Higher Probability Of Progression Research Articles

Progression of Myopic Maculopathy Based on the ATN Classification System

Introduction: Myopic maculopathy is a sight-threatening disease, which causes irreversible vision faults and central vision loss. The purpose of this study is evaluating the risk factors of the myopic maculopathy progression according to the ATN classification system. Methods: Clinic data of 69 high myopia patients aged older than 40 years with a follow-up time of more than 2 years, who underwent fundus photography and OCT examination were retrospectively collected. Fundus changes were evaluated with ATN classification at the first and last follow-up times. The related factors affecting progress including axial length (AL), spherical equivalence (SE), subfoveal choroidal thickness (SFCT), disc-foveal distance (DFD), optic disc tilt, and parapapillary atrophy (PPA) were analyzed. Results: This study included 69 high-myopia patients with mean age 54.29 ± 10.41 years. The progression rate of myopic maculopathy (MM) was approximately 25.56%. Elongated DFD (5.37 ± 0.11 mm vs. 4.86 ± 0.37 mm; p < 0.001) and thinner SFCT (138.52 ± 29.38 μm vs. 184.87 ± 48.72 μm; p = 0.008) at baseline were linked with MM progression. In multiple logistic regression analysis, DFD was a substantial hazard risk factor (adjusted OR = 1.672, 95% CI: 1.135–2.498, p < 0.05) after adjusting for age, AL and SFCT. Receiver operating characteristic curve showed that DFD might serve as a predictor to discriminate the MM progression with a cut-off value of 5.15 mm and a substantial receiver operating characteristic curve area (AUC: 0.794). Compared with the non-progression group, the progression group had older age (p < 0.001), longer AL (p = 0.001), higher optic disc tilt rate (p < 0.001), and higher proportion of pre-existing PPA (p = 0.038) at baseline, the differences were statistically significant. Conclusion: Based on the ATN classification system, we found that the progression of MM was related to older age, longer AL, high disc tilt, pre-existing PPA, thinner SFCT, and longer DFD. The parameter of DFD was an important factor affecting the progression of MM, which is considered to have a higher probability of progression when the length is beyond 5.15 mm.

Role of pancreatic ductal adenocarcinoma risk factors in intraductal papillary mucinous neoplasm progression.

Pancreatic ductal adenocarcinoma (PDAC) is lethal due to its late diagnosis and lack of successful treatments. A possible strategy to reduce its death burden is prevention. Intraductal papillary mucinous neoplasms (IPMNs) are precursors of PDAC. It is difficult to estimate the incidence of IPMNs because they are asymptomatic. Two recent studies reported pancreatic cysts in 3% and 13% of scanned subjects. The possibility of identifying a subgroup of IPMN patients with a higher probability of progression into cancer could be instrumental in increasing the survival rate. In this study, genetic and non-genetic PDAC risk factors were tested in a group of IPMN patients under surveillance. A retrospective study was conducted on 354 IPMN patients enrolled in two Italian centres with an average follow-up of 64 months. With the use of DNA extracted from blood, collected at IPMN diagnosis, all patients were genotyped for 30 known PDAC risk loci. The polymorphisms were analysed individually and grouped in an unweighted polygenic score (PGS) in relation to IPMN progression. The ABO blood group and non-genetic PDAC risk factors were also analysed. IPMN progression was defined based on the development of worrisome features and/or high-risk stigmata during follow-up. Two genetic variants (rs1517037 and rs10094872) showed suggestive associations with an increment of IPMN progression. After correction for multiple testing, using the Bonferroni correction, none of the variants showed a statistically significant association. However, associations were observed for the non-genetic variables, such as smoking status, comparing heavy smokers with light smokers (HR = 3.81, 95% 1.43-10.09, p = 0.007), and obesity (HR = 2.46, 95% CI 1.22-4.95, p = 0.012). In conclusion, this study is the first attempt to investigate the presence of shared genetic background between PDAC risk and IPMN progression; however, the results suggest that the 30 established PDAC susceptibility polymorphisms are not associated with clinical IPMN progression in a sample of 354 patients. However, we observed indications of cigarette smoking and body mass index (BMI) involvement in IPMN progression. The biological mechanism that could link these two risk factors to progression could be chronic inflammation, of which both smoking and obesity are strong promoters.

The Role of Methylation of Host and/or Human Papillomavirus (HPV) DNA in Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) Lesions.

