Period Of Stable Disease Research Articles

Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis.

Early relapse outcomes in long-term stable patients switching from interferon β/glatiramer acetate (IFNβ/GA) to oral therapy are unknown. The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNβ/GA, relative to a propensity-matched comparator of patients remaining on IFNβ/GA. The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNβ/GA ('stayers') using a Cox marginal model. Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

Balance between inflammatory and regulatory cytokines in systemic lupus erythematosus.

To investigate the cytokine profile in serum and cerebrospinal fluid (CSF) from patients with systemic lupus erythematosus (SLE) and central nervous system infection, we measured interferon-g (IFN-g), interleukin-1b (IL-1b), IL-4, IL-6, IL-8, IL-10, and IL-17 levels in serum and CSF from 50 SLE patients and 38 matched controls. In patients with active compared to quiescent disease, serum levels were higher for IL-1b (P = 0.042) and IL-17 (P = 0.041) but we found no significant correlation between IL-1b and IL-17 and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (r = 0.055, r = 0.219, respectively). IL-10 level in active patients was lower compared to that in quiescent controls (P = 0.032). When comparing specific disease manifestations, IL-1b levels in patients with fever (P = 0.035) and IL-6 (P = 0.048) and IL-8 (P = 0.048) levels in those showing nervous system involvement were higher than in controls. Based on MRI results, we found that only increased cerebral ischemia was associated with increased IFN-g levels (P = 0.009). In neuropsychiatric lupus erythematous patients, CSF levels of IL-6 (P = 0.002), IL-8 (P = 0.009), and IL-17 (P = 0.034) were significantly higher when compared with control patients. IL-10:IL-1b ratio in patients with moderate and quiescent disease was higher than in patients with disease activity (P = 0.000). Pro-inflammatory adaptive cytokines were elevated during disease flare, while regulatory mediators were elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may be targets for novel immunotherapeutic agents for managing autoimmune diseases.

TO A QUESTION OF FEASIBILITY OF APPLICATION OF 100 HZ VIBRATION IN TREATMENT AND REHABILITATION OF THE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

The aim of this research is study of feasibility of application of instrumental 100 Hz vibration of the thorax for rehabilitation of COPD patients. Materials and methods . This aim is achieved by clinical observation of 43 COPD patients of 1st and 2nd severity, 77.4 % from which were patients with low risk of exacerbations. Research has been carried out during the stable period of disease. The following parameters have been analyzed: dynamics of the clinical state, spirometry data, clinical - biochemical indicators of blood reflecting presence of the inflammatory process activity, a number of indicators of immune system. Two groups of patients, which were equivalent in an initial state on age, disease severity, expressiveness of functional violations, have been isolated. The 1st group contained 20 persons was the main one. It received 100 Hz vibration impact on the thorax on the background of exercises with physical therapy and inhalations of physiological solution. The 2nd group contained 23 persons obtained in addition sea-buckthorn paste. Results. It has been revealed that the course of 100 Hz vibration impact on the thorax is accompanied, mainly, with positive subjective dynamics in the form of decrease of frequency and expressiveness of complaints. At that it has been noted improvement of bronchial passability due to improved drainage of bronchial tubes, but only at the patients with initial violations of ventilation. Only additional reception of sea-buckthorn paste on the background of vibrotherapy contributes to decrease of subclinical inflammation activity and strengthening of immunological protection. Essential positive results of treatment have been reached only for a half of the surveyed patients that allows to speak about non-expediency or low expediency of use of 100 Hz vibration for CODT patients even 1st and 2nd severity in the stable period of course of the disease.

