Primary End Research Articles

The impact of muscle mass loss after esophagectomy for esophageal cancer on prognosis.

107 Background: Several reports revealed that preoperative presence of sarcopenia was related with poor prognosis for esophageal cancer. However, the influence of muscle mass loss during perioperative period on prognosis is unknown. The alternation of muscle mass during perioperative period is attractive topic as surgeon have chance to intervene for maintaining muscle mass in perioperative care. The aim of this study was to assess the influence of loss of muscle after esophagectomy to discharge on prognosis. Methods: This study retrospectively analyzed 150 consecutive patients with esophageal and gastroesophageal junction cancer, who underwent the open right thoraco−abdominal approach esophagectomy, pathologically diagnosed as squamous cell carcinoma or adenocarcinoma, between September 2011 and June 2015. Patients who had pathologically diagnosed as T4 or stageⅣ according to the UICC 7th edition TNM classification were excluded. This study investigated the influence of muscle mass loss after esophagectomy to discharge on prognosis. Body composition was analyzed using the Tanita MC−190EM bioelectrical impedance analyzer, evaluated within 1 week before surgery and at discharge. The primary end−point is over−all survival after esophagectomy. Results: The median % muscle mass loss was 4.38% (range −3.3 to +18.8). Patients were divided into two groups based on the % muscle mass loss by cut−off 4.38 (group A: less % muscle mass loss, group B: more % muscle mass loss). N stage (0/1/2/3) was 39/28/6/2 in group A, and 26/23/19/7 in group B. The rate of 2/3 was significantly higher in group B. Postoperative complication rate was 31% (23/75) in group A, and 48% (36/75) in group B. The complication rate was significantly higher in group B. The 3−years survival rate was 89.2% in group A, and 70.9% in group B. Group B was significantly worse for over−all survival than group A (p = 0.033). Multivariate Cox regression analysis showed that the patients who had % muscle mass loss over 4.38 (p = 0.045; HR 2.008; HR 95% CI 1.014−3.977), T2/3 (p = 0.001; HR 3.649; HR 95% CI 1.660−8.019) associated with worse over−all survival. Conclusions: Our study found correlation between loss of muscle after esophagectomy to discharge and worse outcomes.

Endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments.

130 Background: OBP-301 (telomelysin) is an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase (hTERT) promoter to regulate viral replication. OBP-301 causes selective replication and lysis of a variety of cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. We aimed to assess intratumoral injection of OBP-301 with radiotherapy in esophageal cancer patients unfit for standard treatments. Methods: An open-label, phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed esophageal cancer patients who deemed unfit to receive surgery or chemotherapy. Study treatment consisted of intratumoral OBP-301 injections on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral needle injection of the primary tumor through a flexible endoscope. The primary and secondary end points were incidence of dose-limiting toxicities and objective response rate. Results: Of 13 patients, seven, three, and three patients were treated in the cohorts with 1010, 1011, and 1012 virus particles of OBP-301, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed a transient, self-limited lymphopenia. Eight patients had local complete response (CR); all of them exhibited pathologically no viable malignant cells in biopsy specimens, and three had partial response. The objective response rate was 84.6%. The clinical CR rate was 80.0% in stage I and 66.7% in stage II/III, respectively. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8+ cells in three partially responded tumors. Conclusions: Multiple courses of endoscopic OBP-301 injection with radiotherapy were feasible and provided definite clinical benefits in patients with esophageal cancer. Clinical trial information: 000010158.

Patient reported abdominal pain as a surrogate of the clinical benefit of tipifarnib in pancreatic cancer patients.