Cervical intraepithelial neoplasia grade 2 (CIN2) is an intermediate stage between CIN 1, which is a low-grade lesion, and CIN3, which is the immediate precursor of cervical cancer (CC). Traditionally, CIN2 was regarded as a high-grade lesion and was treated with conization or ablative methods. In recent years, there has been a shift in the management of younger patients, who are now more often being managed conservatively due to frequent spontaneous CIN2 regression and possible adverse effects of treatment on future pregnancies. Because the risk of progression to CC still exists with conservative management, a personalized approach is needed to identify patients with a higher probability of progression. In this regard, research has focused on the role of host and human papillomavirus (HPV) gene methylation. This systematic review summarizes the current knowledge regarding conservative CIN2 management focusing on the main methylation markers and its implementation in conservative CIN2 management, and it describes major ongoing longitudinal studies on the subject. The review showed that DNA methylation is an accurate predictor of disease progression and a valid triage tool for HPV-positive women, with CIN2 performing better than triage cytology. Because virtually all CCs are methylation-positive, methylation-negative women at baseline have an extremely low risk of CC.

Abstract B020: Distinct spatiotemporal tumor-immune ecologies enable disease prediction in NSCLC patients

Abstract Purpose of study: Non-small cell lung cancer (NSCLC) is the most common and fatal of cancers. In this work, we examine multiplexed images of NSCLC tumors to investigate both the spatial and spatiotemporal eco-evolutionary interactions between the tumor and its microenvironment, to better understand NSCLC tumor progression and therapy response. Methods: We developed a scalable, computational image analysis pipeline using cell-segmentation and quadrat-based approaches to analyze the spatial and temporal features of high-dimensional multiplexed NSCLC images. Multiplexed images enable the spatial readouts of numerous biomarkers per tissue sample and allow the interpretation of cellular states and the characterization of tumor-immune interactions across tissue ensembles. We also implement statistical approaches for ecological niche modelling combined with machine learning and deep learning models to predict disease progression and identify clinical imaging biomarkers. Data: Images were obtained from two 9-patient cohorts having advanced/metastatic NSCLC who were treated with the oral HDAC inhibitor vorinostat combined with the PD-1 inhibitor pembrolizumab. The first cohort had 4 progressors (PD) and 5 with stable disease (SD). The second cohort had 3 patients each in the PD, SD and partial response (PR) categories. Images were collected from all patients both pre- and on-treatment (during the third week). Results: Using our computational framework based on cell segments and quadrats, we confirm that different spatial neighborhoods exist that distinguish PD from SD, and that these spatial ecologies aid disease progression: PD patients have distinct ecologies with higher colocalization of PanCK+PD-1+FoxP3 indicating an immunosuppressive environment, whereas SD patients have a higher colocalization of PanCK+PD-L1 along with T cells, suggesting immunoactive tumor regions. These can be considered as potential biomarker candidates for predicting tumor progression. In an additional experiment where we include PR samples in our analyses, these distinct spatial neighborhoods are reinforced amongst PD, SD and PR patient groups corroborating the existence of spatiotemporal patterns. Further, we were able to predict treatment response with &amp;gt;91% accuracy given each patient’s spatial distribution of cell types from pre-treatment images. Using these predictions, we can generate risk maps at the patient level to identify areas of the tumor that are indicators of a higher probability of progression during treatment. Conclusions: We leveraged both single-cell and quadrat-resolution analysis of multiplexed imaging data and identified fundamentally distinct spatial ecologies between PD and SD patients. The ecology in PD patients appears to be primed for immune resistance even before treatment. This ecological diversity between SD and PD patients acts as a biomarker that enables accurate disease progression prediction. Our disease progression predictions can be used in conjunction with standard PD-L1 status to further strengthen personalized treatment strategies. Citation Format: Sandhya Prabhakaran, Chandler Gatenbee, Mark Robertson-Tessi, Amer A. Beg, Jhanelle Gray, Scott Antonia, Robert A. Gatenby, Alexander R.A. Anderson. Distinct spatiotemporal tumor-immune ecologies enable disease prediction in NSCLC patients [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B020.

Clinical and Biological Variables Influencing Outcome in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Anti-PD-1/PD-L1 Antibodies: A Prospective Multicentre Study.

