ABSTRACT
BACKGROUND: There is limited knowledge on long-term bowel, sexual, and urinary function after combined modality therapy for anal squamous-cell cancer. OBJECTIVE: This study aimed to evaluate long-term changes in patients treated with combined modality. DESIGN: This was a retrospective study of prospectively collected patient-reported outcome surveys. SETTING: This study was conducted at a single institution. PATIENTS: There were 143 patients with stage I to III anal cancer who were treated with chemoradiation and had completed the survey. MAIN OUTCOME MEASURES: This study included patient-reported outcomes reflecting bowel, sexual, and urinary function. RESULTS: Thirty-nine percent of patients had major low anterior resection syndrome at baseline. Major low anterior resection syndrome remained stable (38%; 95% CI, 31%-46%) with no change over time (OR 0.95; 95% CI, 0.74-1.21; p = 0.7). Higher rates of major low anterior resection syndrome were observed for patients who had major low anterior resection syndrome at baseline (OR 20.7; 95% CI 4.70-91.3; p < 0.001) and for females (OR 2.14; 95% CI, 1.01-4.56; p = 0.047). On 5-point scales, we saw a nonsignificant increased level of sexual arousal during sexual activity after therapy for women (ß for 1 year = 0.15; 95% CI, -0.01 to 0.32; p = 0.072) and nonsignificant decreased confidence in getting and keeping an erection after therapy for men (ß for 1 year = -0.33; 95% CI, -0.66 to 0.00; p = 0.053). LIMITATIONS: This was a single-institution study and only patients who answered the questionnaire were included in the study. CONCLUSIONS: A significant proportion of patients have major low anterior resection syndrome at baseline and after successful treatment for anal cancer. Having major low anterior resection syndrome at baseline was the biggest predictor of having major low anterior resection syndrome after treatment. Bowel, sexual, and urinary function did not improve over time up to 2 years after end of treatment. Physicians should counsel their patients before treatment that baseline poor bowel function is a risk factor for posttreatment bowel dysfunction. See Video Abstract at http://links.lww.com/DCR/C29 . EVALUACIN DE LOS RESULTADOS INFORMADOS POR LOS PACIENTES CON CNCER ANAL DE CLULAS ESCAMOSAS QUE SE SOMETEN A UNA TERAPIA DE MODALIDAD COMBINADA: ANTECEDENTES:Existe un conocimiento limitado sobre la función intestinal, sexual y urinaria a largo plazo después de la terapia de modalidad combinada para el cáncer anal de células escamosas.OBJETIVO:Evaluar los cambios a largo plazo en la función intestinal, sexual y urinaria en pacientes tratados con modalidad combinada.DISEÑO:Este fue un estudio retrospectivo de encuestas de resultados informadas por pacientes recolectadas prospectivamente.ESCENARIO:Institución única.PACIENTES:Fueron 143 pacientes con cáncer anal en estadio I-III que fueron tratados con quimiorradiación y completaron la encuesta.PRINCIPALES MEDIDAS DE RESULTADO:Resultados reportados por el paciente que reflejan la función intestinal, sexual, y urinaria.RESULTADOS:Treinta y nueve por ciento de los pacientes tenían puntajes importantes de síndrome de resección anterior bajo al inicio del estudio. Las puntuaciones del síndrome de resección anterior baja mayor permanecieron estables (38 %; IC del 95%: 31 %, 46 %) sin cambios con el tiempo (OR 0,95, IC del 95%: 0,74, 1,21, p = 0,7). Se observaron tasas más altas de puntuaciones del síndrome de resección anterior baja mayor para los pacientes que tenían puntuaciones del síndrome de resección anterior baja mayor desde el inicio (OR 20,7; IC del 95%: 4,70; 91,3, p < 0,001) y para las mujeres (OR 2,14; IC del 95%: 1,01, 4,56; p = 0,047). En escalas de 5 puntos, observamos un aumento no significativo del nivel de excitación sexual durante la actividad sexual después de la terapia para las mujeres (ß durante 1 año = 0,15; IC del 95%: -0,01, 0,32; p = 0,072) y una disminución no significativa de la confianza en lograr y mantener una erección después de la terapia para hombres (ß para 1 año = -0,33; IC del 95%: -0,66, 0,00; p = 0,053).LIMITACIONES:Este es un estudio de una sola institución. Solo se incluyeron en el estudio los pacientes que contestaron el cuestionario.CONCLUSIONES:Una proporción significativa de pacientes tienen puntajes de síndrome de resección anterior muy bajos al inicio del estudio y después de un tratamiento exitoso para el cáncer anal. Tener puntajes de síndrome de resección anterior bajos importantes al inicio del estudio fue el predictor más importante de tener puntajes de síndrome de resección anterior bajos importantes después del tratamiento. La función intestinal, sexual y urinaria no mejoró con el tiempo hasta 2 años después de finalizar el tratamiento. Los médicos deben aconsejar a sus pacientes antes del tratamiento que la mala función intestinal inicial es un factor de riesgo para la disfunción intestinal posterior al tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/C29 . (Traducción-Dr. Yolanda Colorado ).
