Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.

BACKGROUND: The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches. METHODS: We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT. RESULTS: The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers. CONCLUSIONS: As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

Expression of vascular endothelial growth factor receptor-1 and -2 in normal and diseased canine eyes.

OBJECTIVE: To immunohistochemically evaluate expression of vascular endothelial growth factor receptor-1 (VEGFR1) and -2 (VEGFR2) in ocular tissue of healthy dogs and dogs affected with primary glaucoma, uveitic glaucoma, and intraocular neoplasia. SAMPLE POPULATION: Enucleated globes from five dogs with primary glaucoma, five dogs with uveitic glaucoma, six dogs with intraocular neoplasms and three ophthalmically normal control dogs. PROCEDURE: Ocular tissues were obtained from enucleated globes of clinical cases or immediately following euthanasia for control dogs. Tissue sections were stained immunohistochemically for VEGFR1 and VEGFR2 via standard techniques and vascular tissue was qualitatively evaluated. Vascular endothelial VEGFR1 and VEGFR2 expression patterns are reported for normal and diseased ocular tissues. In addition, VEGFR1 and VEGFR2 expression patterns are reported for all normal ocular tissues. RESULTS: A constitutive expression pattern was detected for VEGFR1 by ocular vascular endothelial cells as well as nonvascular cells in the cornea, uvea, lens, and retina. VEGFR2 demonstrated limited expression in normal ocular tissue, but was widely expressed in vascular endothelium of diseased eyes, particularly in pre-iridal fibrovascular membranes. CONCLUSIONS: The results of this study suggest a role for VEGF receptors in both physiologic and pathologic angiogenesis in canine ocular tissue. Manipulation of this pathway may be a rational consideration for therapeutic intervention in canine ocular disease exhibiting pathologic neovascularization.

Acremonium keratomycosis in a cat.

A 14-year-old, female spayed Domestic Short-haired cat was presented for evaluation of progressive superficial corneal ulceration with mucoid ocular discharge, blepharospasm, and conjunctival hyperemia OD. Upon examination, ulcerative keratitis with stromal loss, chemosis, corneal edema, miosis, aqueous flare, and hyphema were noted. Corneal cytology revealed branching, septate fungal hyphae with bulbous terminations and associated ovoid structures, with suppurative inflammation. Fungal culture of corneal swabs confirmed the presence of Acremonium, although PCR of the cytology sample was negative. Ten days of treatment with topical 1% miconazole resulted in clinical deterioration before switching to topical 1% voriconazole solution, which was successful in resolving the infection. The apparent clinical efficacy of the topical antifungals used contrasted with the in vitro susceptibility profile.

Evaluation of nasolacrimal fluorescein transit time in ophthalmically normal dogs and nonbrachycephalic cats.

OBJECTIVE: To evaluate fluorescein nasolacrimal transit (NLT) times in ophthalmically normal dogs and nonbrachycephalic cats by use of 2 methods of the Jones test. ANIMALS: 73 dogs and 36 cats. PROCEDURES: Fluorescein dye was applied to the ocular surface of both eyes by means of a wetted fluorescein strip and, in a subsequent test, by administration of a drop of 0.2% fluorescein solution. During each test, the nares were monitored for the appearance of fluorescein for up to 30 minutes after application. Time of fluorescein appearance at the nares was recorded as NLT time. Recorded variables for all study animals included age, reproductive status, body weight, and Schirmer tear test values. For dogs, skull index, snout length, and cephalic conformation were also recorded. Data were grouped for statistical comparisons according to test results. RESULTS: In both dogs and cats, NLT was faster when the fluorescein solution versus fluorescein strip was used. In cats, none of the recorded variables had a significant effect on NLT, irrespective of the testing method used. In dogs, several variables had a significant effect on NLT, including cephalic conformation, snout length, age, and reproductive status, but these findings varied with testing method and testing group. CONCLUSIONS AND CLINICAL RELEVANCE: NLT was highly variable in dogs and cats, regardless of testing method used. Assessment of nasolacrimal patency in brachycephalic dogs by use of either method evaluated here is not likely to be clinically useful. In cats, assessment of nasolacrimal patency with the fluorescein drop method was faster and more conclusive than with the fluorescein strip method.