Abstract B100: Panvac-F and Panvac-V: Phase I study of intratumoral and systemic vaccination

Abstract Patients with adenocarcinoma of the pancreas were treated using a combination of EUS-guided intrapancreatic tumor injection and systemic boost using PANVAC-F and PANVAC-V in this first-in-man Phase I trial. The study represents the translation of our unique demonstration in murine models of bladder and orthotopic mammary tumors that anergy to systemic immunization using antigen encoding vaccinia recombinants could be overcome by immunization into the tumor microenvironment. Consented patients with locally advanced or minimally metastatic pancreatic cancer received EUS-guided intrapancreatic injections (IT) of recombinant Panvac-F (Fowlpox encoding MUC-1, CEA, TRICOM), systemic subcutaneous (SC) Panvac-V (vaccinia) and SC Panvac-F boosts. Systemic SC vaccines were accompanied by subcutaneous rH-GM-CSF, 100 mcg X 4 days. Patients received 2 intrapancreatic injections of Panvac-F (2 weeks apart) with systemic Panvac-V and Panvac-F boosts given with GMCSF extending to day 71 (total of 2 IT Panvac-F, 1 SC Panvac-V, 4 SC Panvac-F). Patients were allowed to transition to standard care at day 31. Patients were evaluated for toxicity and tumor progression. Follow-up care was provided by referring oncologists. In this dose escalation study, the first cohort of 6 pts received IT Panvac-F (10 8 PFU), SC Panvac-V (2 X 10 8 PFU), and SC Panvac-F (10 9 PFU). The second dose cohort of 8 pts received IT Panvac-F (10 9 PFU), SC Panvac-V (2 X 10 8 PFU), and SC Panvac-F (10 9 PFU ). At dose level 1, two of six patients were removed from study after approximately two weeks due to rapid disease progression and died one and six months after trial initiation. At dose level 2, one patient was removed due to rapidly progressive disease and died at 1 mo and a second patient withdrew following 1 IT inoculation and died at month 16. Of the remaining 10 pts, 3 presented with distant metastatic disease (Median Survival 7 mos, range 1-25) and 7 presented without distant metastases (Median Survival 16 mos, range 3-35). Of note, none of the 7 patients presenting without metastatic disease developed distant visceral metastases, by imaging available to us but died of sequellae associated with progressive local disease. Of the above 10 pts, all but one transitioned initially to treatment with gemcitabine-based therapy. (the remaining pt did not begin systemic treatment). Initial RNAseq transcriptome analysis of Fine Needle Aspirate (FNA) comparing Day 1 and Day 14 samples demonstrated a significant increase in a series of chemokines associated with the induction of an immune response in the tumor microenvironment. A planned series of immunologic and genetic analyses are underway. Results demonstrate that the “first in man” intrapancreatic administration of recombinant poxvirus was well tolerated with the complete regimen suggesting an encouraging period of stable disease. The finding that none of the patients who presented without distant visceral metastases developed such would be consistent with the generation of a systemic immune response with effects on seeded metastatic cells. Analysis of local and systemic immune responses is currently proceeding and may provide further insights. This study is supported by the NCI Cancer Therapeutics Evaluation Program (CTEP) and by NCI U01-CA07031 and P30-CA72720. Citation Format: Elizabeth A. Poplin, David A. August, Rebecca A. Moss, Tamir Ben-Menachem, Hazar Michael, Aparna Repaka, Renee Artymyshyn, Chang Chan, James L. Gulley, Robert S. DiPaola, Edmund C. Lattime. Panvac-F and Panvac-V: Phase I study of intratumoral and systemic vaccination. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B100.

Altered innate, adaptive, and TNF-superfamily soluble inflammatory mediators mark impending systemic lupus erythematosus disease flare, while regulatory mediators distinguish lack of impending disease flare in African-American lupus patients (CCR5P.201)