Subject(s)
Anus Neoplasms , Carcinoma, Squamous Cell , Rectal Neoplasms , Male , Humans , Female , Retrospective Studies , Postoperative Complications , Rectal Neoplasms/surgery , Syndrome , Anus Neoplasms/therapy , Combined Modality Therapy , Carcinoma, Squamous Cell/therapy , Patient Reported Outcome MeasuresABSTRACT
BACKGROUND: The worsening opioid epidemic has led to an increased number of surgical patients with chronic preoperative opioid use. However, the impact of opioids on perioperative outcomes has yet to be fully elucidated. The purpose of this study was to assess the association between preoperative opioid dose and surgical outcomes among colectomy patients. METHODS: Adult colectomy patients in the IBM MarketScan database (2010-2017) were stratified based on preoperative opioid dose, calculated as the average opioid dose in morphine milligram equivalents (MME) in the 90 days prior to surgery: 0 MME, 1 to 49 MME, and 50 or more MME. The association between preoperative opioid dose and anastomotic leak, the primary outcome of interest, as well as other postoperative complications, was assessed using multivariable regression. RESULTS: Among 45,515 adult colectomy patients, 71.4% did not use opioids (0 MME), 27.4% had an opioid dose between 1 and 49 MME, and 1.2% had an opioid dose at or above 50 MME. Patients with preoperative opioid use exhibited a higher incidence of anastomotic leak (0 MME: 4.8%, 1-49 MME: 5.5%, ≥50 MME: 8.3%; p trend = 0.001). Multivariable analysis demonstrated a dose-response relationship between preoperative opioids and surgical outcomes, as the odds of anastomotic leak worsened with increasing opioid dose (1-49 MME: OR 1.19, 95% CI 1.08-1.31, p < 0.001; ≥50 MME: OR 1.64, 95% CI 1.20-2.24, p = 0.002). Similar dose-response relationships were seen after risk-adjustment for lung complications, pneumonia, delirium, and 30-day readmission (p < 0.05 for all). CONCLUSIONS: Providers should exercise caution when prescribing opioids preoperatively, as increasing doses of preoperative opioids were associated with worse surgical outcomes and higher 30-day readmission among adult colectomy patients.
Subject(s)
Colorectal Surgery , Opioid-Related Disorders , Adult , Analgesics, Opioid/therapeutic use , Anastomotic Leak , Humans , Pain, Postoperative/drug therapy , Pain, Postoperative/epidemiology , Practice Patterns, Physicians' , Retrospective Studies , Treatment OutcomeABSTRACT
AIM: Depression is a prevalent disorder that is associated with adverse health outcomes, but an understanding of its effect in colorectal surgery remains limited. The purpose of this study was to examine the impact of history of depression among patients undergoing colectomy. METHOD: United States patients from Marketscan (2010-2017) who underwent colectomy were included and stratified by whether they had a history of depression within the past year, defined as (1) a diagnosis of depression during the index admission, (2) a diagnosis of depression during any inpatient or (3) outpatient admission within the year, and/or (4) a pharmacy claim for an antidepressant within the year. The primary outcomes were length of stay (LOS) and inpatient hospital charge. Secondary outcomes included in-hospital mortality and postoperative complications. Logistic, negative binomial, and quantile regressions were performed. RESULTS: Among 88 981 patients, 21 878 (24.6%) had a history of depression. Compared to those without, patients with a history of depression had significantly longer LOS (IRR = 1.06, 95% CI [1.05, 1.07]), increased inpatient charge (ß = 467, 95% CI [167, 767]), and increased odds of in-hospital mortality (OR = 1.37, 95% CI [1.08, 1.73]) after adjustment. History of depression was also independently associated with increased odds of respiratory complication, pneumonia, and delirium (all P < 0.05). CONCLUSION: History of depression was prevalent among individuals undergoing colectomy, and associated with greater mortality and inpatient charge, longer LOS, and higher odds of postoperative complication. These findings highlight the impact of depression in colorectal surgery patients and suggest that proper identification and treatment may reduce postoperative morbidity.