Outcomes of nonsurgical management and efficacy of demecarium bromide treatment for primary lens instability in dogs: 34 cases (1990-2004).

OBJECTIVE: To determine outcome of initial conservative management for primary lens luxation and evaluate topically administered demecarium bromide miotic treatment for prevention of anterior lens luxation, glaucoma, and vision loss in dogs. DESIGN: Retrospective case series. ANIMALS: 34 dogs with primary lens luxation. PROCEDURES: Medical records of affected dogs were reviewed for times to anterior luxation, luxation of the lens in the opposite eye, development of glaucoma, and vision loss. RESULTS: At 4 to 6 weeks and at 3 months after diagnosis of lens instability (subluxation or posterior luxation), 100% (34/34 and 29/29, respectively) of conservatively managed eyes retained vision. At 1 year after diagnosis of lens instability, 80% (16/20) of conservatively managed eyes retained vision, and at 2 years after diagnosis of lens instability, 11 of 19 conservatively treated eyes retained vision. The only significant effect of miotic treatment was to delay anterior lens luxation in eyes with lens instability. Miotic treatment did not significantly affect the time from anterior lens luxation in 1 eye to anterior luxation in the other eye, time to onset of glaucoma, or time to loss of vision in eyes with an unstable lens. CONCLUSIONS AND CLINICAL RELEVANCE: Prophylactic topically administered miotic treatment may be effective at delaying anterior luxation of an unstable lens in eyes affected by primary lens instability. Conservative medical management of dogs with primary lens instability is a reasonable alternative to surgical removal of a subluxated or posteriorly luxated lens via intracapsular lens extraction.

Mitochondrial DNA depletion analysis by pseudogene ratioing.

The mitochondrial DNA (mtDNA) depletion status of rho(0) cell lines is typically assessed by hybridization or polymerase chain reaction (PCR) experiments, in which the failure to hybridize mtDNA or amplify mtDNA using mtDNA-directed primers suggests thorough mitochondrial genome removal. Here, we report the use of an mtDNA pseudogene ratioing technique for the additional confirmation of rho0 status. Total genomic DNA from a U251 human glioma cell line treated with ethidium bromide was amplified using primers designed to anneal either mtDNA or a previously described nuclear DNA-embedded mtDNA pseudogene (mtDNApsi). The resultant PCR product was used to generate plasmid clones. Sixty-two plasmid clones were genotyped, and all arose from mtDNApsi template. These data allowed us to determine with 95% confidence that the resultant mtDNA-depleted cell line contains less than one copy of mtDNA per 10 cells. Unlike previous hybridization or PCR-based analyses of mtDNA depletion, this mtDNApsi ratioing technique does not rely on interpretation of a negative result, and may prove useful as an adjunct for the determination of rho0 status or mtDNA copy number.

Duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in clinically normal cats.

OBJECTIVE: To determine duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in domestic shorthair (DSH) cats. ANIMALS: 20 clinically normal DSH cats. PROCEDURES: Baseline corneal touch threshold (CCT) was established by use of a Cochet-Bonnet aesthesiometer. Treatment consisted of a single 50-microL topical application of an ophthalmic preparation of 0.5% proparacaine solution to a randomly selected eye of each cat. The corneal touch threshold was assessed 1 and 5 minutes after application to the cornea and at 5- minute intervals thereafter for 60 minutes. RESULTS: Corneal sensitivity, as determined by Cochet-Bonnet aesthesiometry, was significantly reduced from baseline for 25 minutes following topical administration of ophthalmic proparacaine. Maximal anesthetic effect lasted 5 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: As determined by Cochet-Bonnet aesthesiometry, duration of anesthetic effects on the cornea induced by a single topical application of an ophthalmic preparation of 0.5% proparacaine solution in DSH cats is considerably shorter than the reported duration of corneal anesthesia in dogs.