Introduction: Immune checkpoint inhibitors (ICIs) have become the standard of treatment for patients with non-small cell lung cancer (NSCLC). However, there are still many uncertainties regarding the selection of the patient who could benefit more from this treatment. This study aims to evaluate the prognostic and predictive role of clinical and biological variables in unselected patients with advanced NSCLC candidates to receive ICIs. Methods: This is an observational and prospective study. The primary objective is the evaluation of the relationship between clinical and biological variables and the response to ICIs. Secondary objectives included: safety; assessment of the relationship between clinical and biological parameters/concomitant treatments and progression-free survival at 6 months and overall survival at 6 and 12 months. Nomograms to predict these outcomes have been generated. Results: A total of 166 patients were included. An association with response was found in the presence of the high immunohistochemical PD-L1 expression, squamous cell histotype, and early line of treatment, whereas a higher probability of progression was seen in the presence of anemia, high LDH values and neutrophil/lymphocyte ratio (NLR), pleural involvement, and thrombosis before treatment. The nomogram showed that anemia, PD-L1 expression, NLR, and LDH represented the most informative predictor as regards the three parameters of interest. Conclusions: In the era of personalized medicine, the results are useful for stratifying the patients and tailoring the treatments, considering both the histological findings and the clinical features of the patients.

Two Cases of Heavy Chain MGUS.

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

Microrna Mir-21 Is Upregulated after Different Microenvironmental Stimuli and Controls Proliferation, Chemotaxis and Chemoresistance in Chronic Lymphocytic Leukemia

Aberrant expression of diverse microRNAs (miRNAs) has been related to pathogenesis and clinical outcome in patients with CLL. miR-21 is overexpressed in a wide variety of neoplasms where it participates in oncogenic events such as proliferation, resistance to treatment and metastasis. In CLL, miR-21 expression has been associated to refractoriness to fludarabine and to shorter overall survival. In addition, high expression of ZAP-70 protein in CLL is related to shorter overall survival and higher probability of progression. Several biological mechanisms have been described explaining the adverse prognosis associated with high ZAP-70 expression. In this sense, ZAP-70 protein increases the capability of CLL cells to respond to different survival and migration signals provided by the microenvironment. In a previous work, we found that transfected B-cell lines with a ZAP-70 expressing vector (Calpe at al, Blood 2011) had an increased expression of several molecules, including miR-21. Against this background, we studied the relationship between ZAP-70 protein and miR-21. For this, we firstly analyzed the correlation of ZAP-70 with miR-21 in primary CLL cells from 32 patients. In this series we observed that miR-21 expression analyzed by QRT-PCR was significantly higher in patients with high expression of ZAP-70 compared to patients with low expression of ZAP-70 (mean miR-21 in high ZAP-70 (N=17) = 5.781 ± 1.517; mean miR-21 in low ZAP-70 (N=15) = 0.6783 ± 0.2730; p=0.0082). In order to further analyze the molecular mechanisms regulating the induction of miR-21 and the potential role of ZAP-70 protein in this process, we co-cultured primary CLL cells (N=16) in conditions mimicking the microenvironment in the proliferation centers (bone marrow stromal cells with concomitant stimulation of CD40 and TLR9). In these conditions, besides ZAP-70 activation, we observed a 3.6 ± 0.78 mean fold induction in miR-21 expression after 48 hours compared to cells in suspension. Interestingly, this increase was only significant in patients with high expression of ZAP-70 (N=8; p= 0.0379). To define the role of ZAP-70 in miR-21 regulation, we stably transfected Ramos B-cells with ZAP-70 protein and found that both MAPK and STAT3 participate in the induction of miR-21 expression after ZAP-70 activation upon BCR crosslinking. Moreover, using this system we observed downregulation of the tumor suppressors PTEN, PDCD4 and PIAS3, all of which have been found to be targeted by miR-21 in malignant cells. Next, we aimed to study the functional role of miR-21 in primary CLL cells co-cultured in conditions mimicking the microenvironment from the proliferation centers. For this, we analyzed survival, proliferation and response to fludarabine after inhibition of miR-21 expression by transfecting primary CLL cells with antisense miR-21 inhibitor. The co-culture of primary CLL cells significantly increased their survival after 48 hours regardless the inhibition of miR-21. However, the induction of proliferation (measured as percentage of Ki-67 positive cells) was significantly inhibited by the suppression of miR-21 (N=13; p=0.022). Next, the analysis of a small pilot cohort showed a consistent but not yet significant overcoming of the chemoresistance induced by the co-culture after the inhibition of miR-21 Interestingly, the sensitivity to fludarabine of primary CLL cells cultured in suspension was also increased by the inhibition of miR-21. Finally, we examined the ability of primary CLL cells to migrate towards CXCL12 and observed that inhibition of miR-21 resulted in a 2.62-fold reduction of the migration index (ratio of cells migrating towards culture media to cells migrating towards media with 200ng/mL CXCL12). In conclusion, we have showed the correlation and participation of ZAP-70 protein in the regulation of miR-21. We have also observed that miR-21 contributes to CLL proliferation, resistance to fludarabine, and chemotaxis towards CXCL12. Although further experiments are warranted in order to fully elucidate the regulation and functional role of miR-21 in CLL, these results help to enlighten the biology behind the adverse clinical outcome of patients with CLL and high expression of ZAP-70, and could potentially be exploited for the development of new treatments in a near future. DisclosuresBosch:Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Regulation Of Microrna Mir-21 Expression By ZAP-70 Protein In Chronic Lymphocytic Leukemia

