A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma.

BACKGROUND: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. METHODS: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30). RESULTS: First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. CONCLUSION: These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.

Proinflammatory environment and role of TNF-α in endometrial function of obese women having polycystic ovarian syndrome.

BACKGROUND/OBJECTIVES: A high percentage of women having polycystic ovarian syndrome (PCOS) exhibit hyperinsulinemia and obesity. Transforming necrosis factor-α (TNF-α) is an adipokine that increases in obesity and negatively affects insulin action in several tissues, including the endometrium. In fact, it has been reported that insulin signaling is altered in the endometrium of PCOS women, affecting its reproductive function. The aim of this study was to determine the proinflammatory environment and TNF-α signaling in endometrium from obese women with PCOS, and also to evaluate the effect of TNF-α on endometrial cell energy homeostasis. METHODS: Serum and endometrial tissues were obtained from four study groups: normal-weight, normal-weight-PCOS, obese and obese-PCOS (hyperandrogenemia/hyperinsulinemia) (n=7 per group). Serum TNF-α level was assayed by enzyme-linked immunosorbent assay (ELISA); endometrial TNF-α level and its receptors (TNFR1/TNFR2) as well as nuclear factor (NF)-κB content were determined by immunohistochemistry. Finally, we evaluated TNF-α effect on glucose uptake in cultured human endometrial stromal cells (T-HESC) treated or not with testosterone/insulin resembling partially the PCOS condition. RESULTS: TNF-α plasma levels were similar between groups, whereas cytokine levels and macrophage number increased in endometrium from obese-PCOS women (P<0.001). Both receptor types were higher in obese vs normal-weight women, particularly TNFR2 content in the obese-PCOS group (P<0.001). Furthermore, an increased NF-κB nuclear content in endometrium from obese-PCOS was observed (P<0.001). Finally, TNF-α treatment of T-HESC cultures exhibited a decrease of glucose uptake (P<0.05), although similar to cells treated with testosterone or testosterone/insulin/TNF-α. CONCLUSIONS: These results suggest that the PCOS condition induces an inflammatory state exacerbated when obesity is present, where a higher TNF-α signaling is observed, all of which could affect glucose uptake in the tissue and may cause fertility failures in these women.

High-risk features in radiation-associated breast angiosarcomas.

BACKGROUND: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. METHODS: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982-2011 and collected their correlative clinical information. RESULTS: We identified 79 women with RT-AS with a median age of 68 (range 36-87). The median interval between radiation and development of RT-AS was 7 years (range 3-19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72-NA) and 2.48 years (95 % CI 1.29-NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21-NA). Independent predictors of worse disease-specific survival included age 68 years (HR 3.11, 95 % CI 1.20-8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02-10.21, P=0.046.) CONCLUSION: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

Managing obesity in primary care practice: an overview with perspective from the POWER-UP study.

Primary care practitioners (PCPs) have been encouraged to screen all adults for obesity and to offer behavioral weight loss counseling to the affected individuals. However, there is limited research and guidance on how to provide such intervention in primary care settings. This led the National Heart, Lung and Blood Institute in 2005 to issue a request for applications to investigate the management of obesity in routine clinical care. Three institutions were funded under a cooperative agreement to undertake the practice-based opportunities for weight reduction (POWER) trials. The present article reviews selected randomized controlled trials, published before the initiation of POWER, and then provides a detailed overview of the rationale, methods and results of the POWER trial conducted at the University of Pennsylvania (POWER-UP). POWER-UP's findings are briefly compared with those from the two other POWER trials, conducted at Johns Hopkins University and Harvard University/Washington University. The methods of delivering behavioral weight loss counseling differed markedly across the three trials, as captured by an algorithm presented in the article. Delivery methods ranged from having medical assistants and PCPs from the practices provide counseling to using a commercially available call center, coordinated with an interactive website. Evaluation of the efficacy of primary care-based weight loss interventions must be considered in light of costs, as discussed in relation to the recent treatment model proposed by the Centers for Medicare and Medicaid Services.

Phase II trial of neoadjuvant temozolomide in resectable melanoma patients.

BACKGROUND: We treated melanoma patients with temozolomide (TMZ) in the neoadjuvant setting and collected cryopreserved tumor samples before and after treatment. The primary objective was to determine whether the response proportion was higher than previously reported in widely metastatic patients. A secondary objective was to test the feasibility of obtaining adequate tissue before and after treatment for genetic testing. MATERIALS AND METHODS: Chemotherapy-naive melanoma patients who were candidates for surgical resection were eligible. TMZ was administered orally at 75 mg/m(2)/day for 6 weeks of every 8-week cycle. Cycles were repeated until complete response (CR), progression, or stable disease (SD) for two cycles. RESULTS: Of 19 assessable patients, 2 had CRs and 1 had partial response. Four patients had SD; 12 progressed. Tumor O-6-methylguanine-DNA methyltransferase (MGMT) promoter was unmethylated in all nine patients analyzed including from the two CR patients. Pretreatment tumor microarray results were obtained in 16 of 19 patients. CONCLUSIONS: The response proportion to TMZ in the neoadjuvant setting was 16%, not different than in the metastatic setting. Responses were seen even in tumors with a methylated MGMT promoter. Pretreatment cryopreserved tumor adequate for microarray analysis could be obtained in most, but not all, patients. Post-treatment tumor was unavailable in complete responders.

Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours.

BACKGROUND: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. PATIENTS AND METHODS: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. RESULTS: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. CONCLUSIONS: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.

Risk and protective factors of secondary traumatic stress in Intensive Care Units: An exploratory study in a hospital in Madrid (Spain). / Factores de riesgo y protección del estrés traumático secundario en los cuidados intensivos: un estudio exploratorio en un hospital terciario de Madrid.

AIM: To propose a predictive model of secondary traumatic stress. DESIGN: A descriptive cross-sectional study was carried out. CONTEXT: The study was conducted in the Intensive Care Units of a hospital in Madrid (Spain). PARTICIPANTS: The sample comprised 103 health professionals. INTERVENTIONS: A series of questionnaires were created and completed by the participants. Network analysis and multiple regression were used for data analysis. VARIABLES OF INTEREST: Sociodemographic variables such as gender, years of experience and position, secondary traumatic stress, passion for work, work stressors, emotional effort, empathy and self-compassion were evaluated. RESULTS: The result identified the following: a) years of experience as a risk factor for compassion fatigue (ß=0.224 and P=0.029), and harmonious passion as a protector (ß=-0.363 and P=0.001); b) emotional effort and empathy as risk factors for shattered assumptions (ß=0.304 and P=0.004; ß=0.394 and P=0.000, respectively); and c), work stressors and empathy as risk factors for symptomatology (ß=0.189 and P=0.039; ß=0.395 and P=0.000, respectively), and years of experience as a protector (ß=-0.266 and P=0.002). CONCLUSIONS: This predictive model of secondary traumatic stress identifies protective factors which could be reinforced, such as harmonious passion, and risk factors which should be reduced, such as empathy and emotional effort, with a view to promoting quality of care and quality of life among these professionals.

Dual checkpoint inhibitor-associated eosinophilic enteritis.

BACKGROUND: Eosinophilia has been reported as a rare, new biological effect of immune checkpoint inhibition that may be associated with improved treatment response and the development of immune-related adverse events. CASE PRESENTATION: We report a case of dual checkpoint inhibitor-associated hypereosinophilia and eosinophilic enteritis in a patient with advanced cutaneous melanoma. Rapid resolution of peripheral eosinophilia and associated symptoms was achieved with steroids alone. CONCLUSIONS: Immune checkpoint inhibition can trigger inflammation in virtually any organ in the body, leading to diverse clinical manifestations. To our knowledge, this is the first case report of eosinophilic enteritis due to ipilimumab plus nivolumab.

Mental health, positive affectivity and wellbeing in prison: a comparative study between young and older prisoners.

OBJECTIVES: To explore sociodemographic, psychological and psychopathological characteristics, as well as to evaluate the behaviour in an inmate sample. MATERIALS AND METHODS: There is a total sample of 182 young and elderly inmates of the Madrid III Prison. The investigation has been carried out with a battery of self-report psychological questionnaires and objective measurements obtained through the prison files. Comparisons of means were made to see if there are significant differences between the two groups (young and elderly inmates) in the variables analysed. RESULTS: The analysis shows that there are no significant differences in wellbeing between young and elderly inmates. However, young people have higher levels of psychological distress, more presence of negative emotions and have a more maladjusted behaviour in prison (they consume more cannabis and have more disciplinary records). Older people better regulate their emotions, adopt better the perspectives of others, showing themselves to be friendlier. CONCLUSIONS: The elderly inmates in prison, compared with the youngest, have a better psychological adjustment, more internal resources and a better adaptation to the prison environment despite of no differences in related variables such as time in prison.

Corrigendum to "Sarcoma Immunotherapy: Past Approaches and Future Directions".

[This corrects the article DOI: 10.1155/2014/391967.].

Metapopulation dynamics and the quality of the matrix.

In both strictly theoretical and more applied contexts it has been historically assumed that metapopulations exist within a featureless, uninhabitable matrix and that dynamics within the matrix are unimportant. In this article, we explore the range of theoretical consequences that result from relaxing this assumption. We show, with a variety of modeling techniques, that matrix quality can be extremely important in determining metapopulation dynamics. A higher-quality matrix generally buffers against extinction. However, in some situations, an increase in matrix quality can generate chaotic subpopulation dynamics, where stability had been the rule in a lower-quality matrix. Furthermore, subpopulations acting as source populations in a low-quality matrix may develop metapopulation dynamics as the quality of the matrix increases. By forcing metapopulation dynamics on a formerly heterogeneous (but stable within subpopulations) population, the probability of simultaneous extinction of all subpopulations actually increases. Thus, it cannot be automatically assumed that increasing matrix quality will lower the probability of global extinction of a population.