IgM multiple myeloma with an extremely rare non-aggressive presentation: A case report.

In the present study, the case of a 41-year-old man with immunoglobulin (Ig)M multiple myeloma (MM) that presented with an unusually non-aggressive clinical course who has survived for >9 years to date, is presented. Initial diagnosis of symptomatic MM was established according to the International Myeloma Working Group consensus statement and guidelines. Due to the mild symptoms, no therapy was administered and the patient was closely followed up. Eight years after initial diagnosis, clinical, morphological and genetic progression occurred with the development of hypercalcemia, progressively deteriorating polyneuropathy, clonal expansion of plasma cells up to 50% of hematopoietic cells and demonstration of the typical t(11;14) translocation (Ig heavy chain locus rearrangement). Subsequently, 4 cycles of induction chemotherapy with velcade, cyclophosphamide and dexamethasone, were administered. At the time of writing, the patient remained alive in generally good health. To the best of our knowledge, with a survival time of >9 years, this case reports the longest survival time of an IgM MM patient to date, which contradicts previous evidence that suggests IgM MM exhibits an aggressive clinical course.

Molecular characterization of mtDNA depleted and repleted NT2 cell lines.

Transmitochondrial cytoplasmic hybrids (cybrids) enable functional assessment of mitochondrial DNA (mtDNA)-encoded proteins. Cybrid production often utilizes cell lines depleted of endogenous mtDNA (rho0 cells), and a number of suitable rho0 cell lines exist for this purpose. We now provide molecular data characterizing an NT2 human teratocarcinoma rho0 cell line, as well as NT2 cybrid derivatives. NT2 rho0 cells contained no detectable mtDNA on a sensitive PCR assay. Eight weeks after exogenous mtDNA transfer cybrids showed no evidence of endogenous mtDNA reversion, and heteroplasmic ratios of a single nucleotide substitution roughly reflected that of the blood samples used to repopulate their mtDNA.

Emerging options for the management of non-small cell lung cancer.

Lung cancer is one of the leading causes of death in industrialized and developing countries. Approximately 80% of patients are diagnosed with non-small cell histology. Although a multidisciplinary approach is necessary for the treatment of patients at early or locally-advanced stages of the disease, further successes in the treatment of patients with advanced disease will largely rely on improved systemic tumor control. Although therapies directed against the epidermal growth factor receptor (EGFR) have been incorporated into daily clinical practice, the value of other treatments remains to be elucidated. The current review highlights the most important driver mutations in non-small cell lung cancer (NSCLC) and describes recent study results and the status of EGFR-directed therapy, anaplastic lymphoma kinase (ALK)-directed agents, antiangiogenic therapy, and mesenchymal-epithelial transition factor (MET) inhibitors. However, many other agents with different modes of action are being examined in clinical research.

Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker.

Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50-75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy.

Pulmonary toxicity among cancer patients treated with a combination of docetaxel and gemcitabine: a meta-analysis of clinical trials.

PURPOSE: The combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast, and pancreatic cancers and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some trials. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel-gemcitabine-dependent pulmonary toxicity. METHODS: We searched MEDLINE/Pubmed, EMBASE, and Cochrane Clinical Trials database for prospective full-text studies that used a schedule of docetaxel and gemcitabine to treat a malignant disease. We performed a meta-analysis for proportions using the arcsine transformation and a meta-regression using a generalized linear mixed model based on a binomial distribution and a logit link. RESULTS: We included 103 trials with 113 treatment arms comprising 5,065 patients (major entities included non-small cell lung cancer (n = 2,550), breast cancer (n = 1,119), pancreatic cancer (n = 466), and urothelial cancer (n = 161)). For the incidence of severe lung toxicity (common toxicity criteria [CTC] grades 3-5), we found a combined estimate of 2.70% (95% CI 2.26, 3.14). The estimate for the proportion of fatal cases was 0.35% (95% CI 0.21, 0.58). We found that the sequence of the chemotherapy schedule had no influence on the incidence of severe pulmonary adverse events (F-test F = 0.65, df = 3,113, P = 0.58) nor did the study phase, treatment line or ethnicity of the participants. We found that patients with breast cancer, compared to lung cancer patients, developed severe lung toxicity less frequently (OR = 0.18, 95% CI (0.09, 0.36)). CONCLUSION: We could not demonstrate that a particular chemotherapy sequence of docetaxel-gemcitabine is associated with excess pulmonary toxicity. Patients with lung cancer are at a higher risk for severe pulmonary side effects with docetaxel-gemcitabine than are patients with breast cancer.

