Doc Group Research Articles

11-Deoxycorticosterone (DOC)'s Action on the Gill Osmoregulation of Juvenile Rainbow Trout (Oncorhynchus mykiss).

In aquaculture, stress can negatively affect fish growth. For years, the cortisol hormone has been thought to play both glucocorticoid and mineralocorticoid functions. Nevertheless, recent research has suggested that 11-deoxycorticosterone (DOC) released during stress could contribute to cortisol actions, though this process is still misunderstood. Here, we evaluated the DOC effects on physiological and early transcriptional responses by RNA-seq. Juvenile rainbow trout were treated with DOC and/or glucocorticoids (mifepristone) or mineralocorticoid (eplerenone) receptor antagonists. Subsequently, plasma was collected, and cDNA libraries were generated from the gills of vehicle (control), DOC, mifepristone, mifepristone with DOC, eplerenone, and eplerenone with DOC groups. Calcium and phosphate levels in plasma were changed. Results revealed 914 differentially expressed transcripts (DETs) induced by DOC compared with control, mainly associated with sodium ion transmembrane transport, gluconeogenesis, negative regulation of transmembrane transport, and activation of innate immune response. DOC versus eplerenone with DOC comparison displayed 444 DETs related to cell-cell junction organization, canonical glycolysis, positive regulation of immune response, and potassium ion transport. Conversely, no DETs were detected in DOC versus mifepristone with DOC comparison. These data suggest that DOC has a relevant role in gill stress response and ion transport, which is differentially regulated by mineralocorticoid receptors.

Real-world efficacy of chemotherapy in patients with advanced extramammary Paget's disease: A retrospective, multicenter study of 204 Japanese patients.

e21579 Background: Extramammary Paget's disease (EMPD) is a rare skin cancer that develops in the vulva, anus, and axilla. The incidence rate of EMPD is 0.13 per 100,000 population/year in Caucasians and 0.28 in Asians; thus, it is more frequent in Asians. Although distant metastases have been reported to occur in 10%-20% of all cases of EMPD, standard systemic chemotherapy for advanced EMPD has not been established worldwide. Retrospective studies conducted thus far have been insufficient due to their small sample sizes. Furthermore, there are no reports comparing the effectiveness of multiple treatments. To establish a standard treatment for advanced EMPD, prospective clinical trials are necessary, and we are planning a prospective clinical trial. As a pilot study, we investigated a large sample of patients with advanced EMPD and analyzed the efficacy of systemic chemotherapies. Methods: Patients with advanced EMPD who were treated in 16 Japanese institutions during 2011-2022 were evaluated. The efficacy of each treatment was estimated by determining the objective response rate (ORR) or progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier analysis. Multivariable analysis was performed to account for potential confounding factors, such as age, sex, and performance status (PS). A total of 204 patients were enrolled, of which 164 (80.4%) patients were treated as follows: Docetaxel hydrate (DOC), n = 108 (52.9%); tegafur/ gimeracil/ oteracil potassium (S-1)/DOC, n = 16 (7.8%); fluorouracil/cisplatin (FP), n = 26 (12.8%); fluorouracil/epirubicin/carboplatin/vincristine/mitomycin C (FECOM), n = 3 (1.5%); and other, n = 11 (5.4%). Forty (19.6%) patients received the best supportive care. Results: OS and PFS did not differ significantly among the DOC, S-1/DOC, FP, FECOM, and other groups (p = 0.176 and p = 0.568, respectively). The ORRs in the S-1/DOC, DOC, FP, and FECOM groups were 75.0%, 51.9 %, 38.5%, and 66.7%, respectively. The odds ratio for the ORR of the S-1/DOC group compared with the DOC group estimated by the logistic regression analysis with adjustment for age, sex, and PS was 2.72, (95% CI: 1.09-6.78, p = 0.032). S-1/DOC was the only treatment with a significantly higher ORR than that of DOC, which is the most frequently used treatment for advanced EMPD in Japan. Conclusions: Although there were no significant differences in PFS and OS between the multiple regimens, the S-1/DOC group showed significantly higher ORR compared with the DOC group. Because the high response rate to S-1/DOC greatly improves the quality of life of patients with advanced EMPD, S-1/DOC may be more beneficial than DOC and other regimens for the treatment of advanced EMPD. A phase II clinical trial of S-1/DOC is currently planned in Japan.

Electroencephalogram-Based Brain Connectivity Analysis in Prolonged Disorders of Consciousness.

