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Purpose:Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets.Patients and Methods:Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment.Results:We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas.Conclusions:Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Supplementary Figure 3

Background We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

One three-dimensional Gd(III) coordination polymer with 1,2-phenylenediacetate (PDA2 −), [Gd2(PDA)3(H2O)2]·3H2O (1), has been successfully synthesized and characterized. Single crystal X-ray diffraction analysis shows that 1 consists of 1D wave Gd-based chain unit and PDA2 − linker. Magnetic studies suggest the presence of ferromagnetic Gd ⋯ Gd coupling in the 1D chain unit of 1. Meanwhile, 1 has a significant cryogenic magnetocaloric effect with the maximum − ΔSm of 33.44 at 2 K and 7 T.

Purpose: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. Patients and Methods: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. Results: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Kernel adaptive filters are a class of powerful nonlinear filter developed in reproducing kernel Hilbert space (RKHS).The Gaussian kernel is usually the default kernel in KAF algorithm, because the Gaussian kernel has the universal approximation. However, in previous research the kernel adaptive filtering algorithms were mostly based on mean square error criterion and assumed to be in a Gaussian noise environment. When environmental noise is changed, the performance of conventional kernel adaptive filtering algorithm based on mean square error criterion is seriously reduced to failure due to the interference of non-Gaussian noise and the influence of inappropriate non-Gaussian modeling. Therefore, it is important to develop a new method of suppressing the noise of non-Gaussian signals. In this paper, a new kernel fractional lower power adaptive filtering algorithm is proposed by combining the benefits of the kernel method and a new loss function which is robust against non-Gaussian impulsive interferences and has fast convergence under a similar stability condition. The proposed SP-KFLP algorithm generates a new framework of cost function which combines the Softplus function with the KFLP algorithm by updating its weight vector according to the gradient estimation while nonlinear saturation characteristics of output error are used. Compared with the features of sigmoid function the features of the Softplus function guarantee the SP-KFLP an excellent performance for combatting impulsive interference and speeding up the convergence rate. In the kernel fractional low power criterion the reciprocal of the system error is used as the coefficient of the weight vector update formula, and the method of error burst is used to make the weight vector not update to resist the impulse noise. The mean square convergence analysis for SP-KFLP is conducted, and a sufficient condition for guaranteeing convergence is therefore obtained by using the energy conservation relation. The proposed algorithm is very simple computationally. Simulations in a system identification show that the proposed SP-KFLP algorithm outperforms the kernel least-mean-square algorithm, kernel fractional lower power algorithm, and sigmoid kernel fractional lower algorithm in terms of convergence rate and the robustness of against impulsive interference. The proposed algorithm improves not only the capability of resisting impulsive interference, but also the convergence rate. In other words, the contradiction between convergence and tracking performance stability is well taken into account, and the performance under Gaussian noise is also better than the performance of the traditional kernel adaptive algorithm.

BACKGROUND: Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain. CMV-TC in GBM tumor tissue have their effector function suppressed. Highly functional CMV pp65 specific T cells can be expanded in vitro from peripheral blood (PB) of GBM patients. METHODS: Autologous polyclonal CD8+ and CD4+ CMV-TC from patients with recurrent GBM were expanded ex vivo under GMP-compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (ddTMZ, 100 mg/m2); 4 dose levels (5 x 10(6) cells to 1 x 10(8) cells), 3 + 3 design. Treatment was repeated q 6 weeks; total of 4 cycles. Eligibility: ≥18 years of age, KPS ≥60, CMV sero+, on ≤ 2 mg of dexamethasone daily, any number of relapses. Imaging response evaluated by MRI q 6 weeks. In vivo persistence and expansion of adoptively-infused CMV-TC determined by dextramer staining and multiparameter flow cytometry in serially-sampled PB. RESULTS: 34 patients screened, 18 underwent leukapheresis, 15 completed cycle 1. Median age 56 (27–69), median KPS 90; 11 were at 1st, 3 at 2nd and 1 at 3rd relapse. MGMT methylated in 6, unmethylated in 3, indeterminate/unknown in 6. IDH status wildtype in 10, mutated in 3, unknown in 2. No dose limiting toxicities (DLTs) observed. Complete radiographic response observed in 1 patient, partial response in 2, stable disease in 6, and progressive disease in 6. Repeated infusions of CMV-TC were associated with significant increase in circulating CMV+ CD8+ T-cells, but cytokine production (CD107a, TNFα, IFNγ, IL2) was suppressed (dose level 4 analysis ongoing). CONCLUSIONS: Adoptive infusion of CMV-TC after lymphodepleting therapy with ddTMZ was well tolerated with no DLTs; 1 x 10e8 confirmed as safe dose. Effector function in PB was suppressed. Correlative studies of CMV-specific T cell effector function in tumor microenvironment will be assessed in window-of-opportunity expansion cohort.