A phase II study of weekly docetaxel-cisplatin as first-line treatment for advanced non-small cell lung cancer.

INTRODUCTION: The combination of docetaxel and cisplatin is an effective first-line regimen in patients with advanced non-small cell lung cancer. However, the recommended three-weekly schedule is associated with frequent neutropenia and infections. Because of the toxicity of cisplatin, patients may need to be hospitalized to ensure adequate hydration. The aim of this study was to assess the efficacy and tolerability of a weekly schedule of docetaxel and cisplatin. PATIENTS AND METHODS: Patients with inoperable stage International Union Against Cancer IIIB (malignant effusion) or IV non-small cell lung cancer received docetaxel (35 mg/m(2), 30 minutes infusion) and cisplatin (25 mg/m(2), 30 minutes infusion) on days 1, 8, and 15, every 4 weeks for 4 to 6 cycles. Ondansetron (8 mg) and dexamethasone (8 mg) were given intravenously before chemotherapy. The patients received oral dexamethasone 2 x 4 mg daily from the day before until the day after chemotherapy. NK1-antagonists were given at the investigator's discretion. The majority of patients was treated in outpatient departments. Safety was assessed using CTCAE v3.0. The primary end point was response rate (RECIST). RESULTS: Forty-four patients were included. Twelve of 44 patients achieved an objective response (11 partial, 1 complete, intent-to-treat response rate 27%). Median time to progression was 4.4 months (95% confidence interval: 4.0-4.7) and median survival 9.6 months (95% confidence interval: 2.9-16.2). Patients received a median of three full cycles. Four patients (9%) required dose reductions. No cases of febrile neutropenia or grade 2 to 4 thrombocytopenia were observed. One patient (2%) experienced grade 3/4 nausea and vomiting. CONCLUSIONS: Weekly docetaxel-cisplatin demonstrated comparable efficacy with three-weekly schedules. Although the frequencies of neutropenia and febrile neutropenia were low, non-neutropenic infections remained a problem. Because of relatively short hydration, the schedule can be safely administered in an outpatient setting.

A highly sensitive particle agglutination assay for the detection of P53 autoantibodies in patients with lung cancer.

BACKGROUND: Numerous assays have been described for the detection of p53 autoantibodies. These assays are highly specific with low sensitivity. In this report, the authors describe a highly sensitive and simple particle agglutination immunoassay using superparamagnetic particles for capturing p5 autoantibodies, p53 protein, and p53 protein-antibody complexes from large volumes of serum samples (2 mL). METHODS: Superparamagnetic particles were coated with different peptides spanning the entire p53 protein. These particles were incubated with serum samples from healthy blood donors (n=180), from patients without malignancies (n=27), and from patients with various forms of lung cancer (n=166). The particles were washed and placed into the reaction chamber of a gel card. After centrifugation, agglutination results were read visually. Positive reactions were defined by a layer of particles on top of the gel or agglutinated particles dispersed through the gel matrix. RESULTS: Depending on the peptide used, p53 autoantibodies were detected in from 17.5% to 35% of the investigated patients with lung cancer. By using a commercially available enzyme-linked immunoadsorbent assay (ELISA) kit, p53 autoantibodies were detected in only 3% of those patients. P53 protein and p53 protein-antibody complexes were not detected in patients with lung cancer (n=20). CONCLUSIONS: The newly developed assay was easy to perform and had sensitivity superior to that of the currently available p53 ELISAs.