Prolonged disorders of consciousness (pDOC) are common in neurology and place a heavy burden on families and society. This study is aimed at investigating the characteristics of brain connectivity in patients with pDOC based on quantitative EEG (qEEG) and extending a new direction for the evaluation of pDOC. Participants were divided into a control group (CG) and a DOC group by the presence or absence of pDOC. Participants underwent magnetic resonance imaging (MRI) T1 three-dimensional magnetization with a prepared rapid acquisition gradient echo (3D-T1-MPRAGE) sequence, and video EEG data were collected. After calculating the power spectrum by EEG data analysis tool, DTABR ((δ + θ)/(α + β) ratio), Pearson's correlation coefficient (Pearson r), Granger's causality, and phase transfer entropy (PTE), we performed statistical analysis between two groups. Finally, receiver operating characteristic (ROC) curves of connectivity metrics were made. The proportion of power in frontal, central, parietal, and temporal regions in the DOC group was lower than that in the CG. The percentage of delta power in the DOC group was significantly higher than that in the CG, the DTABR in the DOC group was higher than that in the CG, and the value was inverted. The Pearson r of the DOC group was higher than that of CG. The Pearson r of the delta band (Z = -6.71, P < 0.01), theta band (Z = -15.06, P < 0.01), and alpha band (Z = -28.45, P < 0.01) were statistically significant. Granger causality showed that the intensity of directed connections between the two hemispheres in the DOC group at the same threshold was significantly reduced (Z = -82.43, P < 0.01). The PTE of each frequency band in the DOC group was lower than that in the CG. The PTE of the delta band (Z = -42.68, P < 0.01), theta band (Z = -56.79, P < 0.01), the alpha band (Z = -35.11, P < 0.01), and beta band (Z = -63.74, P < 0.01) had statistical significance. Brain connectivity analysis based on EEG has the advantages of being noninvasive, convenient, and bedside. The Pearson r of DTABR, delta, theta, and alpha bands, Granger's causality, and PTE of the delta, theta, alpha, and beta bands can be used as biological markers to distinguish between pDOC and healthy people, especially when behavior evaluation is difficult or ambiguous; it can supplement clinical diagnosis.

Unique Characteristics of Patients with Von Hippel-Lindau Disease Defined by Various Diagnostic Criteria.

Von Hippel-Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion). We aimed to compare the characteristics of patients with VHL-related pancreatic neuroendocrine tumor (vPNET) meeting either the clinical Danish criteria only (DOC) or IC to those with sporadic PNET (sPNET). The cohort included 33 patients with VHL (20 vPNETs) and 65 with sPNET. In terms of genetic testing and family history of VHL, 90.0% of the patients with vPNET in the IC group had a germline VHL pathogenic variant, and 70.0% had a family history of VHL vs. 20% and 10% in the DOC group, respectively (p < 0.05 for both). Patients with vPNET were younger at diagnosis compared with sPNET (51.6 ± 4.1 vs. 62.8 ± 1.5 years, p < 0.05). Patients in the IC group were younger at diagnosis with VHL, vPNET, pheochromocytoma, or paraganglioma (PPGL) and renal-cell carcinoma (RCC) than those in the DOC group (p < 0.05 for all comparisons). The most prevalent presenting manifestations were hemangioblastoma (42.8%) and PPGL (33.3%) vs. RCC (58.3%) and PNET (41.7%) in the IC vs. DOC groups. In conclusion, patients with vPNET meeting DOC criteria show greater similarity to sPNET. We suggest performing genetic testing, rather than solely using clinical criteria, for establishing the diagnosis of VHL.

Real-world first-line systemic therapy patterns in metastatic castration-resistant prostate cancer.

IntroductionSeveral systemic therapies have demonstrated a survival advantage in metastatic castration resistant prostate cancer (mCRPC). Access to these medications varies significantly worldwide. In Australia until recently, patients must have received docetaxel first, unless unsuitable for chemotherapy, despite no evidence suggesting superiority over androgen receptor signalling inhibitors (ARSIs). Our study investigated real‐world systemic treatment patterns in Australian patients with mCRPC.MethodsThe electronic CRPC Australian Database (ePAD) was interrogated to identify mCRPC patients. Clinicopathological features, treatment and outcome data, stratified by first‐line systemic therapies, were extracted. Comparisons between groups utilised Kruskal–Wallis tests and Chi‐Square analyses. Time‐to‐event data were calculated using Kaplan–Meier methods and groups compared using log‐rank tests. Factors influencing overall survival (OS) and time to treatment failure (TTF) were analysed through Cox proportional hazards regression models.ResultsWe identified 578 patients who received first‐line systemic therapy for mCRPC. Enzalutamide (ENZ) was most commonly prescribed (n = 240, 41%), followed by docetaxel (DOC, n = 164, 28%) and abiraterone (AA, n = 100, 17%). Patients receiving ENZ or AA were older (79, 78.5 years respectively) compared with DOC (71 years, p = 0.001) and less likely to have ECOG performance status 0 (45%, 44%, 59% in ENZ, AA and DOC groups respectively p < 0.0001). Median TTF was significantly higher in those receiving ENZ (12.4 months) and AA (11.9 months) compared to DOC (8.3 months, p < 0.001). PSA50 response rates and OS were not statistically different. Time to developing CRPC > 12 months was independently associated with longer TTF (HR 0.67, p < 0.001) and OS (HR 0.49, p = 0.002).ConclusionIn our real‐world population, ENZ and AA were common first‐line systemic therapy choices, particularly among older patients and those with poorer performance status. Patients receiving ENZ and AA demonstrated superior TTF compared to DOC, while OS was not statistically different. Our findings highlight the important role of ARSIs, given the variability of access worldwide.

