Background
Bariatric surgery is currently the most effective treatment for morbid obesity. It provides not only substantial weight loss, but also resolution of obesity-related comorbidities. ...Laparoscopic sleeve gastrectomy (LSG) has rapidly been gaining in popularity. However, there are limited data on the reduction of obesity-related comorbidities for LSG compared to laparoscopic Roux-en-Y gastric bypass (LRYGB). The aim of this study was to assess the effectiveness of laparoscopic LSG versus LRYGB for the treatment of obesity-related comorbidities.
Methods
A total of 558 patients who underwent either LSG or LRYGB for morbid obesity at the Westchester Medical Center between April 2008 and September 2010 were included. Data were collected prospectively into a computerized database and reviewed for this study. Fisher’s exact test analyses compared 30-day, 6-month, and 1-year outcomes of obesity-related comorbidities.
Results
A total of 558 patients were included in the analysis of obesity-related comorbidity resolution; 200 underwent LSG and 358 underwent LRYGB. After 1 year, 86.2 % of the LSG patients had one or more comorbidities in remission compared to 83.1 % LRYGB patients (
P
= 0.688). With the exception of GERD (−0.09 vs. 50 %;
P
< 0.001), similar comorbidity remission rates were observed between LSG and LRYGB for sleep apnea (91.2 vs. 82.8 %;
P
= 0.338), hyperlipidemia (63 vs. 55.8 %;
P
= 0.633), hypertension (38.8 vs. 52.9 %;
P
= 0.062), diabetes (58.6 vs. 65.5 %;
P
= 0.638), and musculoskeletal disease (66.7 vs. 79.4 %;
P
= 0.472).
Conclusions
Laparoscopic sleeve gastrectomy markedly improves most obesity-related comorbidities. Compared to LRYGB, LSG may have equal in reducing sleep apnea, hyperlipidemia, hypertension, diabetes, and musculoskeletal disease. LRYGB appears to be more effective at GERD resolution than LSG.
•Neoadjuvant ipilimumab and IFNα were evaluated in regionally advanced melanoma.•Immune cellular profiling investigated tumor immune susceptibility and resistance.•Higher levels of peripheral Th1 ...cell subsets predicted favorable clinical outcomes.•Higher levels of peripheral Th2 cells was associated with poor prognosis.•Significant reductions in peripheral T-reg and MDSC were seen in responders.
Neoadjuvant therapy with ipilimumab in combination with high dose IFNα was evaluated in patients with locally/regionally advanced melanoma in a previously reported clinical trial NCT01608594. In this study, peripheral immune cell profiling was performed in order to investigate the underlying mechanisms of tumor immune susceptibility and resistance. Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 28) were collected at baseline and then at 6-weeks, 3-months and 12-months. High complexity (14-color) flow cytometry, designed to detect key immunological biomarkers was used to evaluate the frequencies of immune cell subsets. Statistical significance was determined using R-package employing Kruskal's test. We found that higher levels of Th1 cells at baseline (defined as CD45RA- CCR6- CXCR3+ CCR4-) correlated with the preoperative radiological response (p = 0.007) while higher Th2 cells (defined as CD45RA- CCR6- CXCR3- CCR4+) were associated with progressive disease (p = 0.009). A multimarker score consisting of higher levels of Th1 cells and CD8+ central memory T-cells was associated with pathologic complete response (pCR) (p = 0.041) at surgical resection. On the other hand, high TIM3 expression on T-cells correlated with gross viable tumor (p = 0.047). With regard to immune related toxicity, higher levels of phenotypically naive (defined as CCR7+CD45RA+) and effector memory (defined as CCR7-CD45RO+) CD8+ T-cells (p = 0.014) or lower levels of Th2 cells were associated with lower toxicity (p = 0.024). Furthermore, a multimarker score consisting of higher CD19+ and CD8+ cells was associated with lower toxicity (p = 0.0014). In conclusion, our study yielded mechanistic insights related to the immune impact of CTLA4 blockade and IFNα and potential biomarkers of immune response and toxicity.
