To evaluate idiotype (Id) vaccination as a single agent in previously treated patients with indolent non-Hodgkin's lymphoma.
Patients underwent biopsy for determination of their lymphoma-specific Id ...sequence. Recombinant Id protein was manufactured and covalently linked with keyhole limpet hemocyanin (KLH) to generate Id/KLH. Patients received Id/KLH 1 mg on day 1 subcutaneously, with granulocyte-macrophage colony-stimulating factor 250 mug on days 1 to 4, monthly for 6 months. Booster injections were administered until progression. Both clinical and immune responses were evaluated.
Thirty-two previously treated patients received at least one injection of Id/KLH, and 31 were assessed for efficacy. Responses were observed in four patients (one complete response and three partial responses). Median time to onset of response was 5.9 months (range, 2.3 to 14.1 months). Median duration of response has not been reached but should be at least 19.4 months (range, 10.4 to 27.2+ months). Median time to progression is 13.5 months. The most common adverse events were mild to moderate injection site reactions. Six (67%) of nine patients tested demonstrated a cellular immune response, and four (20%) of 20 patients demonstrated an antibody response against their Id.
This trial demonstrates that Id/KLH alone can induce tumor regression and durable objective responses. Further study of Id/KLH is recommended in other settings where efficacy may be further enhanced as in first-line therapy or after cytoreductive therapy.
Electrospray ionization mass spectrometry-guided isolation of extracts from
Didiscus aceratus led to the discovery of several new derivatives of the bioactive bisabolene-type sponge metabolite (
...S)-(+)-curcuphenol (
1). The compounds obtained by this method included a mixture of known (
2) and new (
3) dihydroxylated analogs as well as a novel family of dimeric derivatives, dicurcuphenols A–E (
4–
8), and dicurcuphenol ether F (
9). Dimers
4–
9 were also subsequently obtained through a hemisynthetic method in which
1 was incubated with the enzyme laccase. Atropisomeric dimers
5 and
6 were subjected to vibrational circular dichroism analysis thereby establishing their absolute biaryl axial chirality as
P and
M, respectively. In contrast to
1, metabolites
2–
9 exhibited weak or no cytotoxic or lipoxygenase inhibitory effects.
We present observations of three distinct transits of HD 17156b obtained with the Fine Guidance Sensors on board the Hubble Space Telescope. We analyzed both the transit photometry and previously ...published radial velocities to find the planet-star radius ratio Rp /R = 0.07454 ? 0.00035, inclination i = 86.49+0.24 --0.20 deg, and scaled semimajor axis a/R = 23.19+0.32 --0.27. This last value translates directly to a mean stellar density determination Delta *r = 0.522+0.021 --0.018 g cm--3. Analysis of asteroseismology observations by the companion paper of Gilliland et al. provides a consistent but significantly refined measurement of Delta *r = 0.5308 ? 0.0040. We compare stellar isochrones to this density estimate and find M = 1.275 ? 0.018 M and a stellar age of 3.37+0.20 --0.47 Gyr. Using this estimate of M and incorporating the density constraint from asteroseismology, we model both the photometry and published radial velocities to estimate the planet radius Rp = 1.0870 ? 0.0066 RJ and the stellar radius R = 1.5007 ? 0.0076 R . The planet radius is larger than that found in previous studies and consistent with theoretical models of a solar-composition gas giant of the same mass and equilibrium temperature. For the three transits, we determine the times of mid-transit to a precision of 6.2 s, 7.6 s, and 6.9 s, and the transit times for HD 17156 do not show any significant departures from a constant period. The joint analysis of transit photometry and asteroseismology presages similar studies that will be enabled by the NASA Kepler Mission.
BACKGROUND: Interpatient variability in the kinetics of peripheral blood progenitor cell (PBPC) mobilization is commonly seen with conventional chemotherapy‐based mobilization regimens. This ...necessitates the availability of leukapheresis (LP) facilities 7 days a week.
STUDY DESIGN AND METHODS: The efficacy of an approach where LP was invariably commenced on Day 11 after intermediate‐dose cyclophosphamide followed by sequential administration of granulocyte‐macrophage–colony‐stimulating factor (CSF) and granulocyte–CSF (Cy/GM/G) was retrospectively analyzed in 225 consecutive, unselected patients undergoing autologous hematopoietic stem cell transplantation for all diagnoses other than acute leukemia at our center. Cy/GM/G was scheduled to avoid weekend LP.
