Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies

Background Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.Methods This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20.Results We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively).Conclusion Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.Subject terms: Cancer, Cancer therapy     

Ablation of porcine ligamentum flavum with Ho:YAG,q‐switched Ho:YAG,and quadrupled Nd:YAG lasers

Background and Objectives

Ligamentum flavum (LF) is a tough, rubbery connective tissue providing a portion of the ligamentous stability to the spinal column, and in its hypertrophied state forms a significant compressive pathology in degenerative spinal stenosis. The interaction of lasers and this biological tissue have not been thoroughly studied. Technological advances improving endoscopic surgical access to the spinal canal makes selective removal of LF using small, flexible tools such as laser‐coupled fiber optics increasingly attractive for treatment of debilitating spinal stenosis. Testing was performed to assess the effect of Ho:YAG, Q‐switched Ho:YAG, and frequency quadrupled Nd:YAG lasers on samples of porcine LF. The objective was to evaluate the suitability of these lasers for surgical removal of LF.

Study Design/Materials and Methods

LF was resected from porcine spine within 2 hours of sacrifice and stored in saline until immediately prior to laser irradiation, which occurred within an additional 2 hours. The optical absorbance of a sample was measured over the spectral band from 190 to 2,360 nm both before and after dehydration. For the experiments using the Ho:YAG (λ = 2,080 nm, t_p = 140 µs, FWHM) and Q‐Switched Ho:YAG (λ = 2,080 nm, t_p = 260 ns, FWHM) lasers, energy was delivered to the LF through a laser‐fiber optic with 600 µm core and NA = 0.39. For the experiment using the frequency quadrupled Nd:YAG laser (λ = 266 nm, t_p = 5 ns FWHM), rather than applying the laser energy through a laser‐fiber, the energy was focused through an aperture and lens directly onto the LF. Five experiments were conducted to evaluate the effect of the given lasers on LF. First, using the Ho:YAG laser, the single‐pulse laser‐hole depth versus laser fluence was measured with the laser‐fiber in direct contact with the LF (1 g force) and with a standoff distance of 1 mm between the laser‐fiber face and the LF. Second, with the LF remaining in situ and the spine bisected along the coronal plane, the surface temperature of the LF was measured with an IR camera during irradiation with the Ho:YAG laser, with and without constant saline flush. Third, the mass loss was measured over the course of 450 Ho:YAG pulses. Fourth, hole depth and temperature were measured over 30 pulses of fixed fluence from the Ho:YAG and Q‐Switched Ho:YAG lasers. Fifth, the ablation rate and surface temperature were measured as a function of fluence from the Nd:YAG laser. Several LF staining and hole‐depth measurement techniques were also explored.

Results

Aside from the expected absorbance peaks corresponding to the water in the LF, the most significant peaks in absorbance were located in the spectral band from 190 to 290 nm and persisted after the tissue was dehydrated. In the first experiment, using the Ho:YAG laser and with the laser‐fiber in direct contact with the LF, the lowest single‐pulse fluence for which LF was visibly removed was 35 J/cm². Testing was conducted at 6 fluences between 35 and 354 J/cm². Over this range the single‐pulse hole depth was shown to be near linear (R² = 0.9374, M = 1.6), ranging from 40 to 639 µm (N = 3). For the case where the laser‐fiber face was displaced 1 mm from the LF surface, the lowest single‐pulse fluence for which tissue was visibly removed was 72 J/cm². Testing was conducted at 4 energy densities between 72 and 180 J/cm². Over this range the single‐pulse hole depth was shown to be near linear (R² = 0.8951, M = 1.4), ranging from 31 to 220 µm (N = 3). In the second experiment, with LF in situ, constant flushing with room temperature saline was shown to drastically reduce surface temperature during exposure to Ho:YAG at 5 Hz with the laser‐fiber in direct contact with the LF. Without saline, over 1 minute of treatment with a per‐pulse fluence of 141 mJ/cm², the average maximum surface temperature measured 110°C. With 10 cc's of saline flushed over 1 minute and a per‐pulse laser fluence of 212 mJ/cm², the average maximum surface temperature was 35°C. In the third experiment, mass loss was shown to be linear over 450 pulses of 600 mJ from the Ho:YAG laser (212 J/cm², direct contact, N = 4; 108 J/cm², 1 mm standoff, N = 4). With the laser‐fiber in direct contact, an average of 53 mg was removed (R² = 0.996, M = 0.117) and with 1 mm laser‐fiber standoff, an average of 44 mg was removed (R² = 0.9988, M = 0.097). In the fourth experiment, 30 pulses of the Ho:YAG and Q‐Switched Ho:YAG lasers at 1 mm standoff, and 5 Hz produced similar hole depths for the tested fluences of 9 J/cm² (151 and 154 µm, respectively) and 18 J/cm² (470 and 442 µm, respectively), though the Ho:YAG laser produced significantly more carbonization around the rim of the laser‐hole. The increased carbonization was corroborated by higher measured LF temperature. In all tests with the Ho:YAG and Q‐Switched Ho:YAG, an audible photo‐acoustic affect coincided with the laser pulse. In the fifth experiment, with the frequency quadrupled Nd:YAG laser at 15 Hz for 450 pulses, ablation depth per pulse was shown to be linear for the fluence range of 0.18 – 0.73 J/cm² (R² = 0.989, M = 2.4). There was no noticeable photo‐acoustic effect nor charring around the rim of the laser‐hole.