275 Background: Tumor CXCL12 expression identifies patients who may benefit from tipifarnib therapy. In pancreatic cancer, CXCL12 is known to decrease abdominal pain by inducing the migration of pain suppressing Schwann cells to tumor lesions. Given the association between CXCL12 and pain suppression, we investigated whether the absence of patient reported abdominal pain could be a surrogate of clinical benefit from tipifarnib in pancreatic cancer patients. Methods: We conducted a retrospective analysis of a randomized placebo-controlled trial comparing gemcitabine plus tipifarnib (GT) versus gemcitabine plus placebo (GP) in pancreatic adenocarcinoma patients. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine at standard dosing. Primary study end point was overall survival. Results: 688 patients were enrolled of whom 155 (22.5%) reported no abdominal pain at study entry, 81 received GT and 74 GP. Baseline characteristics were balanced in the subset of patients with no reported abdominal pain (GT,GP): median age (63,59), female gender (35%,43%), ECOG 0-1 (89%,90%), metastatic disease (64%,70%), 6-month weight loss >10% (48%,39%), 6-month jaundice history (51%,45%), and prior Whipple surgery (16%,13%). Subjects receiving GT who did not report abdominal pain at study entry had higher frequency of locally advanced disease (36% vs 24%) and 6-month jaundice (51% vs 38%), and lower frequency of lung (6% vs 14%) and peritoneum (4% vs 13%) metastases than those reporting pain. No differences in survival were observed in the overall study. Median overall survival for GT was 193 vs 182 days for GP. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 305 vs 176 days, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 184 vs 182 days. A trend for better survival with GT was observed in subset of patients with no abdominal pain at study entry (GT,GP): 305 vs 184 days, p=0.058. Conclusions: Absence of abdominal pain may serve as a surrogate of clinical benefit from tipifarnib in pancreatic cancer. (Van Cutsem et al. JCO 2004;22:1430-8; NCT00005648; Trial Sponsor: J&J PRD). Clinical trial information: NCT00005648.

Feasibility of Spinal Anesthesia Placement Using Automated Interpretation of Lumbar Ultrasound Images: A Prospective Randomized Controlled Trial

Background:This study evaluated the efficacy of spinal anesthesia administration by resident physicians when using an ultrasound system with automated neuraxial landmark detection capabilities.Methods:150 patients were enrolled in this trial. Anesthesiology residents placed spinals in subjects undergoing scheduled cesarean delivery using one of three techniques to identify neuraxial landmarks: palpation, ultrasound, or combined palpation and ultrasound. Ultrasound was performed using a handheld system that automatically identified neuraxial landmarks (e.g. midline, intervertebral spaces). All residents watched a 10-minute video and received 20 minutes of hands-on training prior to participating in the study. First insertion success rate was the primary end point.Results:Among all patients, use of ultrasound resulted in a 11% greater first-insertion success rate (RR: 1.11 [0.85–1.47], p=0.431), a 15% reduction in needle insertions (RR: 0.85, p=0.052), and a 26% decrease in needle passes (RR: 0.74, p=0.070). In obese patients of BMI ≥ 30 kg/m2, use of ultrasound resulted in 26% greater first-insertion success rates (RR: 1.26, p=0.187), a 21% decrease in needle insertions (RR: 0.79, p=0.025), a 38% decrease in needle passes (RR: 0.62, p=0.030), and a 75% decrease in patients reporting neutral or low patient satisfaction with anesthesia administration (RR: 0.25, p=0.004).Discussion:Resident anesthesiologists competently utilized the ultrasound system after receiving minimal training. Technical endpoints and patient satisfaction trended towards improvement when ultrasound was used prior to spinal placement, with stronger trends observed in obese patients. Additional study is required to fully characterize the impact of the ultrasound system on clinical efficacy.

Association of serum angiopoietin-2 with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients: a prospective cohort study