Aberrant expression of diverse microRNAs (miRNAs) has been related to pathogenesis and clinical outcome in patients with CLL. In this regard, miR-21 expression has been associated to refractoriness to fludarabine and to shorter overall survival. MicroRNA miR-21 has been found to be overexpressed in a wide variety of neoplasms where it participates in oncogenic events such as proliferation, resistance to treatment, and metastasis. In CLL, high expression of ZAP-70 protein is related to shorter overall survival and higher probability of progression. Moreover, ZAP-70 protein participates in the signaling of the B cell receptor (BCR) and different chemokine receptors, therefore increasing the capability of CLL cells to respond to survival and migration signals provided by the microenvironment. In order to further elucidate the molecular mechanisms defining bad prognosis CLL we studied the relationship between ZAP-70 protein and miR-21. Firstly, we analyzed the correlation of ZAP-70 with miR-21 in primary CLL cells from 32 patients. In this series we observed that miR-21 expression analyzed by QRT-PCR was significantly higher in patients with high expression of ZAP-70 compared to patients with low expression of ZAP-70 (mean miR-21 in high ZAP-70 (N=17) = 5.781 ± 1.517; mean miR-21 in low ZAP-70 (N=15) = 0.6783 ± 0.2730; p=0.0082). In order to further analyze the molecular mechanisms regulating the induction of miR-21 and the potential role of ZAP-70 protein in this process, we co-cultured primary CLL cells (N=16) with bone marrow stromal cells with concomitant stimulation of CD40 and TLR9. In these conditions, besides ZAP-70 activation, we observed a 3.6 ± 0.78 mean fold induction in miR-21 expression after 48 hours of co-culture compared to cells in suspension. Interestingly, when we independently analyzed patients with low or high expression of ZAP-70 (N=8 for each group) we observed that this increase was only significant in patients with high expression of ZAP-70 (p= 0.0379). We therefore decided to specifically study the role of ZAP-70 in the regulation of miR-21. For this, we stably transfected Ramos cells with a vector expressing a ZAP-70-GFP fusion protein or GFP only as a control. The stimulation of the BCR in these cells caused the activation of ZAP-70 protein and the subsequent activation of the MAPK and AKT pathways, as evidenced by western blot analysis. Interestingly, BCR stimulation for 12 hours in Ramos-GFP cells significantly induced the expression miR-21 (19.55 ± 1.49 vs. 65.03 ±12.98; 3.32 fold change) whereas in those cells transfected with ZAP-70 the increase was greater (13.26 ± 2.13 vs. 138.77 ± 11.72; 10.4 fold change), suggesting that ZAP-70 is directly participating in the pathway leading to miR-21 upregulation. In addition, only after 4 hours of BCR stimulation we already observed upregulation of primary-miR21, specially in cells with expression of ZAP-70 (2.1 fold in Ramos GFP vs. 7.3 fold in Ramos GFP-ZAP-70), indicating that the regulation of miR-21 is at the transcriptional level. Furthermore, inhibition of the MAPK pathway, but not of AKT, impaired the upregulation of miR-21 in both cell lines. STAT-3 transcription factor has been shown to participate in the induction of miR-21 expression in different cell types. In this system, we observed that BCR stimulation induced the activation of STAT-3 and that its biochemical inhibition impaired the upregulation of miR-21, indicating that STAT-3 is probably participating in miR-21 induction in malignant B-lymphocytes. Finally, we analyzed the downregulation of potential miR-21 targets. For this, we studied the downregulation of the tumor suppressors PTEN, PDCD4 and PIAS3, all of which have been found to be regulated by miR-21 in malignant cells. We observed that, after 48 hours of BCR stimulation, the protein levels of all three genes were downregulated, indicating that these proteins may be targeted by miR-21 in this cellular system. In conclusion, we have showed the participation of ZAP-70 protein in the regulation of miR-21, an oncomiR that has been related to short survival and resistance to treatment with fludarabine in CLL. Although further experiments are warranted in order to fully elucidate the role of ZAP-70 in miR-21 induction in CLL, these results enlighten the biology behind the adverse clinical outcome of patients with CLL and high expression of ZAP-70, and can potentially be exploited for the development of new treatments. Disclosures:No relevant conflicts of interest to declare.