The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are ...produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R-3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido2,3-dpyrimidin-2-yl-ethyl-N-pyridin-3-ylmethyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-acetamide (NBI-74330), from the T487 small molecule series. NBI-74330 demonstrated potent inhibition of (125)ICXCL10 and (125)ICXCL11 specific binding (K(i) of 1.5 and 3.2 nM, respectively) and of functional responses mediated by CXCR3, such as ligand-induced guanosine 5'-O-(3-(35)Sthio)triphosphate ((35)SGTPgammaS) binding, calcium mobilization, and cellular chemotaxis (IC(50) of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 >> CXCL10 > CXCL9. A comparison of the rank order of K(i) values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.
Missed accessory spleen (AcS) can cause recurrence of hematologic disease after splenectomy. The objective of the study was to determine whether detection of AcS is more accurate with preoperative ...computed tomography (CT) scan or with exploration during laparoscopic splenectomy.
A retrospective chart review was performed for 75 adult patients who underwent laparoscopic splenectomy for various hematologic disorders from 1999 to 2009. Preoperative CT scans were performed in all patients. Patients were followed for recurrence of disease, and a scintigraphy scan was performed in those with suspected missed AcS.
The most common diagnosis was idiopathic thrombocytopenic purpura in 29 patients (39%), followed by non-Hodgkin's lymphoma in 22 patients (29%). Sixteen AcSs were found during surgery in 15 patients (20%), and preoperative CT scan identified 2 of these. Twelve AcSs were located at the splenic hilum (75%). Nine patients experienced recurrence of their disease, and none had a missed AcS on subsequent scintigraphy. Sensitivity of exploratory laparoscopy for detection of AcS was 100%, and for preoperative CT scan was 12.5% (P = .005).
Exploratory laparoscopy during splenectomy is more accurate than preoperative imaging with CT scan for detection of AcS. Preoperative CT scan misses AcS frequently and should not be obtained for the purpose of its identification.
Immunological Characterization and Therapeutic Activity of an Altered-Peptide Ligand, NBI-6024, Based on the Immunodominant
Type 1 Diabetes Autoantigen Insulin B-Chain (9–23) Peptide
David G. Alleva ...1 ,
Amitabh Gaur 1 ,
Liping Jin 1 ,
Dale Wegmann 2 ,
Peter A. Gottlieb 2 ,
Anil Pahuja 1 ,
Eric B. Johnson 1 ,
Theresa Motheral 2 ,
Amy Putnam 2 ,
Paul D. Crowe 1 ,
Nicholas Ling 1 ,
Stefen A. Boehme 1 and
Paul J. Conlon 1
1 Neurocrine Biosciences, Inc., San Diego, California
2 University of Colorado Health Sciences Center, Barbara Davis Center for Childhood Diabetes, Denver, Colorado
Abstract
The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated
destruction of insulin-producing islet β-cells of the pancreas. The 9–23 amino acid region of the insulin B-chain B (9–23) is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing
a series of B (9–23) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable
of inhibiting B (9–23) -induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these
clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation
and Th2 cytokine production (i.e., interleukin IL-4 and IL-10, but not γ-interferon IFN-γ). These responses were cross-reactive
with the native antigen, B (9–23) , suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B (9–23) -specific Th1 (i.e., IFN-γ-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues
16 and 19 (16Y→A, 19C→A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced
T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B (9–23) . Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed
the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived
from an islet β-cell-specific antigen in type 1 diabetes.
Footnotes
Address correspondence and reprint requests to Dr. David G. Alleva, Neurocrine Biosciences, Inc., 10555 Science Center Dr.,
San Diego, CA 92121-1102. E-mail: dalleva{at}neurocrine.com .
Received for publication 4 December 2001 and accepted in revised form 3 April 2002.
D.G.A., L.J., A.P., E.B.J., N.L., S.A.B., and P.J.C. are employed by and hold stock in Neurocrine Biosciences, Inc.; A.G.
holds stock in Neurocrine Biosciences, Inc.