Abstract SLE is a multifaceted disease characterized by immune dysregulation and varied disease activity. We evaluated changes in plasma soluble mediators (n=52) preceding clinically-defined disease flare, in 13 African American (AA) SLE patients who developed disease flare 6 or 12 weeks after baseline assessment compared to matched SLE patients without impending flare and healthy controls. In addition, mediators within samples preceding SLE disease flare and during a clinically stable period from the same individual were compared in 18 AA SLE patients. Patients with impending flare had significant (q<0.01) alterations in 32 soluble mediators at baseline with significantly higher levels of pro-inflammatory mediators, including innate and adaptive cytokines. Baseline levels of regulatory cytokines, including IL-10 and TGF-β, were higher in non-flare SLE patients, while baseline levels of soluble TNFRI, TNFRII, TRAIL, FasL, and CD40L were significantly greater in pre-flare patients (p<0.05). A normalized and weighted combined soluble mediator score was significantly higher in pre-flare SLE patients versus those with stable disease (p<0.0001). Pro-inflammatory soluble mediators are elevated prior to disease flare, while regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify AA patients at risk of disease flare and help decipher SLE pathogenic mechanisms.

Health-related quality of life in stable, long-term survivors of low-grade glioma.

Patients with low-grade glioma (LGG) often experience long periods of stable disease, emphasizing the importance of maintaining good health-related quality of life (HRQOL). We assessed the changes in HRQOL in long-term survivors of WHO grade I or II astrocytoma, oligodendroglioma, or oligoastrocytoma with clinically and radiologically stable disease. Patients completed self-report measures of generic HRQOL (Short Form-36 [SF-36]) and disease-specific HRQOL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Cancer Module). Assessments took place at midterm and long-term follow-up, on average 6 and 12 years after histologic diagnosis and initial treatment, respectively. Comparisons between patients with LGG and individually matched healthy controls were made, and change within the patients with LGG was calculated, as was minimal detectable change. Although no statistically significant differences between patients with LGG and healthy matched controls were found at midterm follow-up, patients with LGG had worse physical role functioning (P = .004) and general health perceptions (P = .004) than controls at long-term follow-up. Within patients with stable LGG (n = 65), physical HRQOL (the SF-36 physical component summary and the physical functioning subscale) was significantly worse at long-term than at midterm follow-up (both P < .001). Although 48% of patients improved or remained stable on all HRQOL scales, 38.5% of patients experienced detectable decline on one or more scales. Although HRQOL remains mostly preserved in the majority of patients with LGG, a subset of patients experience detectable decline on one or more HRQOL scales despite long-term stable disease. For this subgroup, further research is recommended to better aid patients in dealing with the consequences of LGG.

Genetic determinants of antibiotic resistance in oropharyngeal streptococci in patients with chronic obstructive pulmonary disease and in those with asthma

To identify oropharyngeal Streptococcus species and to analyze the genetic determinants of antibiotic resistance in patients with asthma and in those with chronic obstructive pulmonary disease (COPD). An experimental diagnostic Streptopol+ (Lytech Co. LTD) panel based on a multiplex real-time PCR was applied to investigate the representation of antimicrobial resistance genes (mef and ermB) and the species composition of streptococci isolated from oropharyngeal swab samples from 89 patients with stable COPD and from 51 patients with asthma. In the stable disease period, the oropharyngeal swabs were found to contain Streptococcus pneumoniae in 7.8% of the patients with asthma and in 6.74% of those with COPD; the common feature of these groups was a tendency towards a severe disease course and recurrent exacerbations requiring antibiotics. S. pyogenus was detected in 42.9% of the oropharyngeal swabs from COPD and asthma patients without exacerbations. The oropharyngeal swabs showed the mef gene in 100% of the patients with asthma and in 100% of those with COPD; the ermB gene was encountered in 91% of the patients with COPD and in 82.4% of those with asthma. The COPD patients displayed a direct correlation between the representation of the ermB gene and sputum production and smoking index. The mef and ermB genes were directly correlated with the frequency of exacerbations in patients with COPD. The identified streptococci are a reservoir of antimicrobial resistance genetic determinants - the mef and ermB genes encoding the mechanisms of streptococcal macrolide resistance. The representation of the above genes directly correlates with the frequency of exacerbations and the number of antimicrobial drug uses.

The role of surgery in renal cell carcinoma with pancreatic metastasis.