Separation and isolation of lymphocyte subpopulations of different affinity for the antigen.

In order to separate, isolate, and determine the number and distribution of the subpopulations of lymphocytes of diverse affinities that are present in an immune response toward a single hapten, anti-trinitrophenyl (TNP) lymphocytes from immunized animals were purified by cell chromatography. Non-adherent spleen cells were passed through a column consisting of TNP-substituted polyacrylamide beads. The retained cells were eluted by applying a linear concentration gradient of TNP-lysine. Elution profiles having a limited number of peaks were obtained in all cases. The avidity of the cells in each fraction was measured by inhibition of formation of immune rosettes by free hapten. Results showed that each peak was located along the gradient according to its affinity since there was a direct correlation between the affinity and the concentration of hapten needed for the elution. The cells in each peak appeared to belong to a homogeneous subpopulation as shown by the slope of the curves obtained in the determination of avidity, suggesting that each peak corresponded to one expanded clone.

Molecular characterization of human immunodeficiency virus type 1-infected individuals from bolivia reveals the presence of two distinct genetic subtypes B and F.

Thirty HIV-1-positive samples from Bolivia were genetically characterized on the basis of HMA and DNA sequencing, revealing the presence of B and F subtypes, in accordance with the molecular epidemiology pattern already described for other South American countries such as Brazil and Argentina. The interpatient divergence of subtype B Bolivian specimens was on average 14.2% (4.3-19.8%) at the nucleotide level, whereas the two unlinked subtype F samples (BO23 and BO29) were only 8.2% divergent, suggesting a more recent introduction of this subtype in the country. In our study group, which represents 13% of the HIV/AIDS cases already described in Bolivia as of May 1996, the transmission occurred more frequently through heterosexual exposures (46.7%), followed by homosexual (23.3%), bisexual (10%), intravenous drug use (3.3%), and vertical (3.3%); in one case the potential exposure category could not be defined (3.3%). No association could be established between exposure categories, gender, or clinical classification and subtype distribution in the Bolivian HIV/AIDS patients.

Assessment of an automated immunoassay based on kinetic interaction of microparticles in solution for determination of opiates and cocaine metabolite in urine.

A recently introduced automated immunoassay which is based on kinetic interaction of microparticles in solution (Roche ONLINE), was evaluated for the detection of cocaine metabolite benzoylecgonine (BE) and opiates in human urine. Cross-reactivity for the opiates morphine (100%), codeine (88%), 6-monoacetylmorphine (88%), and morphine 3-glucuronide (72%) was assessed. Analytical recovery evaluated on blank urines spiked with 0, 250, 300, 350, and 500 micrograms/L of morphine and BE (n = 10), varied from 85.2 to 100.2% for opiates and from 81.4 to 93.1% for the cocaine metabolite. The within-day precision ranged from 1.4 to 4.7% for morphine and from 4.2 to 4.8% for BE. The repeatability of the standards over 1 month was 1.0-3.3% for opiates and 1.7-5.1% for BE, and thus allowing measurements to continue over 30 days without re-calibration. This method compared favourably with the SYVA EMIT d.a.u system and gas chromatography/mass spectroscopy (GC/MS) methods.

Patterns of electromyographic activity in subjects with different skeletal facial types.

Integrated electromyographic activity of masseter and anterior temporal muscles was recorded using bipolar surface electrodes in 33 young adults. Subjects were skeletally classified according to ANB angle reading corrected both for maxillary position and rotation of the jaw. Postural activity for both muscles was higher in Class III subjects than in Class I and Class II, whereas in Class I and II subjects activity was similar. During swallowing, masseter muscle activity in Class III subjects was higher than Classes I and II, whereas anterior temporal muscle activity was not different between Classes III and I. During maximal voluntary clenching, activity was not different among classes. High correlations between electromyographic activity and corrected ANB angle as well as with overjet were observed. Skeletal classification used in the present study may have clinical relevance regarding treatment and prognosis, as well as in the assessment of the relationship between muscular activity and craniofacial characteristics.

Influence of stabilization occlusal splint on craniocervical relationships. Part I: Cephalometric analysis.

This study was conducted in order to determine the effect of an occlusal splint on craniocervical relationships, in subjects with muscle spasms in the sternocleidomastoid and trapezius muscles. A full-arch maxillary stabilization occlusal splint was made for each of the 15 subjects. Two lateral craniocervical radiographs were taken for each subject, with and without an occlusal splint. Cephalometric analysis showed that the splint caused a significant extension of the head on the cervical spine. There was also a significant decrease in the cervical spine lordosis in the first, second and third cervical segment. These cervical changes could be a compensation mechanism caused by the extension of the cranium on the upper cervical spine. The change in the curvature implies that it is necessary to periodically evaluate the changes occurring in the craniocervical relationships after the occlusal splint has been inserted.