APL, altered peptide ligand; B (9–23) , 9–23 amino acid region of the insulin B-chain; βCA, β-cell target antigen; CFA, complete Freund’s adjuvant; EAE, experimental
autoimmune encephalomyelitis; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunosorbent spot; IFA, incomplete
Freund’s adjuvant; IFN-γ, γ-interferon; IL, interleukin; MBP, myelin basic protein; MHC, major histocompatibility complex;
MS, multiple sclerosis; NT, neurotensin; PLP, proteolipid protein; SI, stimulation index; SWM (110–121) , sperm whale myoglobin (110–121); TCR, T-cell receptor.
DIABETES
Central pancreatectomy without anastomosis Wayne, Michael; Neragi-Miandoab, Siyamek; Kasmin, Franklin ...
World journal of surgical oncology,
08/2009, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Central pancreatectomy has a unique application for lesions in the neck of the pancreas. It preserves the distal pancreas and its endocrine functions. It also preserves the spleen.
This is a ...retrospective review of 10 patients who underwent central pancreatectomy without pancreatico-enteric anastomosis between October 2005 and May 2009. The surgical indications, operative outcomes, and pathologic findings were analyzed.
All 10 lesions were in the neck of the pancreas and included: 2 branch intraductal papillary mucinous neoplasms (IPMNs), a mucinous cyst, a lymphoid cyst, 5 neuroendocrine tumors, and a clear cell adenoma.
Central pancreatectomy without pancreatico-enteric anastomosis for lesions in the neck and proximal pancreas is a safe and effective procedure. Morbidity is low because there is no anastomosis. Long term endocrine and exocrine function has been maintained.
The binding pocket of family A GPCRs that bind small biogenic amines is well characterized. In this study we identify residues
on CC chemokine receptor 7 (CCR-7) that are involved in agonist-mediated ...receptor activation but not in high affinity ligand
binding. The mutations also affect the ability of the ligands to induce chemotaxis. Two of the residues, Lys 3.33 (137) and Gln 5.42 (227) , are consistent with the binding pocket described for biogenic amines, while Lys 3.26 (130) and Asn 7.32 (305) , are found at, or close to, the cell surface. Our observations are in agreement with findings from other peptide and chemokine
receptors, which indicate that receptors that bind larger ligands contain contact sites closer to the cell surface in addition
to the conventional transmembrane binding pocket. These findings also support the theory that chemokine receptors require
different sets of interactions for high affinity ligand binding and receptor activation.
Exceptional clinical responses produced by the first chimeric antigen receptor T CAR‐T cell therapies, and their entry into commercial markets prompted a logarithmic increase in the number of next ...generation CAR‐T clinical trials. As a result, there is a growing interest in understanding the analytical approaches utilized for reliable monitoring of these “living” drugs, and the challenges encountered during their clinical development. Multiparametric flow cytometry (MFC) assays have played a crucial role in understanding the phenotype and function of first approved CAR‐T therapies. Herein, three main areas for monitoring CAR‐T therapies in clinical trials are discussed: (1) analytical considerations critical for development of MFC assays for the reliable enumeration of CAR‐T levels, (2) operational challenges associated with clinical trial sampling and transportation, and (3) differential cellular kinetics observed by MFC and qPCR analyses and their relationship with efficacy (measurable residual disease levels). Initial experiences described here may enable design of fit‐for‐purpose tools and help to more rapidly advance the development of next generation CAR‐T therapies.