Metastasis of renal cell carcinoma to the pancreas is uncommon and, in most cases, presents as a single pancreatic mass that shows a more favorable prognosis than primary pancreatic tumors. We examined patients with renal cell carcinoma metastatic to the pancreas, and discuss the clinical findings, treatment administered, and final outcomes. The present study is a retrospective analysis of renal cell carcinoma patients with pancreatic metastasis. Pancreatic tumor specimens were obtained by surgical excision, surgical biopsy, fine-needle biopsy, or endoscopic ultrasound biopsy. The surgical approaches included distal splenopancreatectomy, total pancreatectomy, or distal pancreatectomy. The physician determined the postoperative treatment regimen with interferon-α or targeted therapy on the basis of patient's performance. A total of six patients with median age of 50 years were included in the study. The median time from the primary nephrectomy to the development of pancreatic metastasis was 16 years. In the biopsy-only group, the mean stable disease period was 16.5 months. In the patients treated with surgery combined with interferon-α or targeted therapy, the mean stable disease period was 29.5 months. The patients treated with repeat mastectomy showed a mean stable disease period of 33.3 months. Aggressive surgical management is more effective than observation or immunotherapy. Recent advances in the design of targeted therapies may provide alternative treatment strategies. Combination therapy may play an important role in the future. Considering patient compliance and cost-effectiveness, resection of pancreatic metastasis is currently the first choice of treatment.

P15.02 * HEALTH-RELATED QUALITY OF LIFE IN STABLE, LONG-TERM LOW-GRADE GLIOMA SURVIVORS

BACKGROUND: Low-grade glioma (LGG; WHO grade I or II) patients often experience long periods of stable disease, emphasizing the importance of maintaining an optimal health-related quality of life (HRQOL). In this study we assessed the changes in HRQOL in long-term LGG survivors with stable disease. METHODS: Patients completed self-report measures of generic HRQOL (SF-36) and disease-specific HRQOL (EORTC QLQ-BN20). Assessments took place at mid-term and long-term follow-up, on average 6 and 12 years following histological diagnosis and initial treatment, respectively. Wilcoxon signed-rank tests were used for group-level analysis and meaningful intra-individual changes (i.e. a 95% confidence interval around the standard error of measurement of a scale) were calculated where applicable. RESULTS: Stable LGG patients (N = 65) reported poorer physical health at long-term than at mid-term follow-up, as well as more uncertainty about the future and more weakness in the legs. Meaningful decline in physical health was found in 29% and 26% of patients on the SF-36 PCS and physical functioning scale, respectively. Moreover, 28% of patients experienced more feelings of uncertainty concerning the future (BN20) at long-term follow-up. CONCLUSION: Despite long-term stable disease, subtle impairment in HRQOL can be observed in LGG patients. While in the majority of LGG patients, HRQOL remains mostly preserved, over 26% of patients experience meaningful decline in physical functioning or more feelings of uncertainty concerning the future. For this subgroup, further research into associations between HRQOL and patient-, disease- or treatment-related variables is recommended to better aid them in dealing with the mental and physical consequences of a LGG.

Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare.

Systemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study sought to evaluate the changes in plasma concentrations of soluble mediators that precede clinically defined disease flares. Fifty-two different soluble mediators, including cytokines, chemokines, and soluble receptors, were examined using validated multiplex bead-based or enzyme-linked immunosorbent assays in plasma from 28 European American patients with SLE who developed disease flare 6 or 12 weeks after a baseline assessment (preflare), 28 matched SLE patients without impending flare (nonflare), and 28 matched healthy controls. In a subset of 13 SLE patients, mediators within samples obtained preceding disease flare were compared with those within samples from the same individual obtained during a clinically stable period without flare. Compared to SLE patients with clinically stable disease, SLE patients with impending flare had significant alterations (P ≤ 0.01) in the levels of 27 soluble mediators at baseline; specifically, the levels of proinflammatory mediators, including Th1-, Th2-, and Th17-type cytokines, were significantly higher several weeks before clinical flare. Baseline levels of regulatory cytokines, including interleukin-10 and transforming growth factor β, were higher in nonflare SLE patients, whereas baseline levels of soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L were significantly higher (P ≤ 0.002) in preflare SLE patients. The normalized and weighted combined soluble mediator score was significantly higher (P ≤ 0.0002) in preflare samples from SLE patients compared to samples from the same patients obtained during periods of stable disease. The levels of proinflammatory adaptive cytokines and shed TNF receptors are elevated prior to disease flare, while the levels of regulatory mediators are elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may help identify patients at risk of disease flare and help decipher the pathogenic mechanisms of SLE.