Effect of Curvature Location on Fatigue Resistance of Five Nickel-titanium Files Determined at Body Temperature

IntroductionThe purpose of this study was to evaluate the effect of 5 different curvature locations on the fatigue resistance of thermomechanically treated nickel-titanium (NiTi) files and superelastic NiTi files at body temperature and to document the corresponding phase transformations. MethodsEndoSequence (ES; Brasseler USA, Savannah, GA), EndoSequence CM (ESCM, Brasseler USA), K3 (SybronEndo, Orange, CA), K3XF (SybronEndo), and Vortex Blue (VB; Dentsply Tulsa Dental Specialties, Tulsa, OK) NiTi files (size 25/.04) were subjected to fatigue tests inside customized artificial canals containing a curvature of 60° and a 3-mm radius. There were 5 different canals based on the location of initial curvature; these included groups in which the distance between the canal orifice and the location of the curvature (DOC) was 5, 6, 8, 10, and 11 mm. The model canal was immersed in water at 37°C ± 1°C. The number of cycles to failure (Nf) was recorded, and the fracture surface of the fragments was examined by scanning electron microscopy. Two unused files of each brand were examined by differential scanning calorimetry. ResultsThe Nf was highest in the 10-mm and 11-mm DOC groups and lowest with the 5-mm and 6-mm DOC groups (P < .05). ESCM files had the highest fatigue resistance followed by the VB, K3XF, K3, and ES files (P < .05). ESCM files had the highest Nf (P < .05), and ES and K3 files had the lowest Nf (P < .05) depending on the curvature location. Two endothermic peaks were observed on the heating curve of the heat-treated files (ESCM, K3XF, and VB). ConclusionsThe location of the canal curvature had a significant effect on the fatigue resistance of both heat-treated and superelastic NiTi files. The fatigue life of files in the coronal curve was quite short.

A web app nomogram based on real-life patients: Guide decision in first-line treatment for metastatic castration-resistant prostate cancer (mCRPC).

e17538 Background: mCRPC phenotype involves androgen-receptor signalling mechanisms that support the use of abiraterone/enzalutamide (Abi/Ez). These therapies improve overall survival (OS) and quality-of-life, with a favourable safety profile. There is no validated data defining the best drug or sequence to be used. Methods: A retrospective study evaluated if a nomogram helps the decision-making of first-line for mCRPC. The nomogram evaluated time-to-treatment failure (TTF) from Abi/Ez and Docetaxel (Doc) treatment and had C-índex of 0.726. Time from start of androgen deprivation therapy to Abi/Ez or Doc, pain, Gleason score, testosterone and the lowest PSA in castration-sensitive scenario were analysed. All patients (pts) in Doc group used second-line Abi/Ez. The outcomes were: to evaluate whether the nomogram scores were associated with TTF/OS in Abi/Ez population; to compare OS between Abi/Ez and Doc poor prognostic (PP) groups based on the nomogram scores. Kaplan-Meier and Cox-regression models were used for time-to-event analyses. The cut-off was defined by Log-Rank. Statistical significance was fixed at 0.05. Results: From May/12 to Feb/20, 123 pts were assessed (79 received first-line Abi/Ez and 44 Doc). Median follow-up was 25.7 months (1.6 to 93.7). Nomogram scores based on Abi/Ez treatment (medium score of 65, 0-225) were statistically associated with OS (HR 1.02, 95% CI 1.01-1.02, p &lt; 0.001) and TTF (HR 1.02, 95% CI 1.02-1.03, p &lt; 0.001). 79 pts who received Abi/Enz were stratified as having good (GP) (score &lt; 46), intermediate (IP) (score 46-112) and PP (score &gt; 112), and it was associated with 75%, 25-75% and 25% probability to 1-year free from treatment failure, respectively. Pts with GP (n = 24) had a median TTF of 29.8m (15.4-44.2), IP (n = 44) 9.8m (4.1-15.4) and PP (n = 11), 4m (2.5-5.5), p = &lt; 0.001. Pts with GP achieved higher TTF than IP (HR 2.3 95% CI 1.3-4.2 p = 0.005) and PP (HR 8.9 95% CI 3.8-20.6 p &lt; 0.001). The results were similar for OS, once the median for GP was 54.0m (30.5-77.6); IP 34.8m (32.2-37.5); and PP 13.6m (9.3-17.9), p = 0.023 (GP versus IP: HR 2.1 95% CI 1.01-4.4 p = 0.046; GP vs PP: HR 3.6 95%CI 1.4-9.6 p = 0.011). Pts with a higher score and PP from Abi/Ez group were compared with Doc pts at first-line (n = 44), showing worse OS (HR 2.4 95%CI 1.03-5.6 p = 0.042) when treated with Abi/Ez. Conclusions: The nomograns scores showed good correlation with TTF/OS. In PP groups, treatment with Doc was associated with better OS than Abi/Ez, suggesting a possible tool on the first-line decision making.

Head-to-head comparison of the non-G-CSF small molecule single agent (SA) plinabulin with SA pegfilgrastim for the prevention of docetaxel chemotherapy (chemo)-induced neutropenia (CIN) in the protective-1 trial.