RESULTS: After Cy/GM/G, a CD34+ cell yield of at least 2.0 × 106 per kg was achieved in 90.7 percent of patients. Optimal yield (OY; ≥5 × 106 or 10 × 106 CD34+ cells/kg depending on diagnosis) was achieved in 67.6 percent of patients. Only three patients (1.3%) required LP on Saturday or Sunday. Febrile neutropenia (FN) was encountered in 5.3 percent. PBPC yield was highest on Day 1 of LP (p < 0.001). In multivariate analyses, platelet (PLT) count on Day 1 of LP (PLT‐D1LP) was positively associated with achievement of OY (p < 0.001). PLT‐D1LP and diagnosis of myeloma were associated with a shorter time to achieve a CD34+ cell yield of at least 5 × 106 per kg (p < 0.001 and p = 0.002, respectively).
CONCLUSION: Cy/GM/G with scheduled LP commencement on Day 11 enables optimal CD34+ cell yields in most patients undergoing autologous transplantation, despite a low risk of FN and avoidance of weekend LP.
A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The ...synthesis and structure–activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.
Acquired bleeding abnormalities are common in patients with primary amyloid light-chain amyloidosis. Factor X deficiency is the most common coagulopathy associated with life-threatening hemorrhagic ...complications when surgery is indicated. Fresh-frozen plasma (FFP) or prothrombin complex concentrates (PCCs) are the most frequently used blood products in this disease; however, FFP is often ineffective in controlling bleeding and PCCs have a significant risk of thrombosis when used intraoperatively. This report describes a patient with primary amyloidosis and factor X deficiency who underwent hemicolectomy with preoperative and intraoperative administration of recombinant human factor VIIa and postoperative administration of Bebulin (a PCC that contains the highest concentration of factor X). The management was successful with no signs of bleeding postoperatively. To our knowledge, few reports of successful perioperative management of factor X deficiency have been published to date. This is the first case report using recombinant human factor VIIa and Bebulin in the perioperative management of factor X deficiency associated with primary amyloidosis. Recombinant human factor VIIa and Bebulin may allow for successful perioperative management of bleeding disorders in patients with primary amyloidosis.
To examine how the safety net in Michigan is responding to the health care needs of their uninsured population with diabetes and/or mental illness.
We used a multiple-site case study design. Data ...were collected through interviews of key informants in five Michigan communities. Analytic patterns and themes were identified, and compared across communities and by organizational type.
Informants reported they are managing to meet the needs of uninsured diabetics but are having great difficulty caring for the uninsured with mental illness. Specialty care for diabetes is obtainable, but is resource-intensive. Mental health services available for uninsured patients are severely limited. The presence of a county health plan (CHP) appears insufficient to improve access, especially to mental health services.
The safety net for Michigan's uninsured population with diabetes and mental illness is weak. Processes including referrals and care coordination are of poor quality in some communities. The value of integrating mental health services into primary care should be examined.
Abstract
Aims
Sodium–glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating ...the effects of this drug class in patients following acute myocardial infarction are lacking.
Methods and results
In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757–2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower 95% confidence interval (CI) −4.4% to −23.6% after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2–2.9%, P = 0.029), mean E/e′ reduction was 6.8% (95% CI 1.3–11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4–11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7–15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups.
Conclusion
In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters.
ClinicalTrials.gov registration
NCT03087773.
The treatment of low- and intermediate-grade subtypes of malignant lymphoma continues to evolve. Mantle cell lymphoma (MCL) accounts for 6% of all non-Hodgkin lymphoma (NHL) and is generally ...considered incurable. Although high response rates can be achieved with initial chemotherapy, median survival is only 3-4 years. Intensified consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been reported to improve progression-free survival (PFS), but most patients eventually relapse. Indolent lymphoma accounts for 35% of all NHL and is associated with a median survival of 9 years. Similar to MCL, it is also generally considered incurable, and the PFS also appears to be improved following HDT/ASCT. We initiated a pilot study to evaluate idiotype (Id) vaccination following HDT and ASCT for patients with MCL, indolent, and transformed NHL to evaluate the ability of Id-keyhole limpet hemocyanin (KLH) to induce immune responses, and to evaluate overall survival (OS) and PFS. We treated 15 patients: 8 with MCL, 4 with follicular lymphoma, 1 with small lymphocytic lymphoma, and 2 with transformed lymphoma. After a median follow-up of approximately 6.3 years (range: 1-9), PFS and OS at 9.05 years from time of ASCT are 59% and 52%, respectively.
PDF