BackgroundTo examine serum angiopoietin-2 (Angpt-2) in relation to malnutrition, inflammation, atherosclerosis and cardiac valvular calcification, so-called MIAC syndrome and its predictive role in outcomes of peritoneal dialysis (PD) patients.MethodsA prospective observational study was conducted in 324 chronic PD patients. Biochemical analysis was performed at baseline for serum angiopoietins, albumin and high sensitive C-reactive protein (hs-CRP) and echocardiography was done to detect cardiac valvular calcification. Primary study end points were fatal or nonfatal cardiovascular events and mortality.ResultsThe median of serum Angpt-2 levels was 5.44 ng/mL (interquartile range, 3.41–7.85). Across the three tertiles of serum Angpt-2, a significant trend effect was observed for body mass index, normalized protein catabolic rate, calcium × phosphorus product, hs-CRP, brain natriuretic peptide, lower-density lipoprotein cholesterol, left ventricular ejection fraction, total weekly urea clearance and residual renal function (all p < 0.05). Serum Angpt-2 showed a significant increase across the four groups of patients with increasing components of MIAC syndrome (p < 0.001). There were 77 deaths and 57 cardiovascular events. High serum Angpt-2 was an independent predictor of fatal and nonfatal cardiovascular events in PD patients (p = 0.02), however serum Angpt-2 was not an independent predictor of all-cause mortality (p = 0.3).ConclusionsSerum Angpt-2 showed close association with valvular calcification, atherosclerosis, inflammation and malnutrition, having significant independent prognostic value and is useful for cardiovascular event stratification in chronic PD patients. Angpt-2 might be a potential mediator of increased cardiovascular risk in patients undergoing PD treatment.

Infliximab biosimilar CT-P13 therapy in patients with Takayasu arteritis with low dose of glucocorticoids: a prospective single-arm study

To evaluate the efficacy and safety of infliximab biosimilar CT-P13 in patients with active Takayasu arteritis (TAK). In this single-center open-label trial, patients with active TAK received CT-P13 at a starting dose of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks up to week 46. They were followed up until week 54. From week 14 to week 46, patients with inadequate response received increased dose of CT-P13 by 1.5 mg/kg. Concomitant prednisolone was allowed ≤ 10 mg/day. The primary efficacy end point was the achievement of partial or complete remission at week 30. All patients underwent positron emission tomography–computed tomography (PET–CT) at baseline and week 30. Twelve patients with TAK received CT-P13; one patient with protocol violation was excluded from analysis. Nine (81.8%) patients had taken concomitant prednisolone with median dose of 5.0 mg/day. At week 30, three (27.3%) patients achieved complete remission and six (54.5%) patients achieved partial remission. Statistically significant improvements in modified Indian Takayasu Clinical Activity Score (ITAS2010), ITAS-A, and serum levels of erythrocyte sedimentation rate and C-reactive protein were seen at week 30 from baseline. PET parameters were significantly reduced from baseline to week 30, including maximum standardized uptake value, target-to-vein ratio, target-to-liver ratio, and PET Vascular Activity Score. There were no serious adverse events. Treatment with CT-P13 may lead to improvement in clinical, radiographic, and serological activities with lower glucocorticoid requirement in TAK.Trial registration number NCT02457585.

Using the recurrence risk score by Joensuu to assess patients with gastrointestinal stromal tumor treated with adjuvant imatinib: A retrospective cohort study.

In 2014, Joensuu and colleagues devised the first recurrence risk score (RRS) to identify the risk factors for gastrointestinal stromal tumor (GIST) recurrence. However, there are scarce data available on RRS effectiveness and efficiency. Therefore, we retrospectively analyzed clinical data to validate Joensuu's RRS in patients treated with adjuvant imatinib.In this retrospective cohort study, data were collected from patients with GIST who were treated with adjuvant imatinib between December 2005 and May 2017 in the West China Hospital. The study consisted of 137 patients, after application of inclusion and exclusion criteria. Recurrence-free survival (RFS) was the primary end point.The RRSs for 137 patients were divided into 3 groups: low (n = 46), medium (n = 48), and high (n = 43). The RFSs of the 3 groups were significantly different (P < .001). In patients who received adjuvant imatinib for <36 months, the RFS difference was also significant (P < .001), and the result was similar in patients treated with adjuvant imatinib for ≥36 months (P = .03). The area under the curve of the RRS was 0.84 ([95% confidence interval] 0.76–0.92, P < .001), suggesting that the RRS method could accurately assess recurrence risks for patients with GIST who were treated with adjuvant imatinib.It is appropriate to apply the RRS method to assess recurrence risks for patients with GIST who were treated with adjuvant imatinib. A longer adjuvant imatinib duration is recommended for high-risk patients with GIST. It is also important to identify a more effective treatment for patients who are resistant to imatinib.