TPS7087 Background: Plinabulin (Plin) is a small molecule with anti-cancer activity and CIN effects. The Phase (Ph) 2 clinical trial NPI-2358-101 ( NCT00630110 ) evaluated Plin at 20 or 30 mg/m2 on Day (D) 1 and D8) plus D1 Docetaxel (Doc) 75 mg/m2 combination versus D1 Doc alone in patients (pts) with non-small cell lung cancer(NSCLC). In a large ( &gt; 70%) subset of pts with a measurable lung lesion in the lung (per RECIST 1.1) receiving 30 mg/m2 Plin + Doc (n = 38), mOS was 4.6 months longer vs Doc alone (n = 38) (Mohanlal ASCO-SITC 2018). An unexpected post-hoc finding was a CIN benefit with adding at 20 or 30 mg/m2 Plin to Doc: 33% of pts in the Doc arm had grade 4 neutropenia, whereas in the Plin +Doc group 4% of pts (P &lt; 0.0003) (Blayney ASH 2018). Plin boost the number the number of hematopoietic/progenitor cells in bone marrow. We subsequently initiated two global Ph3 programs with Plin: 1. A Ph 3 trial confirming its anticancer activity in NSCLC (study BPI-2358-103; NCT02504489; this trial is ongoing) and 2. An evaluation of Plin for CIN prevention through studies BPI-2358-105 (NCT03102606; PROTECTIVE-1), and study 106 (NCT03294577; PROTECTIVE-2). We previously reported from the Ph 2 portion of study 105, that SA Plin and Pegfigrastim (Peg) had comparable protection against CIN induced by Doc, however in contrast to Peg, Plin did not cause bone pain or thrombocytopenia (Blayney IASLC 2018, ESMO 2018). Plin is given by 30 min IV infusion on the same day of Chemo, 30 min after Chemo. The Ph3 portion of Study 105 in ongoing. Methods: In the Ph 3 portion of PROTECTIVE-1, pts with NSCLC, HRPC or BC are randomized (1:1) to either Plin 40 mg (over 30 minutes on D1; n = 75) or Peg 6mg (on D2, n = 75), and the primary endpoint is Duration of Severe Neutropenia (DSN). Plin 20 mg/m2 is similar to a 40 mg fixed dose. Absolute neutrophil counts (ANC) is determined on D 0, 1,2,3,6,8,9,10, 15 in Cycle 1 The trial aims to demonstrate non-inferiority of Plin vs Peg. Non-inferiority will be declared if the non-inferiority margin (NIM) of 0.65 day will be met, which NIM is more conservative than the 1 day NIM, typically employed for G-CSG biosimilar trials. Pts should have at least 1 risk factor as per NCCN guidelines.The trial is double-blinded to enable reliable PRO, Bone Pain and QoL assessments through validated questionnaires (EQ-5D-5L; EORTC QLQ-C30; Wang Baker Faces Pain Rating Scale). Following an Interim Analysis, the trial will continue without modifications. Clinical trial information: NCT03102606 .

Development of disturbance of consciousness is associated with increased severity in acute pancreatitis

BackgroundDisturbance of consciousness (DOC) may develop in acute pancreatitis (AP). In clinical practice, it is known that DOC may worsen the patient’s condition, but we have no exact data on how DOC affects the outcome of AP. MethodsFrom the Hungarian Pancreatic Study Groups’ AP registry, 1220 prospectively collected cases were analyzed, which contained exact data on DOC, included patients with confusion, delirium, convulsion, and alcohol withdrawal, answering a post hoc defined research question. Patients were separated to Non-DOC and DOC, whereas DOC was further divided into non-alcohol related DOC (Non-ALC DOC) and ALC DOC groups. For statistical analysis, independent sample t-test, Mann-Whitney, Chi-squared, or Fisher exact test were used. ResultsFrom the 1220 patients, 47 (3.9%) developed DOC, 23 (48.9%) cases were ALC DOC vs. 24 (51.1%) Non-ALC DOC. Analysis between the DOC and Non-DOC groups showed a higher incidence of severe AP (19.2% vs. 5.3%, p < 0.001), higher mortality (14.9% vs. 1.7%, p < 0.001), and a longer length of hospitalization (LOH) (Me = 11; IQR: 8–17 days vs. Me = 9; IQR: 6–13 days, p = 0.049) respectively. Patients with ALC DOC developed more frequently moderate AP vs. Non-ALC DOC (43.5% vs. 12.5%), while the incidence of severe AP was higher in Non-ALC vs. ALC DOC group (33.3% vs. 4.4%) (p < 0.001). LOH showed a tendency to be longer in Non-ALC DOC compared to ALC DOC, respectively (Me:13; IQR:7–20 days vs. Me:9.5; IQR:8–15.5 days, p = 0.119). ConclusionDOC during AP is associated with a higher rate of moderate and severe AP and increases the risk of mortality.

Vulnerable Strata to Non-Adherence and Overuse in Treatment for Patients with Cognitive Impairment.