Subject(s)
Colectomy , Depression , Depression/epidemiology , Depression/etiology , Hospital Mortality , Humans , Length of Stay , Postoperative Complications/epidemiology , Retrospective Studies , United States/epidemiologyABSTRACT
BACKGROUND: Prior randomized trials showed comparable short-term outcomes between open and minimally invasive proctectomy (MIP) for rectal cancer. We hypothesize that short-term outcomes for MIP have improved as surgeons have become more experienced with this technique. METHODS: Rectal cancer patients who underwent elective abdominoperineal resection (APR) or low anterior resection (LAR) were included from the American College of Surgeons National Surgical Quality Improvement Program database (2016-2018). Patients were stratified based on intent-to-treat protocol: open (O-APR/LAR), laparoscopic (L-APR/LAR), robotic (R-APR/LAR), and hybrid (H-APR/LAR). Multivariable logistic regression analysis was used to assess the impact of operative approach on 30-day morbidity. RESULTS: A total of 4471 procedures were performed (43.41% APR and 36.59% LAR); O-APR 42.72%, L-APR 20.99%, R-APR 16.79%, and H-APR 19.51%; O-LAR 31.48%, L-LAR 26.34%, R-LAR 17.48%, and H-LAR 24.69%. Robotic APR and LAR were associated with shortest length of stay and significantly lower conversion rate. After adjusting for other factors, lap, robotic and hybrid APR and LAR were associated with decreased risk of overall morbidity when compared to open approach. R-APR and H-APR were associated with decreased risk of serious morbidity. No difference in the risk of serious morbidity was observed between the four LAR groups. CONCLUSION: Appropriate selection of patients for MIP can result in better short-term outcomes, and consideration for MIP surgery should be made.
Subject(s)
Elective Surgical Procedures/methods , Minimally Invasive Surgical Procedures/methods , Postoperative Complications/epidemiology , Proctectomy/methods , Rectal Neoplasms/surgery , Aged , Databases, Factual , Female , Follow-Up Studies , Humans , Male , Middle Aged , Morbidity/trends , Time Factors , Treatment Outcome , United States/epidemiologyABSTRACT
BACKGROUND: We aimed to assess patient and demographic factors, treatment trends, and survival outcomes of patients with colorectal cancer with metastasis to the liver, lung, or both sites. Differences remain among national guidelines about the optimal management strategy. METHODS: Adults from the National Cancer Database (2010 to 2015) with a primary diagnosis of colorectal liver, lung, or liver and lung metastases were included and stratified by metastasis site. The primary end point was 5-year overall survival, analyzed using Kaplan-Meier survival curves, log-rank test, and the Cox proportional hazards model. RESULTS: Among 82,609 included patients, 70.42% had liver, 8.74% had lung, and 20.85% had simultaneous liver and lung metastases. Treatment with chemotherapy alone was used the most (21.11%), followed by chemotherapy with colorectal radical resection (CRRR) (19.4%), no treatment (14.35%), CRRR alone (9.03%), and chemotherapy with CRRR and liver/lung resection (8.22%). Patients with lung metastasis had significantly better 5-year overall survival rates than the other 2 metastatic groups (15.99%, 16.70%, and 5.51%; p < 0.001), even after stratifying by treatment type and adjusting for other factors. Chemotherapy with CRRR and liver/lung resection was associated with the greatest reduction in mortality risk for all sites in both unadjusted (35.15%, 44.52%, and 20.10%; p < 0.001) and adjusted analyses (hazard ratio 0.42; 95% CI, 0.38 to 0.47; p < 0.001; hazard ratio 0.31; 95% CI, 0.18 to 0.53; p < 0.001; and hazard ratio 0.79; 95% CI, 0.62 to 1.01; p = 0.064 for trend), and forgoing treatment or CRRR alone offered the worst overall survival. CONCLUSIONS: Patients with metastasis to lung had increased overall survival compared with other sites of metastases, regardless of treatment modality. Combined resection of primary tumor, metastasectomy, and chemotherapy appears to offer the greatest chance of survival.