ZAP-70 Enhances Infiltration of Malignant B Lymphocytes Into the Bone Marrow by Increasing Migratory and Survival Responses to CXCR4 Stimulation

Abstract 1779Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the accumulation and proliferation of monoclonal CD5+ B lymphocytes in peripheral blood, secondary lymphoid tissues, and bone marrow. In CLL, high expression of ZAP-70 is a strong prognostic factor that identifies patients with higher probability of progression and shorter survival. Increasing evidence shows that the microenvironment plays a relevant role in the natural history of this disease, providing CLL cells with proliferative and anti-apoptotic signals. In this sense, despite that the role of ZAP-70 in the biology of CLL has not been fully elucidated, it is well known that it is associated with enhanced response to several microenvironmental stimuli. Herein, we aimed to analyze the effect of ZAP-70 on the interaction of B-cells with the microenvironment in an in vivo xenograft model of disseminated B-cell leukemia. For this, we stably transfected Raji B-cells with a vector expressing a GFP-ZAP-70 fusion protein or GFP only as a control. Cells were then intravenously injected into 7- to 9-weeks old female C.B-17 SCID mice (Raji GFP n=12; Raji GFP-ZAP-70 n=9). This xenograft model develops hind legs paralysis at around 14 to 19 days after cell injection due to central nervous system (CNS) infiltration, which precedes death by 1 to 2 days; therefore, paralysis was considered the end point of the study. The infiltration of the CNS was not influenced by ZAP-70 expression; thus, median survival was of 16 days for both Raji GFP and Raji GFP-ZAP-70-injected mice. Analysis of the infiltration of Raji B-cells in the different organs by flow cytometry and immunohistochemistry disclosed a significantly increased infiltration in the bone marrow of Raji GFP-ZAP-70 mice compared to Raji GFP mice (67% ± 5.76% vs 2.9% ± 1.49%; P <.001). Based on that, we analyzed the in vitro migrative capacity of cells toward SDF-1α, the main chemokine regulating lymphocyte trafficking into the bone marrow. We observed that, despite that Raji GFP-ZAP-70 and Raji GFP transfectants had similar surface expression of CXCR4, GFP-ZAP-70 cells had higher migration toward SDF-1α compared to GFP cells (migration index: 34.6 ± 4.11 vs 9.9 ± 1.47; P =.0079). Of note, B-cells expressing ZAP-70 also migrated more toward bone marrow stromal cells than B-cells non-expressing ZAP-70 (migration index: 27.1 ± 1.6 and 9.43 ± 0.77, respectively; P =.028). This increased migrative capacity independent of CXCR4 expression could be explained by the observation that Raji GFP-ZAP-70 cells showed enhanced response to CXCR4 stimulation by SDF-1α, evidenced by increased phosphorylation of ZAP-70, Akt and ERK1/2 proteins. Accordingly, we found that primary CLL subclones with high expression ZAP-70 also had increased migration toward SDF-1α. The relevance of the CXCR4/SDF-1α axis in the migrative capacity of Raji B-cells was demonstrated by the blockage of CXCR4 with a mAb, which resulted in reductions of more than 85% in the in vitro migration to both SDF-1α and to bone marrow stromal cells in both cell lines. To evaluate this axis in the xenograft model, SCID mice were injected with malignant B-cells treated with anti-CXCR4 mAb (Raji GFP n=5; Raji GFP-ZAP-70 n= 8) or isotypic control antibody (Raji GFP n=5; Raji GFP-ZAP-70 n= 8). In mice injected with Raji-GFP cells, CXCR4 blockage resulted in a delayed onset of the disease (median survival: 15 days vs 69 days; p<0.01), having these cells restored their CXCR4 expression. Surprisingly, CXCR4 blockage in Raji GFP-ZAP-70 cells produced different effects, with 7 out of 8 mice remaining asymptomatic without detectable malignant B-cells during follow-up (> 100 days). This suggests that ZAP-70-positive malignant B-cells developed dependence on CXCR4-derived survival signals. In summary, we showed that ZAP-70 is responsible for an enhanced cellular infiltration into the bone marrow caused by an amplified response to CXCR4 as regards signaling and migration. Interestingly, ZAP-70-positive malignant B-cells apparently became addicted to survival signals derived from CXCR4 as a consequence of the enhanced signaling. Further elucidation of the role of ZAP-70 in signaling from the microenvironment, particularly from the CXCR4/SDF-1α axis, will contribute to enlighten the biology behind the adverse clinical impact of high ZAP-70 expression in CLL, and will also provide a rationale for the development of novel therapies. Disclosures:No relevant conflicts of interest to declare.

Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. We analysed data on 12,574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. FINDINGS During 24,310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/microL, adjusted hazard ratios were 0.74 (95% CI 0.62-0.89) for 50-99 cells/microL, 0.52 (0.44-0.63) for 100-199 cells/microL, 0.24 (0.20-0.30) for 200-349 cells/microL, and 0.18 (0.14-0.22) for 350 or more CD4 cells/microL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100,000 copies/microL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3.4% (2.8-4.1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43-58) in patients in the highest-risk strata. The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

Parental alcohol use disorders and alcohol use and disorders in offspring: a community study.

We examined the association between parental alcohol use disorders and patterns of alcohol consumption and DSM-IV alcohol use disorders in their offspring in a community-based sample of young adults. Data are based on baseline and 4-year follow-up data of 2427 respondents aged 14-24 at baseline. Alcohol use and disorders in respondents were assessed using the Munich-Composite-international-Diagnostic-Interview with DSM-IV algorithms. Diagnostic information about parents was collected by family history information from the respondents, and by direct interview with one parent (cohort aged 14 to 17 years only). Although the association between maternal and paternal alcohol use disorders and non-problematical drinking in offspring was minimal, there was a strong effect for the transition to hazardous use and for alcohol abuse and dependence; the effect of parental concordance for transition into hazardous use was particularly striking. Maternal history was associated with a higher probability of progression from occasional to regular use, whereas paternal history was associated with progression from regular to hazardous use. Parental alcoholism increased the risk for first onset of hazardous use and alcohol dependence between the ages of 14-17, and for an earlier onset of the alcohol outcomes in offspring. The impact of parental alcohol use disorders was comparable for male and female offspring. Parental alcoholism predicts escalation of alcohol use, development of alcohol use disorders and onset of alcohol outcomes in offspring.

DETERMINANTS OF PROGRESSION IN SANDBLASTERS' SILICOSIS

Abstract Chest roentgenograms and pulmonary function studies were completed on 83 silicotic sandblasters; 61 returned for longitudinal study, with follow-up ranging from 1 to 7 yr. Estimates of respirable free silica concentrations were based on extensive measurements of airborne dust and protective equipment used. Sixty-three percent exhibited X-ray evidence of disease progression between initial and latest films. Probability of progression increased as duration and level of past silica dust exposure increased and was higher among blacks than whites. Those with large opacities and/or certain symbols (ILO U/C classification) on initial X-ray had a higher probability of progression than those with only small opacities. Declines in pulmonary function were associated with average concentration of silica dust exposure. Those in the lowest category (≤ 1.25 mg m-3) experienced normal mean annual rates of decline (29 ml for FEV1 although 50% (5/10) had exhibited X-ray progression over the same period. Mean annual decline in FEV for the middle and upper (> 3.0 mg m-3) concentration categories were 87 and 166 ml, respectively; 59 and 100% of these categories, respectively, exhibited X-ray progression. Antibody prevalences and immunoglobulin levels were high but unrelated to disease state, X-ray progression or pulmonary function decline.