Metagenomic and Functional Analysis of Athletes Identify an Exercise-Promoting Microbiome

To characterize the athlete microbiome, we have sequenced stool samples from marathon runners, ultramarathon runners, Olympic-caliber rowers, and sedentary controls (n=50) with each individual providing on average 7 samples (∼350 samples total). We have identified substantial alterations to the microbiome associated with athletic performance. In particular, we identified a bacteria genus, Veillonella, that increases in abundance after exercise. Veillonella’s primary source of energy is lactate - a metabolite that accumulates in the blood after exercise and is associated with fatigue. Through de novo assembly of ∼40 million contigs, we have developed a novel reference database from our athlete metagenomic/metatranscriptomic data sets - which consists of &amp;gt;2.5 million none redundant genes. Querying this database has yielded insights into potentially significant allelic variation, at the microbiome gene-level, involved in lactate related metabolic processes as well as multi’omic evidence of pathways that change between performance and recovery states. To validate this, we have isolated from our samples three species from this and introduced this cocktail of isolates to C57BL/6 mice prior to exhaustive exercise on a treadmill. Gavage of the Veillonella cocktail to mice four hours prior to exercise results in a significant decrease in serum lactate (lactate AUC of 40.31 mmol/L*hr relative to 66.07 mmol/L*hr in sham control mice; P &amp;lt; 0.05). Follow-up work currently being conducted involves assessing the role of Veillonella’s primary metabolic end product, the short chain fatty acid propionate, on limiting exercise-induced inflammation, and the effects of these components on recovery from exercise. Taken together, our study encompasses both high-resolution metagenomic analysis and experimental validation to understand the role that the microbiome naturally plays in the performance of elite athletes. Disclosure A. Kostic: None.

Should ablation of atrial fibrillation be proposed to all patients with symptomatic heart failure? – CASTLE-AF randomized controlled trial

Atrial fibrillation ablation in patients with heart failure gains more and more recognition. Published research report improvement of quality of life, physical capacity and left ventricle ejection fraction among others. Yet there used to be no data published on influence of AF ablation on overall survival among patients with heart failure. Published in 2018, CASTLE-AF study partially covers this gap. The study enrolled 363 patients randomly allocated to AF ablation (the study group) or conservative treatment (controls). After a median observation of 37.8 months the primary composite end point - death from any cause or hospitalization for worsening heart failure, occurred in significantly fewer patients in the ablation group than in the medical therapy: 28.5% vs. 44.6%, HR 0.62; 95% CI 0.43-0.87. What was more, there were fewer deaths from any cause in the study group: 13.4% vs. 25.0%, HR 0.53; 95% CI 0.32-0.86.

Remarks on Conversation and Negotiated Collective Belief

Gilbert (1989) and Gilbert and Priest (2013) have argued that paradigmatic conversations involve a collectivity of the conversers who participate in the conversation, in the sense that the conversers put forth and negotiate proposals of propositions to be collectively believed by them. Here I explore the plausibility of this Negotiated Collective Belief (NCB) thesis. I begin by supporting a more basic claim, that the nature of conversation itself entails that a conversation always involves a collectivity of the conversers. I then endorse and supplement Gilbert and Priest’s argument for the NCB thesis. I trace resistance to the thesis to the view that collective belief plays no important role in two primary social ends of conversation, exchanging information and making personal connections. I concede that this is so, but I endorse the view (with roots in Taylor 1985) that collective belief does play an important role in a different primary social end of conversation, the creation of a public space of thought. Thus, the NCB thesis is supported by argument and contributes to an explanation of how conversation fulfills one of its primary social ends.

