p> <p>Results</p> <p>Erlotinib was slightly superior to gefitinib in all measures of response, although the differences were not statistically significant. The most robust clinical predictors of time to progression (TTP) were best response and rash (p < 0.0001). A higher level of pEGFR was associated with longer TTP, while the total EGFR level was not associated with response. Higher levels of pAKT and pSTAT3 were also associated with longer TTP. In contrast, a higher level of pERK1/2 was associated with shorter TTP.</p> <p>Conclusion</p> <p>These observations suggest the hypothesis that tumor cells that have activated EGFR pathways, presumably being utilized for survival, are clinically relevant targets for pathway inhibition. An accurate molecular predictive model of TKI response should include activated members of the EGFR pathway. TKIs may be best reserved for tumors expressing pEGFR and pAKT or pSTAT, and little pERK. In the absence of molecular predictors of response, the appearance of a rash and a positive first scan are good clinical indicators of response.</p

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies

EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer

Introduction: We assessed the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a pooled analysis of individual patient data. Methods: Nine European NSCLC CTC centres were asked to provide reported/unreported pseudo-anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 to March 2017. We used Cox regression models, stratified by centres, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinicopathological models using likelihood ratio (LR) statistics and c-indices. Results: Seven out of nine eligible centres provided data for 550 patients with prognostic information for overall survival. CTC counts of ≥2 and ≥ 5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: hazard ratio [HR] = 1.72, p &lt; 0·001; ≥5 CTCs: HR = 2.21, p &lt; 0·001) and overall survival (≥2 CTCs: HR = 2·18, p &lt; 0·001; ≥5 CTCs: HR = 2·75, p &lt; 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinicopathological models (log-transformed CTCs p &lt; 0·001; ≥2 CTCs p &lt; 0·001; ≥5 CTCs p ≤ 0·001 for both survival end-points), whereas moderate improvements were observed with the use of c-index models. There was some evidence of between-centre heterogeneity, especially when examining continuous counts of CTCs. Conclusions: These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC and also reveal some evidence of between-centre heterogeneity. CTC count improves prognostication when added to full clinicopathological predictive models

A Retrospective Review of Supratherapeutic Modafinil Exposures

Modafinil is a non-amphetamine wakefulness-promoting agent used for the treatment of various sleep disorders characterized by excessive daytime sleepiness. There is little information in the medical literature with respect to supratherapeutic doses of this medication. We performed a retrospective review of the California Poison Control System database for all cases of single-substance ingestion of modafinil with follow-up to a known outcome for the time period 1998–2008. Data collected included age, gender, dose ingested, clinical effects, and medical outcome. There were a total of 87 patients, 53 (61%) of which were female. Patient ages ranged from 1.25 to 72 years with a mean of 30 years; 17 (20%) patients were aged 6 years or less. Thirty-three (38%) were intentional overdoses. Most commonly reported effects were tachycardia (n = 23), agitation (n = 14), anxiety (n = 11), headache (n = 8), hypertension (n = 6), dystonia/tremor (n = 6), and dizziness (n = 5). Forty-nine patients (56%) were managed at home, and 38 (44%) were managed in a healthcare setting. Therapies administered included activated charcoal (n = 8), benzodiazepines (n = 7), antihistamines (n = 2), intravenous fluids (n = 2), haloperidol (n = 2), and beta-blockers (n = 1). Effects were classified as none (n = 22), minor (n = 54), and moderate (n = 11). No major effects and no deaths occurred. Effects of modafinil overdose appear to be mild in most cases, with tachycardia and CNS symptoms predominating. Clinically significant effects requiring treatment occurred in a small number of patients

Sex ratio biases in termites provide evidence for kin selection

Contains fulltext : 142755.pdf (publisher's version ) (Closed access)Molecular testing of tumor samples to guide treatment decisions is of increasing importance. Several drugs have been approved for treatment of molecularly defined subgroups of patients, and the number of agents requiring companion diagnostics for their prescription is expected to rapidly increase. The results of such testing directly influence the management of individual patients, with both false-negative and false-positive results being harmful for patients. In this respect, external quality assurance (EQA) programs are essential to guarantee optimal quality of testing. There are several EQA schemes available in Europe, but they vary in scope, size and execution. During a conference held in early 2012, medical oncologists, pathologists, geneticists, molecular biologists, EQA providers and representatives from pharmaceutical industries developed a guideline to harmonize the standards applied by EQA schemes in molecular pathology. The guideline comprises recommendations on the organization of an EQA scheme, defining the criteria for reference laboratories, requirements for EQA test samples and the number of samples that are needed for an EQA scheme. Furthermore, a scoring system is proposed and consequences of poor performance are formulated. Lastly, the contents of an EQA report, communication of the EQA results, EQA databases and participant manual are given

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

Bryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as a weekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease as defined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. There were no disease responses and the main toxicity was myalgia