Subject(s)
Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Aged , Colorectal Neoplasms/pathology , Combined Modality Therapy , Female , Hepatectomy , Humans , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Metastasis , Pneumonectomy , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Anal squamous cell carcinoma (ASCC) is the most common histological subtype of anal cancer. Rates have been observed to increase in recent years. Combined chemoradiotherapy (CCRT) is currently the gold standard of treatment. The aim of this study is to assess ASCC prevalence, treatment trends, and overall survival (OS) in the United States. METHODS: Patients diagnosed with stage I-IV ASCC were identified from the National Cancer Database from 2004 to 2015. The primary outcome was 5-year OS, which was analyzed using Kaplan-Meier survival curves, log-rank test, and Cox proportional hazards models. RESULTS: 34,613 cases were included (stage I: 21.45%; II: 41.00%; III: 31.62%; IV: 5.94%), with an increasing trend in prevalence. CCRT was the most used treatment. Multimodal treatment, combining surgery with CCRT, offered the best OS rates for stage I, II, and IV cancers (I: 84.87%; II: 75.12%; IV: 33.08%), comparable with survival of stage III patients treated with CCRT (III: 61.14%). Radiation alone had the worse OS rates, and on adjusted analysis, radiation treatment alone had the greatest risk of mortality (I: hazard ratio, 2.01; 95% confidence interval, 1.14-3.54; P = 0.016; II: 2.05, 1.44-2.93, P < 0.001; IV: 1.99, 0.99-4.02, P = 0.054). CONCLUSIONS: ASCC has increased in prevalence, notably in stage III and IV disease. Although CCRT is the most commonly used treatment type for all stages of ASCC, multimodal treatment offers better OS in stages I, II, and IV. Treatment with radiation alone offers the worst OS no matter the stage and should no longer be used as a solitary treatment modality.
Subject(s)
Anus Neoplasms/therapy , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy/statistics & numerical data , Proctectomy/statistics & numerical data , Radiotherapy/statistics & numerical data , Aged , Aged, 80 and over , Anus Neoplasms/epidemiology , Anus Neoplasms/pathology , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , Chemoradiotherapy/standards , Chemoradiotherapy/trends , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Patient Selection , Prevalence , Proctectomy/standards , Proctectomy/trends , Radiotherapy/standards , Radiotherapy/trends , Retrospective Studies , Survival Rate , Treatment Outcome , United States/epidemiologyABSTRACT
BACKGROUND: The aim of this study is to assess treatment trends and overall survival (OS) in small bowel (SB) and colorectal (CR) gastrointestinal stromal tumors (GIST) with respect to the introduction of imatinib in 2008. METHODS: Patients diagnosed with SB and CR GIST were identified from the National Cancer Database (2004-2015). The primary outcome was 5- and 10-year OS. Patients were stratified by tumor site, time period (before and after imatinib), and treatment type. OS was analyzed using Kaplan-Meier survival curves, log-rank test, and Cox proportional hazards models. RESULTS: A total of 8441 cases were included (SB 81.66%; CR 18.34%). Radical resection was the most common treatment (SB 42.33%; CR 38.69%). The addition of chemotherapy to radical resection for SB GIST increased between the two time periods (31.76 to 40.43%; p < 0.001), and was associated with improved unadjusted and adjusted OS (2009-2015: adjusted HR [AHR] 0.73, 95% CI 0.59-0.89, p = 0.002). Patients with SB GIST had better 5- and 10-year OS compared with CR (SB 69.83% and 47.68%; CR 61.33% and 45.39%; p < 0.001), even after stratifying by treatment type and tumor size and adjusting for other factors (SB 5-year AHR 1.35, 95% CI 1.19-1.53; 10-year AHR 1.23, 95% CI 1.09-1.38; each p < 0.001). CONCLUSION: CR GIST are associated with lower OS than SB GIST. Radical resection is the most common treatment type for both sites. Chemotherapy with radical resection offers better OS in SB GIST, but not in CR GIST. Further studies are needed to assess the biology of CR GIST to explain the worse OS.