Love, leadership and McDonald's

ABSTRACTUnderstanding leadership as a process of influence towards a goal, this paper considers the primary end towards which ecclesial leadership is appropriately directed. It first examines the narrative of managerialism, sometimes called the McDonaldization thesis, and explores its impact on the discourse and practice of ecclesial leadership. Arguing that the McDonaldization of ecclesial leadership is theologically bankrupt, the paper then engages the ecclesiology of Ray S. Anderson to advocate an alternative narrative for determining the proper primary telos of ecclesial leadership. This alternative narrative proposes a telos described here in terms of Spirit-enabled participation in Christ’s ministry of love, a love which in its extension towards human others constitutes, simultaneously, a response to God’s love in Christ.

Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort

To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. To characterize the clinical features of OA-MCL. This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Overall survival, disease-specific survival, and progression-free survival were the primary end points. Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region. These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.

Safety and effectiveness assessment of 2011–2012 seasonal influenza vaccine produced in China: a randomized trial

ABSTRACTObjective: This study evaluated the effectiveness and safety of the egg-based, trivalent, inactivated split influenza vaccine produced by the Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, China.Methods: From March 2012 through May 2012, we enrolled a total of 1390 healthy volunteers between the ages of 3 and 80 years in a randomized clinical trial at the Hebei Disease Control Center Vaccine Clinical Evaluation Center. For all subjects, body part adverse reactions and whole-body adverse reactions were observed 30 min, 6 h, and 1–7 days’ post-inoculation. If no severe adverse effects were observed 7 days’ post-vaccination, the local and systemic reactions of preliminary test participants were recorded until day 28. There was no placebo group in this study. Blood samples were taken for serological testing before vaccination and 28 days’ post-vaccination.Results: Twenty-eight days after vaccination, the seroconversion rates of experimental and control groups were H1N1 75.3% and 75.7%, H3N2 75.8% and 71.8%, B 70.7% vs. 69.4%, (P > 0.05). The antibody Geometric Mean Titer（GMT）of experimental and control groups were H1N1 (179.7, 182.4), H3N2 (584.0, 445.7), B (201.4,191.6). The protection rate of experimental and control groups was not statistically significant (H1N1: 86% vs. 87%, H3N2: 99% vs. 98%, B: 98% vs. 98%). Also, 95% confidence intervals of the protection rate difference between the experimental and the control group were H1N1: −0.1% (−4.1,3.8) %, H3N2: 0.3% (−1.0,1.7) % and B: 0.2% (−1.5,1.9) %; confidence intervals exceeded the limit of −5%. The rates of adverse reactions between experimental and control groups were 6.3% and 7.7% in local response reactions, and 19.5% and 18.0% in systemic reactions. Three hundred and twenty-seven adverse events (AEs) in 1200 (27.76%) subjects were reported within 28 d after vaccination. No serious adverse events occurred during the study.Conclusions: The experimental vaccine three-antibody protection rate was non-inferior to the control vaccine. Our results demonstrated that the experimental vaccine achieved the primary immunogenic end point of the intended clinical protocol, as well as a secondary immunogenic end-point, with an acceptable level of safety. IRB approval for this study was issued under #2012Y0005 and registered as Clinical Trial No. NCT01551810.

Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer

The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. clinicaltrials.gov Identifier: NCT01426880.

Outcomes of primary central nervous system lymphoma in the era of immunotherapy: Cleveland Clinic experience.