Background and purposeAppropriate medication treatment could enable both cognitively impaired patients and caregivers to hold on their cognitive functioning and quality of life. Thus, medication management and the factors influencing how management for this condition is carried out must be identified. In this study we aimed to evaluate the frequency of medication nonadherence (MNA) or drug overuse for cognitive impairment (DOC) and to extract significant variables, including the demographic and social characteristics, vascular risk factors, and cognitive status, for the diagnosis of MNA and DOC in Korean patients.MethodsWe investigated patients aged over 50 years between March 2019 and June 2019 via the cognitive enHancement of patIents with acQuired cognitive impairment (HIQ) campaign. MNA was defined as a participant who was classified as having cognitive impairment but did not take any cognition-related drugs, whereas DOC was defined as a participant who had normal cognition but was taking cognition-related drugs.ResultsWe included 10,767 patients. The MNA group consisted of 337 participants, whereas the DOC group comprised 1,107 participants. The factors that could differentiate the MNA group from the normal-behavior group were age, education, sex, and the total Korean version of Mini-Mental State Examination (K-MMSE) score. The factors that could differentiate the DOC group from the normal medication-behavior group were age, sex, residential distinction, experience of a dementia screening test, and the total K-MMSE score.ConclusionsThe underlying factors contributing to inadequate dementia-medication management must be understood, and intervention or support is needed to enable safe medication management.

Inhibitory effect of docetaxel combined with oncolytic adenovirus carrying short hairpin RNA targeting special AT rich sequence binding protein-1 on proliferation and invasion of breast cancer MDA-MB-231 cells

Objective To investigate the effect of docetaxel and oncolytic adenovirus carrying short hairpin RNA (shRNA) targeting special AT rich sequence binding protein-1 (SATB1) (ZD55-SATB1) on the proliferation and invasion of breast cancer MDA-MB-231 cells. Methods MDA-MB-231 cells were divided to 5 groups and treated with phosphate buffer (PBS), docetaxel (DOC, 1×10-6 mol/L), ZD55-enhanced green fluorescent protein (EGFP) (10 multiplicity of infection, MOI), ZD55-SATB1 (10 MOI), ZD55-SATB1 plus DOC (10 MOI + 1×10-6 mol/L) respectively. The viability of MDA-MB-231 cells treated with DOC (1×10-9, 1×10-8, 1×10-7, 1×10-6, 1×10-5 mol/L) alone and ZD55-SATB1 (0, 0.1, 1.0, 10.0, 100.0 MOI) alone for 96 h was assessed by cell counting kit-8 (CCK-8) assay. And the viability of MDA-MB-231 cells of 5 groups with 48-h treatment was assessed by CCK-8 assay. Cell invasion and migration capacities of MDA-MB-231 cells were detected by Transwell assay and Wound-Healing Assay respectively. The expression of E1A, SATB1 and invasion associated protein matrix metalloproteinase (MMP)-2, Vimentin, DE-cadherinF in MDA-MB-231 cells was detected by Western blotting. Results CCK-8 assay showed that DZD55-SATB1F (10 MOI) plus DOC (1×10-6 mol/L) (35.16±2.17)%, compared with corresponding dose ZD55-SATB1 (10 MOI) (58.26±2.02)% (P=0.015), ZD55-EGFP (10 MOI) (71.25±3.49)% (P=0.023), DOC (1×10-6 mol/L) (50.16±3.17)% (P=0.018), could significantly inhibit the viability of MDA-MB-231 cells after 48 h. Wound-healing assay showed that ZD55-SATB1 plus DOC could significantly inhibit the ability of cell migration as compared with ZD55-SATB1 group, ZD55-EGFP group or DOC group. Transwell assay showed the number of transmembrane cells in combination group (356.2±101.5), produced obvious inhibition of cell invasion and migration capacity of the MDA-MB-231 cells as compared with ZD55-SATB1 group (576.1±89.4) (P=0.035), ZD55-EGFP group (935.2±201.3) (P=0.027) and DOC group (878.4±178.7) (P=0.016), and the difference was significant. Western blotting showed that the adenovirus ZD55-SATB1 and ZD55-EGFP were efficient replication in MDA-MB-231 cells and DOC had no effect on adenovirus replication. In addition, SATB1 expression in the ZD55-SATB1 plus DOC group was lower than PBS group, DOC group, ZD55-SATB1 group and ZD55-EGFP group. Western blotting analysis also confirmed that ZD55-SATB1 plus DOC could increase the expression level of E-cadherin, concomitant with down-regulating the protein expression of MMP-2, Vimentin (P=0.000). Conclusion Oncolytic adenovirus carrying shRNA targeting SATB1 gene could inhibit the growth and invasion of MDA-MB-231 cells. The combined use of ZD55-SATB1 with DOC could significantly inhibit the proliferation and invasion of MDA-MB-231 cells. And the combination of the treatment of oncolytic adenovirus and DOC is better than DOC or adenovirus alone. Key words: Special AT rich sequence binding protein-1; Breast cancer; Docetaxel; Invasion; Migration

1215PD - Long-term outcomes with nivolumab (Nivo) vs docetaxel (Doc) in patients (Pts) with advanced (Adv) NSCLC: CheckMate 017 and CheckMate 057 2-y update