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Imatinib Mesylate/therapeutic use , Aged , Colorectal Neoplasms/drug therapy , Databases, Factual/statistics & numerical data , Female , Gastrointestinal Neoplasms/epidemiology , Gastrointestinal Neoplasms/mortality , Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/epidemiology , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/surgery , Humans , Intestine, Small , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , United States/epidemiologyABSTRACT
BACKGROUND: Immunotherapy advances for the treatment of cutaneous melanoma question its efficacy in treating anorectal mucosal melanoma (ARMM). We aimed to identify the prevalence, current management, and overall survival (OS) for ARMM. METHODS: Review of patients with ARMM from 2004 to 2015 National Cancer Database. Factors associated with immunotherapy were identified using multivariable logistic regression. The primary outcome was 2- and 5-year OS. Subgroup analysis by treatment type was performed. RESULTS: A total of 1331 patients were identified with a significant increase in prevalence (2004: 6.99%, 2015: 10.53%). ARMM patients were older, white, on Medicare, and from the South. The most common treatment was surgery (48.77%), followed by surgery + radiation (11.75%), surgery + immunotherapy (8.68%), and surgery + chemotherapy (8.68%). 16.93% of patients received immunotherapy, with utilization increasing (7.24%: 2004, 21.27%: 2015, p < 0.001). Patients who received immunotherapy had a significantly better 2-year OS (42.47% vs. 49.21%, p < 0.001), and other therapies did not reveal a significant difference. Adjusted analysis showed no difference in 2- and 5-year OS based on therapy type. CONCLUSION: The prevalence of ARMM has increased. The use of immunotherapy has increased substantially. Some survival benefit with the administration of immunotherapy may exist that has yet to be revealed. A more aggressive treatment paradigm is warranted.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Anus Neoplasms/therapy , Immunotherapy , Melanoma/therapy , Rectal Neoplasms/therapy , Aged , Aged, 80 and over , Combined Modality Therapy , Databases, Factual , Female , Humans , Male , Middle Aged , Survival Rate/trendsABSTRACT
BACKGROUND: An area of contention among colorectal surgeons is when it is safe to discharge patients who have undergone closure of diverting ostomies. This study aimed to review the trends in outpatient stoma closure (OSC), to assess the safety of this practice, and to identify appropriate surgical candidates for the outpatient procedure. METHODS: Patients were queried from the ACS National Surgical Quality Improvement Program database (2005-2016). Main outcomes included Clavien-Dindo (C-D) III-V class surgical complications, and readmission. Outpatient stay was defined as a hospital stay of less than or equal to 1 day. Multivariable logistic regression analysis was used to identify risk factors for C-D III-V complications and readmission. RESULTS: Of 24,393 patients, 668 (2.74%) underwent an OSC. OSC has increased over the last decade (3.16% 2005-2006, 4.14% 2016, p < 0.001). Outpatients had significantly lower ASA class and fewer comorbidities than inpatients. Outpatient complication rate was significantly lower than the inpatient rate (2.99% vs. 7.25%, p < 0.001). Readmissions were comparable (8.92% outpatient vs. 9.77% inpatient, p = 0.54). ASA > 2, smoking, COPD, dyspnea, steroid use, bleeding disorder, and partial/total dependency were associated with increased risk of complications and readmission. Patients without any risk factors had lower complication (4.75%) and readmission rates (8.09%) compared to those with ≥ 2 risk factors (11.50% complication and 13.07% readmission rate, p < 0.001). CONCLUSIONS: There is an increasing trend in the percentage of stoma closures being performed as outpatient procedures. Appropriate selection of patients preoperatively who are suitable candidates for OSC can be helpful in managing patient expectations and hospital resources.