e13516 Background: Primary central nervous system lymphoma (PCNSL), a form of extranodal non-Hodgkin lymphoma represents 3% of primary CNS tumors. It is aggressive but typically confined to the CNS. Despite improvements in the management of PCNSL, more than 50% of patients eventually relapse. There are limited data on PCNSL from larger cohort studies. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center database was used to identify patients treated between 2006-2015 for PCNSL. Overall survival (OS) from the diagnosis of PCNSL and progression free survival (PFS) were the primary and secondary end points respectively. Cox proportional hazards models were used for data analysis. Results: 86 PCNSL patients were included in the analysis. Only 5% (4/76) were HIV positive. The median age of diagnosis was 63 (range 15 - 86) and 50% were males. 88% of patients presented only with brain lesion, 8% only in eye and 4% had both brain and eye involvement. 15% of patients (12/81) had positive CSF findings. Treatment included: chemotherapy (CT) alone (39% of patients); chemoimmunotherapy (CIT) (32%); CIT with radiotherapy (RT) (13%); RT alone (11%); CT with RT (4%); and immunotherapy (IT) alone (1%). Among 23 patients (31%) who received RT upfront, 74% had WBRT (n = 17). The most common upfront therapy was high dose methotrexate (HD MTX) (44%), followed by HD MTX with rituximab (23%), RTOG 0227 (12%), RTOG 1114 (11%) and rest 14% included rituximab or temozolomide or other cytotoxic chemotherapy alone or in combinations. The most common relapse site was brain (72%), followed by eyes (12%) and spine (8%). The median follow-up was 26 months. At last follow up, 41% had died and 93% of which were PCNSL-related. The median PFS and OS were 17.7 months and 84 months, respectively. There was a trend towards superior PFS in upfront IT vs. no IT (20 vs. 14 months, p 0.08). Better performance status (KPS &gt; 80 vs. &lt; 80, HR 0.42 (p = 0.033)) and PFS ≥ 24 months compared to ≤ 24 months (p = 0.0012) were associated with improved OS. Conclusions: We report a large single institution cohort of PCNSL patients treated in the era of immunotherapy. In our cohort, better KPS (≥80) and PFS ≥ 24 months had improved OS. Upfront IT showed a trend towards improved PFS.

Combination treatment with transarterial chemoembolization, radiotherapy, and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumor thrombosis: Final results of a prospective phase II trial.

Background & AimsThis study was designed to evaluate the efficacy and safety of combination transarterial chemoembolization (TACE) followed by radiotherapy (RT) and hyperthermia (CERT) in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).MethodsThis single-institution, single-arm, prospective phase II study was performed from October 2013 to February 2016. The objective response rate (ORR) was evaluated at 3 months after CERT completion, and overall ORR was the primary end point.ResultsDuring the study period, 69 of 77 patients who consented to participate underwent at least one session of hyperthermia and RT. More than half of the patients (39, 56.5%) complained of severe hyperthermia-related pain. The overall ORR was 43.5% (30/69), and the ORR of the RT target area was 69.6% (48/69). Liver function status was not significantly affected by CERT. Overall survival, local progression-free survival, and progression-free survival of all enrolled patients at 2 years was 62.9%, 47.6%, and 14.3%, respectively.ConclusionsAn overall ORR of 43.5% was observed after CERT, but a promising ORR of 69.6% was achieved in the RT target area. Toxicities related to CERT were manageable, and pain intolerance to hyperthermia was the main obstacle to treatment maintenance.

EFFECT OF CONTINUOUS TRANSCRANIAL DOPPLER ON THROMBOLYSIS IN ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION

Purpose: Recombinant tissue plasminogen activator (rtPA) activity may be enhanced with ultrasound, 2 MHz transcranial Doppler (TCD). We performed the trial to determine the efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous rtPA). Subjects and methods: We treated 80 patients who had acute ischemic stroke due to occlusion of the middle cerebral artery with intravenous rtPA within 4.5 hours after the onset of symptoms. The patients were randomly assigned to receive continuous 2-MHz transcranial Doppler ultrasonography (the target group) or placebo (the control group). The primary combined end point was complete recanalization as assessed by transcranial Doppler ultrasonography and dramatic clinical recovery at 2 hours. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Secondary end points included recovery at 24 hours, a favorable outcome at three months. Results: A total of 80 patients were randomly assigned to receive continuous ultrasonography (40 patients) or placebo (40 patients). Complete recanalization and dramatic clinical recovery within two hours after the administration of a rtPA bolus occurred in 13 patients in the target group (32,5%), as compared with 8 patients in the control group (20%) (P=0.038). At three months, 22 patients in the target group who were eligible for follow-up analysis (55%) and 13 in the control group (32,5%) had favorable outcomes (as indicated by a score of 0 to 1 on the modified Rankin scale) (P=0.012). Intracerebral hemorrhage occurred in five patients in the target group and in four in the control group. Conclusion: In patients with acute ischemic stroke due to occlusion of the middle cerebral artery, continuous transcranial Doppler augments rtPA-induced arterial recanalization, with an increased rate of recovery from stroke, as compared with placebo. Continuous 2-MHz transcranial Doppler ultrasonography for 2 hours is safe. Key words: Stroke, transcranial Doppler, tissue plasminogen activator