The phase III trials CheckMate 017 (NCT01642004) and CheckMate 057 (NCT01673867) demonstrated improved OS with the anti-programmed death (PD)-1 antibody nivo vs doc as treatment (tx) for adv previously treated squamous (SQ) and non-SQ (NSQ) NSCLC, respectively. Approval of nivo in these indications was based on results of these studies. Updated results based on a minimum follow-up (f/u) of 2 y are reported. Pts received nivo 3 mg/kg Q2W or doc 75 mg/m2 Q3W (1:1 randomization) until progression or discontinuation. The primary objective of each study was OS; additional objectives included investigator-assessed ORR, PFS, efficacy by PD ligand 1 (PD-L1) expression, and safety. With ≥2 y of f/u, 8% and 9% of pts remained on tx in the nivo groups of CheckMate 017 and 057, respectively, vs 0 pts in either doc group. 2-y OS and PFS rates and ORRs were higher with nivo vs doc in both studies (table). Median duration of response was ≥3 times longer with nivo (25.2 and 17.2 mo) vs doc (8.4 and 5.6 mo), with responses in the nivo groups lasting up to 30.4 and 33.7+ mo (table). Responses were ongoing in 37% and 34% of nivo responders vs 0 doc responders. In CheckMate 057, complete responses (n = 4; 1%) were observed across PD-L1 expression levels (PD-L1 ≥1%: n = 2; PD-L1 <1%: n = 1; PD-L1 not quantifiable: n = 1). Rates of grade 3–4 tx-related (TR) AEs remained lower with nivo vs doc (table), despite longer mean tx durations in the nivo vs doc groups (CheckMate 017: 7.5 vs 2.5 mo; CheckMate 057: 7.0 vs 3.3 mo). Rates of TR select AEs with nivo also remained low (table).Tabled 1CheckMate 017 (SQ NSCLC)CheckMate 057 (NSQ NSCLC)Efficacy measureNivo (n = 135)Doc (n = 137)Nivo (n = 292)Doc (n = 290)OSMedian, mo9.26.012.29.5HR (95% CI)0.62 (0.47, 0.80)0.75 (0.63, 0.91)2-y OS, %2382916PFSMedian, mo3.52.82.34.3HR (95% CI)0.63 (0.48, 0.83)0.89 (0.75, 1.07)2-y PFS, %16NC121ORR, %2091912Median DOR, mo (range)25.2 (2.9–30.4)8.4 (1.4 + -18.0+)17.2 (1.8–33.7+)5.6 (1.2 + –16.8)Ongoing response,a %370340No. ongoing/total responders10/270/1219/560/36Safety measureNivo (n = 131)Doc (n = 129)Nivo (n = 287)Doc (n = 268)Grade 3–4 TRAEs, %8561154TR select AEbcategory in ≥5% of pts, %Endocrine5010<1Gastrointestinal820923Hepatic5262Pulmonary713<1Skin1091813aResponders who had neither progressed nor initiated subsequent therapy at time of analysis, excluding those censored prior to 14 wk before the data cutoff date. bAEs with a potential immunologic cause. + denotes an ongoing response at database lock or at the time of censoring in pts who initiated subsequent therapy; DOR = duration of response; NC = not calculable because no pts remained on tx. Open table in a new tab aResponders who had neither progressed nor initiated subsequent therapy at time of analysis, excluding those censored prior to 14 wk before the data cutoff date. bAEs with a potential immunologic cause. + denotes an ongoing response at database lock or at the time of censoring in pts who initiated subsequent therapy; DOR = duration of response; NC = not calculable because no pts remained on tx. With ≥2 y of f/u, nivo continued to demonstrate OS benefit and high rates of durable response vs doc in pts with adv NSCLC. Only nivo-treated pts had tx ongoing and responses lasting >2 y. The safety profile of nivo remained favorable vs doc, with no new safety concerns identified. Updated data on time to onset and resolution of TR select AEs will be presented.

Feasibility of classical secondary hormonal therapies prior to docetaxel therapy in Japanese patients with castration-resistant prostate cancer: Multicenter retrospective study.

BackgroundWe retrospectively analyzed castration-resistant prostate cancer (CRPC) patients treated with secondary hormonal therapies (SHTs) prior to docetaxel therapy.MethodsThe cases of 73 CRPC patients who underwent docetaxel therapy in 2005–2011 at four hospitals in Ibaraki, Japan were analyzed. We determined the cause-specific survival (CSS) from the start of docetaxel therapy and the time point of CRPC diagnosis, and we compared the CSS achieved with/without prior classical SHTs, which were defined as low-dose steroid and estramustine phosphate.ResultsOf the 73 enrolled patients, 26 underwent docetaxel therapy (DOC group), and 47 underwent SHTs (SHTs-DOC group) as the initial treatment for CRPC. In the docetaxel therapy, the rate of prostate-specific antigen responses were higher in the DOC group compared with the SHTs-DOC group (76.9% vs. 44.7%, P = 0.0066). The median CSS from the docetaxel therapy initiation was not significant but longer in the DOC group than in the SHTs-DOC group (23.4 months vs. 16.6 months, P = 0.0969). However, the median CSS from the time of CRPC diagnosis did not significantly differ between the DOC and SHTs-DOC groups (23.4 months vs. 24.7 months, P = 0.9233). In a univariate analysis, pain and visceral metastasis appeared to be risk factors for the CSS in the SHTs-DOC group. The patients with pain and/or visceral metastasis had significantly poorer survival than those without these factors in the SHTs-DOC group (31.5 months vs. 16.8 months, P = 0.0053).ConclusionThe induction of SHTs prior to docetaxel therapy is an acceptable treatment option with some survival benefits for CRPC patients without pain and visceral metastases.