Subject(s)
Ambulatory Surgical Procedures/adverse effects , Enterostomy , Patient Readmission/statistics & numerical data , Postoperative Complications/etiology , Aged , Databases, Factual , Female , Health Status Indicators , Humans , Male , Middle Aged , Risk FactorsABSTRACT
BACKGROUND: Patients often have an incomplete understanding of the levels of training and roles of the various surgical providers in teaching hospitals, leading to patient confusion and dissatisfaction. METHODS: Pre-intervention discharge surveys were administered to gastrointestinal surgery inpatients (10/2016-02/2017) to evaluate sentiments regarding their surgical team. During the intervention period (02/2017-05/2017), patients at admission received "facesheets" containing team member profiles, photos, training level, and roles. These patients were evaluated using the survey, and pre- and post-intervention scores compared. RESULTS: 153 pre- and 100 post-intervention surveys were collected. There was a significant increase in patients reporting it was important to know the surgical team members and that they knew team member roles (pâ¯≤â¯0.05). Scores in every domain of the satisfaction survey improved in the post-intervention period, although not reaching statistical significance. CONCLUSIONS: Improving how patients perceive their interactions with their surgical team has implications on patient satisfaction and hospital quality metrics.
Subject(s)
Digestive System Surgical Procedures , Internship and Residency , Patient Care Team/standards , Patient Education as Topic/standards , Patient Satisfaction/statistics & numerical data , Quality Improvement/organization & administration , Adult , Aged , Aged, 80 and over , Female , Health Care Surveys , Health Knowledge, Attitudes, Practice , Humans , Male , Middle Aged , Nurse-Patient Relations , Patient Education as Topic/methods , Patient Education as Topic/organization & administration , Physician-Patient Relations , Prospective Studies , Surgeons/standardsSubject(s)
Gracilis Muscle/transplantation , Minimally Invasive Surgical Procedures , Plastic Surgery Procedures/methods , Prostatic Neoplasms/surgery , Rectal Neoplasms/surgery , Surgical Flaps , Abdomen/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Laparoscopy , Male , Middle Aged , Perineum/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
OBJECTIVES: We have previously demonstrated that HIV-1 p24-specific plasmacytoid dendritic cell-reactive opsonophagocytic antibody (PROAb) responses associate with control of chronic HIV infection. Here, we examined whether HIV-1 p24-specific PROAbs associate with control of early HIV infection and their relationship with HIV-1 p24-specific IgG subclasses. METHODS: Plasma collected at 8 and 52 weeks following primary HIV-1 infection was obtained from antiretroviral therapy-naïve patients who were classified as 'good' (plasma HIV-1 RNAâ<â5000 copies/ml; nâ=â17) or 'poor' (HIV-1 RNAâ>â50â000 copies/ml; nâ=â15) controllers at week 52. HIV-1 p24-specific PROAb responses were assayed using a plasmacytoid dendritic cell line (Gen2.2), and HIV-1 p24-specific IgG3, IgG1 and IgG2 levels were assayed by ELISA. RESULTS: HIV-1 p24-specific PROAb responses increased in 'good controllers' (Pâ=â0.01) but remained unchanged in 'poor controllers' between weeks 8 and 52. Of the HIV-1 p24-specific IgG subclasses measured, only IgG1 increased over this time period in 'good controllers' alone (Pâ=â0.003), which correlated with the increase in HIV-1 p24-specific PROAb responses (râ=â0.83, Pâ<â0.0001). Depletion of IgG1 from IgG preparations of 'good controllers' resulted in the inhibition of HIV-1 p24-specific PROAb responses. In the total patient cohort, plasma HIV-1 RNA levels at week 52 correlated inversely with changes in HIV-1 p24-specific PROAb responses (râ=â-0.37, Pâ=â0.04) and IgG1 (râ=â-0.51, Pâ=â0.003) levels between weeks 8 and 52. CONCLUSION: Control of early HIV-1 infection was associated with an increase in HIV-1 p24-specific PROAb responses, which was mediated by HIV-1 p24-specific IgG1 antibodies. These findings provide further evidence that antibodies to HIV core proteins may contribute to control of HIV-1 infection.