The effect of adjuvant chemotherapy for patients with adverse pathology after neoadjuvant chemotherapy for muscle invasive bladder cancer.

367 Background: While neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) is recognized as the standard of care, the management of patients with locally advanced and/or nodal disease after NAC and radical cystectomy (RC) is not well defined. We sought to evaluate the association of adjuvant chemotherapy (AC) and overall survival (OS) among patients with adverse pathology after NAC and RC. Methods: The National Cancer Database was reviewed to identify patients with adverse pathology (pT3N0, pT4N0, or pTanyN1−3) at RC following NAC from 2006−2012. Patients were stratified by receipt of AC. Clinical and pathologic variables were abstracted. OS was the primary end−point and differences on the basis of AC were assessed by the Kaplan−Meier method and log−rank test. Multivariable Cox proportional hazards regression was used to assess the association of AC with OS controlling for age, sex, race, Charlson score, year of diagnosis, pathologic stage, and receipt of adjuvant radiotherapy. Results: Adverse pathology following NAC and RC was identified in 1,361 patients from 2006−2012, of whom 328 (24.1%) received AC. Staging was pT3N0 in 444 (32.6%), pT4N0 in 162 (11.9%), and pTanyN1−3 in 755 (55.5%). Median OS for the entire cohort was 22.9 months, which differed by pathologic stage: 34.6 months (pT3N0), 21.4 months (pT4N0), and 19.3 months (pTanyN1-3)(p &lt; 0.01). No difference in OS was noted by receipt of AC in the overall cohort (median OS 24.6 months with AC vs 22.0 months without AC; p = 0.18), or when stratified by pathologic stage. On multivariable analysis, receipt of AC was not significantly associated with overall mortality (HR 0.86; 95%CI 0.74−1.01; p = 0.06) for all patients. When stratified by stage, AC was associated with a significantly decreased risk of mortality among patients with pT4N0 disease (HR 0.56; 95%CI 0.33−0.97; p = 0.04), but not pT3N0 or pTanyN1−3 (p &gt; 0.05). Conclusions: Patients with adverse pathology at RC after NAC have a median OS of approximately 2 years. AC was not associated with improved survival, except in the subgroup with pT4N0 disease. Clinical trials with newer systemic therapies are warranted for patients in this setting.

Abstract OT2-01-02: COLET: A multistage, phase 2 study evaluating the safety and efficacy of a doublet regimen of cobimetinib (C) in combination with paclitaxel (P) or triplet regimens of C in combination with atezolizumab (atezo) plus either P or nab-paclitaxel (nab-P) in metastatic triple-negative breast cancer (TNBC)