Combined autophagy and proteasome inhibition

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Candidate Markers Associated with the Probability of Future Pulmonary Exacerbations in Cystic Fibrosis Patients

IntroductionPulmonary exacerbations (PEs) cause significant morbidity and can severely impact disease progression in cystic fibrosis (CF) lung disease, especially in patients who suffer from recurrent PEs. The assessments able to predict a future PE or a recurrent PE are limited. We hypothesized that combining clinical, molecular and patient reported data could identify patients who are at risk of PE.MethodsWe prospectively followed a cohort of 53 adult CF patients for 24 months. Baseline values for spirometry, clinical status using the Matouk Disease Score, quality of life (QOL), inflammatory markers (C-reactive protein (CRP), interleukins (IL)-1β, -6, -8, -10, macrophage inflammatory protein (MIP)-1β, tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF)), polyunsaturated fatty acids and lipid peroxidation in blood plasma were collected for all patients during periods of stable disease, and patients were monitored for PE requiring PO/IV antibiotic treatment. Additionally, we closely followed 13 patients during PEs collecting longitudinal data on changes in markers from baseline values. We assessed whether any markers were predictors of future PE at baseline and after antibiotic treatment.ResultsOut of 53 patients, 37 experienced PEs during our study period. At baseline, we found that low lung function, clinical scoring and QOL values were associated with increased risk of PE events. PEs were associated with increased inflammatory markers at Day 1, and these biomarkers improved with treatment. The imbalance in arachidonic acid and docosahexaenoic acid levels improved with treatment which coincided with reductions in lipid peroxidation. High levels of inflammatory markers CRP and IL-8 were associated with an early re-exacerbation.ConclusionOur results demonstrate that worse clinical and QOL assessments during stable disease are potential markers associated with a higher risk of future PEs, while higher levels of inflammatory markers at the end of antibiotic treatment may be associated with early re-exacerbation.

Best supportive care compared with chemotherapy and radiotherapy for unresectable gallbladder cancer: A tertiary care institute experience

Context: Gallbladder represent the most common cancer among biliary tree, complete surgery offers only chance of cure, but most of patients with unresectable or metastatic stage, in such patients only palliative treatment be given. Aims: The aim of this retrospective study is to evaluate efficacy of chemotherapy with gemcitabine and oxaliplatin (GEMOX), and or with radiotherapy over best supportive care (BSC)) in unresectable gallbladder cancer (GBC). Materials and Methods: Patients with unresectable GBC were evaluated from our center between 2008 and 2011. Three cohorts were identified. Group A, BSC, Group B chemotherapy with GEMOX two weekly for maximum of six cycles. Group C, Chemotherapy with GEMOX and Radiotherapy. Patients underwent percutaneous transhepatic biliary drainage (PTBD) or Endoscopic retrograde cholangiopancreatography (ERCP) when required. Results: Total 50 patients included in analysis. 19 are male and 31 are female. 14 patients in Group A. 18 patients in Group B and 18 in Group C. Median follow up was 8.8 month. The progression free survival (PFS) of patients who received of BSC at 15 month was 18%. PFS of patients who received chemotherapy (CCT) at 28 month was 30%. PFS of patients who received CCT Chemotherapy and radiotherapy PFS at 15 month was 38%. When compared all three group none is statically significant ( P = 0.538). Conclusion: Judicious used of BSC along with chemotherapy and or with radiotherapy may help in increase in period of stable disease along with overall survival (OS) in selected group. In our retrospective analysis CCT with GEMOX and with radiotherapy has helped in improving the OS and PFS in few patients who had good performance status.