Oral v. pulse intravenous cyclophosphamide: A retrospective analysis of adverse events in a setting with a high burden of infectious disease.

Cyclophosphamide (CPM) is still considered to be the first-line treatment for many life-threatening autoimmune conditions. It does, however, carry a significant risk of serious adverse events, especially infections. At present CPM is administered as either a daily oral dose (DOC) or an intravenous pulse (PIVC). There is uncertainty regarding the safety profiles of both regimens in settings with a high burden of infectious diseases. To compare the frequency and nature of adverse events related to the use of DOC and PIVC in such a setting. A cohort of patients treated with CPM for autoimmune diseases at Tygerberg Academic Hospital, Cape Town, South Africa, from 1 January 2008 to 31 May 2013 was studied. We compared participants receiving DOC and PIVC with regard to disease characteristics and the occurrence of major adverse events. A total of 134 participants (92 DOC and 42 PIVC) were included. Participants in the DOC group were treated for longer (174 v. 101 days; p<0.01) and with higher cumulative doses (17 276 v. 3 327 mg; p<0.01). Risk of infection was similar in the two groups, although there were 6 deaths from leucopenic sepsis in the DOC group (v. 0; p=0.18). Nadir leucocyte counts were also lower in the DOC group (median 3.8 v. 5.3 × 109/L; p=0.02). Infection rates in the two groups were similar, but DOC was associated with longer treatment duration, greater cumulative CPM doses and more severe leucopenia. If resources allow and available literature provides support for efficacy, consideration should be given to greater use of PIVC.

Autonomic responsivity and semantic associative competences in disturb of consciousness

Linguistic associative functions in disorders of consciousness patient (DOC) were studied in the present research by using autonomic measures (Skin Conductance Response, SCR; Heart Rate, HR). We intended to verify the preservation of semantic linguistic processes in Vegetative State (VS) and Minimal Consciousness State (MCS) by considering arousal modulation. Twenty-four patients and twenty controls were submitted to an auditory semantic task (congruous or incongruous word sequences). A similar increased SCR/HR was found for both DOC and control group in response to incongruous condition. This modulation was interpreted as a marker of the increased cognitive difficulty in processing and restoring incongruent information. However, MCS and VS groups quantitatively (but not qualitatively) differed in term of degree of increased arousal, since higher SCR and HR increasing was observed for MCS than VS. These results were interpreted as a marker that the semantic processing was partially preserved in both VS and MCS patients.

Anti-fibrotic effect of Aliskiren in rats with deoxycorticosterone induced myocardial fibrosis and its potential mechanism

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (PERK1/2) and matrix metalloproteinase 9 (MMP-9). In the DOC group and ALI group, the CVF and PVCA were significantly increased; the RA and Ang II levels in the plasma and ventricle were remarkably lowered when compared with the CON group. The RA and Ang II levels in the ventricle of the ALI group were significantly lower than those in the DOC group. Moreover, the expressions of ERK1/2, PERK1/2 and MMP9 were the lowest in the CON group, but those in the ALI group were significantly reduced as compared to the DOC group. ALI can inhibit the DOCA induced myocardial fibrosis independent of its pressure-lowing effect, which may be related to the suppression of RA and Ang II production, inhibition of ERK1/2 phosphorylation and MMP9 expression in the heart.

A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

What Does Self-identified Drug of Choice Tell Us About Individuals Under Community Corrections Supervision?

The term "drug of choice" (DOC) refers to substance abusers' preferred drug and this information often adds to the clinical picture of the patient because substance users often meet diagnostic criteria for dependence on multiple drugs. Characteristics such as age, race, marital status, and psychiatric illnesses have been shown to differentiate among individuals with different DOC preferences. However, no studies have examined DOC in the context of criminal behavior and other drug dependencies. The participants (N = 15,475) of a community corrections program, Treatment Alternatives for Safer Communities (TASC), were classified by DOC for the 4 main drugs of abuse (alcohol, marijuana, cocaine, and opioids) and each drug class was compared with the other 3 DOC using binary logistic regression. Alcohol as DOC was associated with being older, white, male, having private health insurance, being medicated for a mental health disorder, and having a criminal history of person offenses. Cocaine as DOC was associated with being older, black, female, attempting suicide, having less than a high school education, living in a shelter or with relatives, being unemployed, being uninsured, being physically and sexually abused, and committing property and court offenses but not person or substance offenses. Marijuana as DOC was associated with being younger, black, male, never being married, and committing substance but not property or court offenses. Opioids as DOC were associated with being white, female, being married, higher education, being unemployed, and being medicated for a mental health disorder. Overall, there were substantial differences between the 4 DOC groups, and the results are commensurate with expectations based on the abuse and dependency literature.