Abstract Preclinical data suggest that upregulation of the MAPK pathway confers resistance to taxane chemotherapy. Mutations and gene amplifications in the MAPK pathway are present in many TNBC tumors and may contribute to taxane resistance. Preliminary data from an initial safety run-in stage of the COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) suggest improvement of clinical outcomes when MEK inhibition is combined with taxane chemotherapy. Additionally, in preclinical models, MEK inhibition was shown to enhance anti–PD-L1 activity. The monoclonal antibody PD-L1 inhibitor atezo has shown promising activity in combination with nab-P in metastatic TNBC. Accordingly, the COLET protocol was amended to include the evaluation of triplet regimens combining atezo with MEK inhibition and taxane chemotherapy[SL1] . COLET is evaluating the safety and efficacy of various combinations of C as first-line treatment for metastatic or locally advanced TNBC. Key eligibility criteria include measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) and left ventricular ejection fraction &amp;gt; institutional lower limit of normal or &amp;gt;50%. Neoadjuvant or adjuvant therapy is allowed if completed &amp;gt;6 months prior to study entry. COLET has 3 cohorts: I, II, and III. Cohort I has 2 stages: an initial safety run-in stage (n∼12) followed by an expansion stage (n∼90) of 1:1 randomization to C + P or placebo (PBO) + P. Patients received P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3-23 of each 28-day cycle. In the expansion stage of Cohort I, randomization is stratified by prior neoadjuvant/adjuvant taxane therapy and disease-free interval from last chemotherapy dose. Cohorts II and III will evaluate the safety and efficacy of adding atezo to C + P or nab-P, respectively. Each cohort has a safety run-in stage (n∼15) and an expansion stage (additional n∼15); each will receive atezo 840 mg on days 1 and 15 and C 60 mg/day on days 3-23 of every 28-day cycle. Cohort II will receive P 80 mg/m2 and Cohort III will receive intravenous nab-P 100 mg/m2 on days 1, 8, and 15. Patients will receive treatment until disease progression or toxicity. The primary efficacy end point is investigator-assessed progression-free survival (PFS) for the expansion stage (Cohort I), and the primary PFS analysis will be performed when 60 PFS events occur across the 2 arms. This provides 77% power to detect a hazard ratio of 0.5 at a two-sided significance level of 0.05. For Cohorts II and III, the primary efficacy end point is overall response rate per RECIST v1.1; secondary end points include duration of response, PFS, and overall survival. Recruitment into the safety run-in stage of Cohort I is complete. Accrual into the randomization stage of Cohort I and the initial safety run-in stage of Cohorts II and III are ongoing. Patients from sites across North America, Europe, and the Asia-Pacific region will be enrolled. Citation Format: Miles D, Kim S-B, McNally V, Simmons B, Wongchenko M, Xu N, Brufsky A. COLET: A multistage, phase 2 study evaluating the safety and efficacy of a doublet regimen of cobimetinib (C) in combination with paclitaxel (P) or triplet regimens of C in combination with atezolizumab (atezo) plus either P or nab-paclitaxel (nab-P) in metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-02.

Effect of intravenous infusion of magnesium sulphate on postoperative analgesia in patients undergoing arthroscopic knee surgeries under spinal anaesthesia

Background: Magnesium sulphate is being used for postoperative pain relief intravenously, intrathecally and epidurally. Currently, it is also gaining popularity as an adjuvant in blocks. The objective of the study was aimed at the postoperative analgesic effects of magnesium sulphate when given as intravenous infusion in patients undergoing arthroscopic knee surgeries under spinal anaesthesia and to compare the postoperative analgesic effects of magnesium sulphate infusion in a study cohort who received magnesium sulphate with the control cohort who were not given magnesium sulphate and underwent arthroscopic knee surgeries under spinal anaesthesia.Methods: After obtaining ethical committee clearance and consent from the patients, 31 patients each were placed in study cohort and control cohort. Spinal anaesthesia was administered in the lateral decubitus position through the L3–4 or L4–5 interspace. Hyperbaric bupivacaine 0.5% solution with fentanyl 20 μg was injected intrathecally. After spinal anaesthesia, patients received magnesium sulphate 50 mg/kg for 15 min and then 15 mg/kg/hr by continuous intravenous infusion until the end of surgery. The other group did not receive magnesium sulphate infusion. Postoperative pain scores and postoperative analgesic consumption were the primary end points.Results: The results of the study reveal the efficacy of perioperative intravenous infusion of magnesium sulphate in prolonging the spinal block as well as reducing the postoperative pain scores without hemodynamic variability or side effects.Conclusions: Post-operative pain and analgesic consumption was reduced with the use of intravenous magnesium following spinal anaesthesia.