The Breast Avastin Trial: phase II study of bevacizumab maintenance therapy after induction chemotherapy with docetaxel and capecitabine for the first-line treatment of patients with locally recurrent or metastatic breast cancer

Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated. In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m(2) on day 1, plus capecitabine 900 mg/m(2) twice daily on days 1-14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity. Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3-4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation). Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation.

Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma

Background: The pancreas is an uncommon but recognizable site for metastases from renal cell carcinoma (RCC). Isolated pancreatic RCC metastases are still rarer and often present years after initial nephrectomy. Surgical resection has been the treatment of choice because of superior patient survival compared with traditional immunotherapy. In recent years, the advent of targeted therapy has transformed the outcomes of patients with metastatic RCC although little evidence is available on its effectiveness on this subset of patients. We report our experience of 6 patients with pancreatic RCC metastases. Patients and Methods: Between 2007 and 2012, 6 patients (2 men, 4 women; median age 78 years) were diagnosed to have pancreatic RCC metastases at our institute. The clinical features, treatment and outcomes were examined. Results: All 6 patients had a primary RCC of clear cell type. The median interval between initial curative nephrectomy and re-presentation with pancreatic metastases was 12.5 years. Four patients were asymptomatic at the time of diagnosis, one presented with obstructive jaundice and another with acute gastrointestinal bleed. Four patients had extra-pancreatic disease. All were deemed unsuitable or unfit for surgical metastasectomy. Five patients had a Memorial Sloan-Kettering Cancer Center (MSKCC) score of 1 (moderate risk) and the other patient had a score of 0 (good risk). Two patients were commenced on Sunitinib, one received Pazopanib and one received Temsirolimus. Two patients did not undergo further treatment. Of the 4 patients who underwent targeted therapy, the median follow up was 33 months with a median progression free survival of 16 months. One achieved complete response but recurred soon after treatment was stopped. Targetted therapy was recommenced and the disease remained stable. A second patient had long period of stable disease before disease progression. A third achieved partial response since started on targeted therapy and a fourth had disease progression despite treatment. Of the four patients who underwent systemic therapy, three are still alive at the time of this report. Conclusion: Pancreatic metastasis from RCC is a unique subgroup of disease which runs an indolent course, and a higher incidence in an elderly population. Our results demonstrate that targeted therapy can be efficacious in some patients where surgical resection is not suitable or possible.

The Adult Cystic Fibrosis Airway Microbiota Is Stable over Time and Infection Type, and Highly Resilient to Antibiotic Treatment of Exacerbations

Cystic fibrosis (CF) is characterized by defective mucociliary clearance and chronic airway infection by a complex microbiota. Infection, persistent inflammation and periodic episodes of acute pulmonary exacerbation contribute to an irreversible decline in CF lung function. While the factors leading to acute exacerbations are poorly understood, antibiotic treatment can temporarily resolve pulmonary symptoms and partially restore lung function. Previous studies indicated that exacerbations may be associated with changes in microbial densities and the acquisition of new microbial species. Given the complexity of the CF microbiota, we applied massively parallel pyrosequencing to identify changes in airway microbial community structure in 23 adult CF patients during acute pulmonary exacerbation, after antibiotic treatment and during periods of stable disease. Over 350,000 sequences were generated, representing nearly 170 distinct microbial taxa. Approximately 60% of sequences obtained were from the recognized CF pathogens Pseudomonas and Burkholderia, which were detected in largely non-overlapping patient subsets. In contrast, other taxa including Prevotella, Streptococcus, Rothia and Veillonella were abundant in nearly all patient samples. Although antibiotic treatment was associated with a small decrease in species richness, there was minimal change in overall microbial community structure. Furthermore, microbial community composition was highly similar in patients during an exacerbation and when clinically stable, suggesting that exacerbations may represent intrapulmonary spread of infection rather than a change in microbial community composition. Mouthwash samples, obtained from a subset of patients, showed a nearly identical distribution of taxa as expectorated sputum, indicating that aspiration may contribute to colonization of the lower airways. Finally, we observed a strong correlation between low species richness and poor lung function. Taken together, these results indicate that the adult CF lung microbiome is largely stable through periods of exacerbation and antibiotic treatment and that short-term compositional changes in the airway microbiota do not account for CF pulmonary exacerbations.

Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study

Since HA-1-specific T cells have been shown to make a significant contribution to the clinical responses in patients with relapsed leukemia, we investigated the feasibility of adoptive transfer of in vitro induced HA-1-specific CD8 positive T cells to patients with relapsed leukemia after allogeneic stem cell transplantation. The in vitro generation of clinical grade HA-1-specific T-cell lines from HA-1 negative donors was seen to be feasible and 3 patients were treated with HA-1-specific T-cell lines. No toxicity after infusion was observed. Although in one patient, during a period of stable disease, HA-1-specific T cells could be detected in the peripheral blood and bone marrow, these patients had no clear clinical response.

Abstract 5378: Phase I trial of EUS-guided intratumoral vaccination with recombinant Panvac-F and systemic Panvac-V in patients with locally advanced pancreatic cancer

Abstract Preclinical studies in our laboratory were the first to demonstrate the superiority of intratumoral poxvirus vaccines in overcoming immune escape and effectively treating murine solid tumor models. Murine models of bladder and orthotopic mammary tumor demonstrated anergy to systemic immunization using antigen encoding vaccinia recombinants while responding to immunization into the tumor microenvironment. We present here the translation of these findings to a Phase I trial in six patients with locally advanced inoperable adenocarcinoma of the pancreas (NCT00669734). The first dose cohort of patients were treated using a combination of EUS-guided intrapancreatic tumor injection of recombinant Panvac-F (Fowlpox encoding MUC-1, CEA, TRICOM, 108 PFU) in addition to systemic Panvac-V (vaccinia, 2 X 108 PFU) and Panvac-F (109 PFU) boosts (accompanied by subcutaneous rH-GM-CSF, 100 mcg X 4 days). Patients received a total of 2 intrapancreatic injections of Panvac-F (2 weeks apart) with systemic Panvac-V and Panvac-F boosts given with GMCSF extending to day 71 (total of 2 intrapancreatic Panvac-F, 1 sc Panvac-V, 4 sc Panvac-F). Patients were allowed to transition to standard care at day 35. Patients were evaluated for toxicity, tumor progression, and serum CA 19-9 and CEA levels. Two of six patients were removed from study after approximately two weeks due to rapid disease progression and died one and six months after trial initiation. Of the remaining four, one had received prior treatment with gemcitabine followed by capecitabine and radiation and received no further treatment after vaccination; three received post-vaccination standard treatment with gemcitabine. Of the 4 patients with followup of greater than 6 mos, all have stable disease with no progression to metastasis (19 mos, 17 mos, 16 mos, 13 mos). One pt had a DLT (pancreatitis) that resolved allowing completion of protocol therapy. Results demonstrate that the “first in human” intrapancreatic administration of recombinant poxvirus was well tolerated with the complete regimen suggesting an encouraging period of stable disease. The trial is currently accruing patients at intrapancreatic dose level 2 (109 PFU). This study is supported by the NCI Cancer Therapeutics Evaluation Program (CTEP) and by NCI U01-CA07031 and P30-CA72720. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5378. doi:1538-7445.AM2012-5378

Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Final Results of a Phase 1 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Patients with Relapsed or Refractory Myeloma

Abstract 1869 BACKGROUND:The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS:Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m2, (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS:We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naïve patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION:Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures:Vogl:Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll:Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi:Millennium Pharmaceuticals: Honoraria, Research Funding.

Abstract A97: Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in patients with advanced solid tumor malignancies.

Abstract Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.