Subject(s)
Dendritic Cells/immunology , HIV Antibodies/blood , HIV Core Protein p24/immunology , HIV Infections/immunology , Immunoglobulin G/blood , Opsonin Proteins/blood , Phagocytosis , Adult , Enzyme-Linked Immunosorbent Assay , HIV-1/immunology , Humans , RNA, Viral/blood , Viral LoadABSTRACT
Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG Abs against HIV-1 Gag proteins (e.g., p24) and/or production of IgG2 Abs against HIV-1 proteins. These Abs likely exert their effect by activating antiviral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG Ab response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by Ab isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG Ab responses against HIV-1 p24 were higher in HIV controllers (HIV RNA < 2000 copies/ml) than noncontrollers (HIV RNA > 10,000 copies/ml), particularly in controllers with low but detectable viremia (HIV RNA 75-2000 copies/ml). Opsonophagocytic Ab responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and, notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these Abs was mediated via FcγRIIa. Isotype diversification (toward IgG2) was greatest in HIV controllers, and depletion of IgG2 from Ig preparations indicated that IgG2 Abs to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of Ab function, such as Ag opsonization. Our findings emulate those for pDC-reactive opsonophagocytic Ab responses against coxsackie, picorna, and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.
Subject(s)
Dendritic Cells/immunology , HIV Antibodies/immunology , HIV Core Protein p24/immunology , HIV Infections/immunology , HIV-1/immunology , Immunoglobulin G/immunology , Viremia/immunology , AIDS Vaccines/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Cell Line , HIV Antibodies/blood , Humans , Immunoglobulin G/blood , Phagocytosis/immunology , RNA, Viral/blood , Receptors, IgG/immunology , Viremia/virologyABSTRACT
The monomeric G-protein Rhes has been described to be present in pancreatic beta-cells, and a putative role in the control of insulin release has been proposed. Here, we show that treatment of beta-cells with the imidazoline insulin secretagogue efaroxan resulted in a concentration- and time-dependent increase in the expression of Rhes, which peaked after 4h of efaroxan exposure; thereafter, Rhes mRNA levels decreased. Marked stereoselectivity was displayed, with (-)-efaroxan (the selectively insulinotropic enantiomer) being much more effective than (+)-efaroxan at raising Rhes transcript levels. The mechanism by which Rhes gene expression is activated in beta-cells appears to require the influx of extracellular calcium and de novo protein synthesis, and is not directly associated with the release of insulin. The present results confirm our earlier proposal that Rhes is an imidazoline-regulated transcript in pancreatic beta-cells. Studies to understand the role of Rhes as a regulator of beta-cell function are, thus, warranted.
Subject(s)
Benzofurans/pharmacology , Calcium/metabolism , GTP-Binding Proteins/physiology , Imidazoles/pharmacology , Insulin-Secreting Cells/metabolism , Adrenergic alpha-Antagonists/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Dihydropyridines/pharmacology , GTP-Binding Proteins/biosynthesis , Glyburide/metabolism , Humans , Hypoglycemic Agents/pharmacology , Imidazolines/pharmacology , RNA, Messenger/metabolism , Transcription, GeneticABSTRACT
SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selectivity and interstrand DNA cross-linking activity, SJG-136 has been selected for clinical trials. This study examines the pharmacological characteristics of SJG-136 and provides the first report of pharmacokinetic properties for this agent. A sensitive, selective and reproducible reversed-phase gradient LC/MS assay has been developed for detection and analysis, where a molecular ion ( m / z 557.2) is detectable for the SJG-136 parent imine. Fluorescence detection (260 nm excitation, 420 nm emission) gives a limit of sensitivity of 5 nM (2.5 ng ml(-1)) for analysis of SJG-136 in mouse plasma. Extraction efficiencies from plasma were >65% across a range of concentrations (5-1000 nM). Following administration to mice at the MTD (i.p., 0.2 mg kg(-1)), high peak plasma concentrations of SJG-136 were seen ( C (max) = 336 nM) at 30 min after dosing. A calculated terminal t (1/2) of 0.98 h and AUC of 0.34 microM.h resulted in a clearance rate of 17.7 ml min(-1) kg(-1). The PBD dimer binds only moderately to proteins (65-75%), and in vitro cytotoxicity studies confirmed IC(50) values of 4-30 nM with a panel of human cell lines. This finding demonstrates that plasma concentrations achieved in the mouse are substantially higher than those required to elicit an anti tumour response in vitro. This report forms an important phase in the pre-clinical characterization of the compound.