A laboratory incubation experiment was performed to study the effects of three trophic level sediments with different nutrition status on the growth including physiological characteristics of Potamogeton crispus by embedding and suspension cultivation ways. The results showed: The high trophic level (HC) sediment was favorable for the early growth and the photosynthesis of Potamogeton crispus but unfavorable for the growth of roots. During the experiment, the POD activity rapidly increased to a maximum value under highly nutritious substrate in embedding groups. Later in the experiment, the content of soluble protein and chlorophyll decreased in the embedding group with HC sediments. To some extent, the normal growth of Potamogeton crispus was inhibited, while there wasn’t an apparente phenomenon that the decline of Potamogeton crispus.

2035Background: Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain, and can be targeted as a tumor-specific antigen. CMV-TC present in GBM tumor tissue have their e...

Palliative care consultation teams (PCCTs) are being established in cancer centers for the management of patients' physical and psychosocial distress. As clinical findings of these teams have been reported infrequently, we aim to describe the experience of our high-volume inpatient PCCT.We obtained clinical and demographic data on patients referred to our PCCT from the palliative care departmental database from September 1, 2003, to August 31, 2004.In 1 year, 1067 consultations took place for 922 hospitalized patients. The patients' mean age was 60 (range, 3-98) years. The most common cancers were thoracic/head and neck, gastrointestinal, genitourinary, gynecologic cancers, and lymphoma. Thirty-four percent of the patients were transferred to the inpatient palliative care unit, while the remainder were followed by the PCCT as consultants. The main problems requiring PCCT consultation were pain (56%), delirium (34%), dyspnea (25%), fatigue (14%), and end-of-life psychosocial (EOL) issues (12%). Twenty-four percent of patients died during the hospitalization. Death during the hospitalization was more common in patients with delirium, dyspnea, and EOL issues and less likely in patients referred to the PCCT for pain or depression. Constipation was more common in patients with solid tumors, whereas EOL issues were more common in patients with hematologic malignancies. Of the patients who were able to be discharged, 56% went home, 37% to hospice, and 7% elsewhere.These results provide insight into the demand and utility of this service for those considering the establishment of a PCCT.

Purpose To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy–Fatigue (FACIT-F). Patients and Methods Patients with fatigue score ≥ 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point. Results Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. Conclusion Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.

Uric acid stone is the most comment radiolucent renal stone with high recurrence rate, which would further cause acute upper urinary tract obstruction and kidney failure. Here we report two cases of renal uric acid stone from December 2012 to April 2013. One 43-year-old male patient suffered from chronic uric acid nephrolithiasis caused by the long-term indwelling of bilateral double-J stent. Another 69-year-old patient was also diagnosed with uric acid nephrolithiasis at the right kidney. Both patients were first treated with extracorporeal shock wave lithotripsy (ESWL), followed by 1.5% sodium bicarbonate dissolution therapy. After a week of the treatment, the uric acid stones in both patients were completely dissolved without retrograde infection. In summary, the use of ESWL and sodium bicarbonate dissolution therapy as a combined modality is a safe, effective, inexpensive treatment for uric acid nephrolithiasis.

Most referrals to palliative care and hospice occur late in the trajectory of the disease although an earlier intervention could decrease patients' symptom distress. The purpose of this study was to determine the interval between first palliative care consult (PC1) and death (D) in patients diagnosed with advanced cancer (aCA) at our comprehensive cancer center and if such interval has increased over time.The study group was 2868 consecutive patients who had their PC1 during a 30-month period. We reviewed the charts for information about demographics, cancer type, date of cancer (CA) diagnosis, aCA diagnosis, PC1, and D. aCA was defined as locally recurrent or metastatic.One thousand four hundred four patients (49%) were female, 1791 (62%) were less than 65 years old, 2563 (89%) had solid tumors, and 2004 (70%) were white. The median PC1-D, aCA-PC1, aCA-D, and CA-D intervals were 42, 147, 250, and 570 days, respectively. The median PC1-D interval was longer in patients with solid tumors (p0.0001), less than 65 years old (p = 0.002), and females (p = 0.004). PC1-D was not affected by ethnicity (p = 0.42). The median PC1-D interval in 5 consecutive half-years was 46, 56, 42, 41, and 34 days, respectively (p = 0.02). The number of PC1 in this period increased from 544 to 654 (20%). The ratio of PC involvement in the aCA-D period (PC1-D/aCA-D) decreased from 0.30 to 0.26 over the 5 half-year periods (p = 0.0004).The first palliative care consultation to death interval has decreased over time at our center. Education is needed among our referring physicians for earlier access to palliative care. Prospective studies are needed to establish the appropriate timing of the first palliative care consultation.