Abstract Purpose Functional dysregulation of B-cells leads to a variety of autoimmune disorders and blood cancers. Multiple B-cell depleting therapies (e.g., BTK inhibitors, antibodies or CAR-Ts) are ...currently in active clinical trial investigation. Following therapeutic elimination of pathogenic B-cells, it is critical to monitor the productive regeneration of fully functional B-cells as they mediate innate and adaptive immune responses. To this end, we developed a multiparametric flow cytometry assay for exquisite monitoring of early stages of B cell development, maturation, and antibody production to correlate it with treatment outcomes and determine if continuous depletion of B-cells is necessary to maintain clinical benefits for patients. Study Design We designed a high throughput 12-parameter flow cytometry panel incorporating primary differentiation markers namely, CD45, CD3, CD38, CD10, CD27, CD19, CD20, IgD, Lambda & Kappa Light Chains required for identification of different developmental stages of B-cells in peripheral blood using an in vitro diagnostic grade flow cytometry system (BD FACSLyric). The optimized method underwent robust fit-for-purpose analytical validation per CLSI H62 guidelines with emphasis on establishing assay sensitivity, specificity, and reproducibility across experimental days, operators, and instruments. Results We were able to reliably identify different stages of B-cell development, namely, Naïve (CD19+CD20+IgD+CD27-), Unswitched/Marginal (CD19+CD20+IgD+CD27+), Memory (CD19+CD20+IgD-CD27+), Transitional (CD19+CD20+IgD+CD27-CD10+), Antibody Secreting Cells (CD19+CD20-IgD-CD27+CD38hi) as well as clonality (CD19+CD20+Lambda+ or Kappa+). The lower limit of quantitation was determined to be around 60 events, based upon analysis of 90 data points with good reproducibility (CV range: 0-11.7%) across experimental days, operators and instruments demonstrating sensitive detection and robust performance. Conclusion In summary, we have developed and validated a 12-parameter flow cytometry assay focusing on monitoring the regeneration of different subsets of B-cells in various B-cell malignancies (Non-Hodgkin’s Lymphoma, B CLL) and autoimmune disorders (Multiple Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus). The high reproducibility/robustness of the assay demonstrates its suitability for use in clinical trials as a valuable tool for safety monitoring and disease evaluation enabling development of novel therapeutic agents. Citation Format: Amit Kumar Mehta, Ruby Tandon, Anil Pahuja, Jane Gao, Kevin Nguyen, Naveen Dakappagari, Zeni Alfonso. A multiparametric flow cytometry assay to monitor regeneration of B-cells following anti B-cell therapy in cancer and autoimmune patients abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6409.
Abstract only
e15036
Background: Patients with locally/regionally advanced melanoma were treated on a clinical trial with a neoadjuvant combination of ipilimumab (ipi) and high dose IFNα2b (HDI) ...(Tarhini et al, JITC 2018). In this study, immune cell composition in peripheral blood samples collected at various time points was measured to determine any correlation with clinical outcomes and investigate the immune modulating effect of the combination therapy. Methods: Patients were randomized to neoadjuvant ipi at 3 mg/kg or 10 mg/kg, both given in combination with HDI. Tumor radiologic responses were designated as complete (CR), partial (PR), stable disease (SD) or disease progression (PD). Pathologic complete response (pCR) was defined as absence of viable tumor on histologic assessment. Peripheral blood mononuclear cells (PBMC) from treated patients (N = 28) were tested at baseline (before initiating ipi-HDI), then at 6-weeks, 3-months and 12-months (following neoadjuvant ipi-HDI). High complexity (14-color) flow cytometry analysis was performed to detect key immunological biomarkers including myeloid derived suppressor cells (MDSCs), B cells, regulatory T cells (Tregs), PD-1 and TIM3 expression on T-cells, and differentiation of T-cells into Th1, Th2 or Th17 phenotype at different time points during systemic immunotherapy. Statistical significance was determined using R-package employing Kruskal’s test. Results: Lower levels of peripheral Tregs (p = 0.02), MDSCs (p = 0.05), and CD4 effector memory cells (p = 0.04) at 3-months post treatment correlated with radiologic response. In addition, lower change from baseline at 3 months in CD4/CD8 ratio (p = 0.04), levels of Tregs (p = 0.01) and CD4 effector memory cells (p = 0.02) was associated with radiologic response. Patients exhibiting pCR had significantly lower Tregs (p = 0.04) at 6-months post treatment and significantly higher CD8 central memory cells at both 3 months (p = 0.04) and 12 month time-points (p = 0.01) as compared to patients without pCR. Finally, patients without pCR had significantly lower change from baseline in CD19 B cells at 6 months (p = 0.01) and 12 months (p = 0.04) as compared to patients with pCR. Conclusions: Our data demonstrates that the levels of immunosuppressive cells including Tregs and MDSCs in periphery are negatively associated with response. Higher levels of CD8 memory cells and B cells on-treatment are associated with clinical benefit.
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