Conclusion

The Ho:YAG, Q‐Switched Ho:YAG, and frequency quadrupled Nd:YAG lasers were shown to remove ligamentum flavum (LF). A single pulse of the Ho:YAG laser was shown to cause tearing of the tissue and a large zone of necrosis surrounding the laser‐hole. Multiple pulses of the Ho:YAG and Q‐Switched Ho:YAG lasers caused charring around the rim of the laser‐hole, though the extent of charring was more extensive with the Ho:YAG laser. Charring caused by the Ho:YAG laser was shown to be mitigated by continuously flushing the affected LF with saline during irradiation. The Nd:YAG laser was shown to ablate LF with no gross visible indication of thermal damage to surrounding LF. Lasers Surg. Med. 47:839–851, 2015. © 2015 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.     

Clinical evaluation of all-ceramic onlays: a 4-year retrospective study

PURPOSE: The aim of the present study was to evaluate the clinical outcome of extensive Empress onlays retained with resin-bonded cement. MATERIALS AND METHODS: One hundred thirty extensive ceramic onlays were placed in premolar and molar regions in 91 patients treated by 2 general practitioners between 1997 and 2000. Seventy-seven percent of the constructions were luted with chemically cured resin composite cement and 23% were luted with dual-cured resin cement. Fifty-nine patients with 81 restorations were clinically evaluated independently by 2 calibrated examiners using the California Dental Association protocol. The mean time in function for all restorations at examination was 49 months. RESULTS: Seventy-five (93%) onlays were still in function after 4 years. Six onlays (7.3%) failed; 1 had lost retention as a result of caries, and 5 had fractured. All failures were in molar regions. CONCLUSIONS: Ceramic onlay therapy is an acceptable treatment alternative over a 4-year period, but further long-term data are necessary before this treatment should be considered for general dental practice.     

A clinical evaluation of cobalt-chromium metal-ceramic fixed partial dentures and crowns: A three- to seven-year retrospective study

STATEMENT OF PROBLEM: In severely compromised dentition, loading of long-span and cantilever metal-ceramic fixed partial dentures (FPDs) could result in framework deformation and porcelain fractures. The use of cobalt-chromium (Co-Cr) alloys may be advantageous, but there is little information on the longevity of, and complications with, prostheses made with these alloys. PURPOSE: The aim of this retrospective study was to report the survival and complication rates of Co-Cr metal-ceramic FPDs and crowns followed over a 3- to 7-year period. MATERIAL AND METHODS: The study included 42 patients with a total of 51 FPDs and 12 single crowns assigned to 1 of 3 groups. The 3 groups comprised patients with abutment teeth with a questionable prognosis (n=10), advanced chronic periodontitis (n=19), or abutment teeth with a positive prognosis (n=13). The FPDs had a mean of 9.7 units (range of 3-14). Of the FPDs, 32 were provided with a cantilever on 1 side (n=24) or both sides (n=8). The mean observation time was 51 months (range of 28-82). All patients were examined by 2 independent prosthodontists using the California Dental Association (CDA) assessment system for evaluation. One-way ANOVA with Fisher's LSD post hoc test and the Mann-Whitney U test were used for statistical analyses (alpha=.05). RESULTS: Seventeen (34%) of the FPDs had biological and/or technical complications. Six (12%) FPDs were completely or partially removed during the observation period, 1 framework fractured, and 9 (17.6%) FPDs had ceramic fractures. Fifteen of the 21 fractured FPD units were related to FPDs that were placed in 3 patients with bruxing habits. The CDA rating for marginal integrity was "excellent" for more than 98% of the abutments. No patients reported adverse reactions to the material. CONCLUSIONS: Metal-ceramic FPDs made of cobalt-chromium alloy performed acceptably in the questionable prognosis and advanced chronic periodontitis groups.     

DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.     

Early cervical neoplasia: advances in screening and treatment modalities

Cervical cancer is one of the most common causes of cancer in women worldwide. However, improvements in screening programs and treatment modalities have significantly reduced the morbidity and mortality of this disease. The discovery that infection with the human papillomavirus is a crucial part of the causative pathway in cervical cancer pathogenesis has revolutionized screening and prompted investigations into alternatives to traditional cytologic evaluation, which may be useful in low-resource settings. Concomitant with improved screening has been a shift towards greater detection of both preinvasive and early-stage neoplastic disease. Earlier detection not only allows for surgical management of disease, with the avoidance of chemotherapy and radiation, but also the possibility of fertility preservation. As surgical technologies advance to encompass minimally-invasive procedures, interventions for early-stage cervical cancer are becoming increasingly effective in disease eradication while permitting patients to maintain their quality of life.     

PTEN loss is a context‐dependent outcome determinant in obese and non‐obese endometrioid endometrial cancer patients

Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3‐kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse‐phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P < 0.006) in obese (body mass index ≥ 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non‐obese population while decreased expression of β‐CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity‐related cancers and impact ongoing clinical trials with PI3K pathway inhibitors.     

Linear reduction of clonal cells in stem cell enriched grafts in transplanted multiple myeloma

In 30 patients with multiple myeloma who were scheduled for peripheral blood stem-cell transplantation, a quantitative analysis of the stem cells following enrichment by anti-CD34 was carried out. To detect the cells of the specific myeloma clone, polymerase chain reaction (PCR) was performed using unique allele-specific oligo primers for the immunoglobulin heavy chain rearrangement. The clonogenic cells before and after stem-cell enrichment, were quantified by a limiting dilution assay and a highly sensitive semi-nested PCR combined with a real-time quantitative PCR. In order to accomplish a statistically adequate end-point analysis, a large number of PCR analyses (40 per sample) were performed. By this technique the lowest detection limit observed was one myeloma cell per 106 cells. Myeloma cells were detected in 29/30 samples from the CD34-enriched fraction. The CD34 selection procedure resulted in a median 28-fold enrichment of CD34+ haemopoietic precursor cells. The stem-cell selection reduced the median concentration of clonal cells per million total cells by half, with a highly significant linear relationship between the number of myeloma cells before and after stem cell enrichment. The median depletion of clonal cells by the overall procedure was 2.15 log units, corresponding to a reduction of the total quantity of clonal cells reinfused into the patients by at least 99.3%. We conclude that CD34+ cell enrichment led to a reliable tumour cell depletion of the order of 2 log, which may not be sufficient since the total number of tumour cells in the leukapheresis product was 7.2 log (median).     

Reduced p18INK4c, p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of primary and secondary hyperparathyroidism

OBJECTIVE: Hyperparathyroidism (HPT) refers to states of excessive production of parathyroid hormone (PTH). The eukaryotic cell cycle is driven forward by cyclins and their cyclin-dependent kinase (CDK) partners. Cyclin-dependent kinase inhibitors (CKIs), which generally inhibit cell cycle progression, modulate the activity of cyclin-CDK complexes. DESIGN: In order to quantify the expression of the CKI genes p18, p21, and p27 semiquantitative RT-PCR with mRNA specific-primers was performed on four normal parathyroid biopsies, 31 parathyroid adenomas of primary HPT and 13 hyperplastic glands from uraemic patients with secondary HPT. PATIENTS: Parathyroid adenomas and secondary hyperplastic glands were obtained from 31 and 13 randomly selected patients undergoing parathyroidectomy in the clinical routine, respectively. Four normal parathyroid gland biopsies were obtained at surgery for pHPT or from normocalcemic patients undergoing thyroidectomy for goitre. RESULTS: The relative p27 expression (p27/GAPDH) was significantly reduced in parathyroid adenomas compared to normal parathyroid gland biopsies. Furthermore, 42% and 53% of the parathyroid adenomas displayed undetectable p18 and p21 expression levels, respectively. All 13 adenomas that lacked p18 expression showed undetectable p21 expression. The p18 expression was significantly lower in tumours of uraemic sHPT as compared to normal parathyroids and an undetectable expression level was observed for p21 and p27 in 61% and 53%, respectively. CONCLUSION: Parathyroid adenomas and secondary hyperplastic glands exhibit aberrant reduced expression of the CKIs p18, p21, and p27. This suggests that deranged collaboration of different CKIs may contribute to the development of both primary and secondary HPT.