Abstract 2697: Enhanced antitumor effect of combination intravesical BCG plus Docetaxel therapy in an orthotopic bladder cancer model

Abstract Introduction and Objective: Little progress in the management of non-muscle invasive bladder cancer (NMIBC) has been made. We explored the combination of intravesical BCG plus Doc in an orthotopic model. Methods: An orthotopic murine bladder cancer model was used. To assess the antitumoral effect of Doc, intravesical Doc therapy was administered at various dose-escalating concentrations: 0 μg (control: PBS), 25 μg, 50 μg and 100 μg (n = 12 for each group; total of 4 groups). Next, a comparative evaluation of tumor growth among the control group, the BCG-alone group, the Doc-alone group, and three combined BCG + Doc groups (a coincident group [CO] and two sequential groups) was performed (n = 12 for each group; total of 6 groups). The sequential combined groups consisted of SA group (SA; Doc administration followed by BCG administration on the next day) and an SB group (SB; BCG administration followed by Doc administration on the next day). Intravesical therapy was administered at 3-day intervals starting on day 5 and was repeated 5 times. To evaluate proliferation, T cell infiltration and apoptosis among the different groups, the tumor cells in the animal model were stained for Ki-67, CD8 and Cleaved caspase 3 after 4 instillations performed every 3 days. Results: In the Doc groups (12 mice each) treated with a dose of 0 μg (survival period: 32.3 ± 9.4 days), 25 μg (36.8 ± 11.4), 50 μg (38.1 ± 11.0) or 100 μg (40.0 ± 12.7), one, two, two and three mice failed to develop tumors and survived, respectively. The survival advantage for intravesical Doc in the 100 μg administration group was statistically significant when compared with that in the control group (p = 0.04). Out of the 12 mice in each group treated with control, Doc-alone, BCG-alone or combined Doc + BCG (CO, SA, SB), 1, 2, 1, 4, 4 and 1 mice failed to develop tumors and survived, respectively. Significant survival advantages were observed in the combined BCG + Doc group (CO: 50.7 ± 9.0, SA: 51.5 ± 6.9) compared with that in the BCG-alone group (33.1 ± 10.4) and the Doc-alone group (38.8 ± 11.5). The Ki-67 index of the cancer cells was significantly lower in the combined group, compared with that in the BCG-alone group (p &amp;lt; 0.0001), the Doc-alone group (p &amp;lt; 0.05) and the control group (p &amp;lt; 0.0001). BCG-alone significantly increased the number of CD8+ T cells (p &amp;lt; 0.05), while Doc-alone reduced the number of CD8+ T cells (p &amp;lt; 0.05), compared with that in the control. Apoptosis was significantly increased when Doc was administrated to the animals irrespective of the presence (p &amp;lt; 0.05) or absence (p &amp;lt; 0.05) of BCG instillation. Conclusions: Our results suggested that the combination of BCG and Doc treatment decreased the tumor appearance rate and improved the survival period. The enhancement in tumor growth inhibition enabled by combination regimens was presumably associated with a reduction in the tumor proliferation rate and might not depend on either CD8+ T cells or apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2011-2697

Docetaxel plus trans-tracheal injection of adenoviral-mediated p53 versus docetaxel alone in patients with previously treated non-small-cell lung cancer

This phase II clinical trial compared the efficacy and safety of two types of treatment in patients with non-small-cell lung cancer (NSCLC) who had previously been treated with chemotherapy. Patients diagnosed with NSCLC (with either measurable or evaluable lesions) and had been treated with chemotherapy were eligible for this study. They were randomly assigned to two groups. The DOCp53 group received trans-tracheal Adp53 injection (1 × 10(12) vp dosage) on day 1 and day 8, as well as docetaxel at 75 mg m(-2) on day 2. The DOC group only received docetaxel at 75 mg m(-2) on day 1. Patients in each group received treatment for two cycles before reevaluation. Between February 2005 and December 2006, 40 patients were recruited for this study. In all, 19 of them were assigned to the DOCp53 group and 21 were assigned to the DOC group. After a mean follow-up of 12 months, the median survival time (MST) was 7.7 months (95% CI, 4.53 to 10.84) for patients in the DOCp53 group and 5.9 months (95% CI, 4.11 to 7.68) in the DOC group (P = 0.44, log-rank test). In the DOCp53 group, two patients with diffuse metastatic disease of lung had partial response (PR) in addition to eight with stable disease (SD). No PR and 13 SD were observed in the DOC group. Toxic reactions that could be attributed to the Adp53 vector were transient fever and limited hemoptysis. For patients with relapsed NSCLC, trans-tracheal injection of Adp53 in addition to docetaxel did not improve overall survival or efficacy. However, direct trans-tracheal injection of Adp53 proved to be a safe procedure, with tolerable levels of toxicity.