Significant Risk Factor For Progression Research Articles

Clinical Course and Prognosis of Smoldering (Asymptomatic) Waldenstrom's Macroglobulinemia

Smoldering Waldenström's Macroglobulinemia (SWM) is defined as a serum IgM monoclonal protein ≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration but no evidence of constitutional symptoms, symptomatic anemia, or hyperviscosity. Forty-eight patients with SWM were identified at Mayo Clinic from 1974 to 1995. Patients with a diagnosis of chronic lymphocytic leukemia or lymphoma or history of any antineoplastic therapy before diagnosis of SWM were excluded. The median age at diagnosis was 63 years (range 39–87 years). Only one patient (2%) was < 40 years of age, but 14 percent were < 50 years old. Thirty-two (67%) were men, and 16 (33%) were women. At diagnosis, hepatomegaly was noted in 10%, splenomegaly in 4%, and lymphadenopathy in 8%. The initial hemoglobin level ranged from 8.7 to 15.3 g/dL (median 11.8). The anemia in all 4 patients with an initial hemoglobin < 10 g/dL was due to other causes such as myelodysplastic syndrome, bronchopleural fistula, Barrett's esophagus, and Coumadin administration. The initial leukocyte level ranged from 3.2 to 13.2 × 109/L (median 5.7), and platelets ranged from 101 to 578 × 109/L (median 285.5). Only one patient had a serum creatinine > 2.0 mg/dL and it was unrelated to SWM. The serum monoclonal protein level at the time of diagnosis ranged from 1.5 to 5.2 g/dL (median 3.3); 12 (25%) were < 3 g/dL, while 10 (21%) were ≥4 g/dL. IgM kappa accounted for 75%, IgM lambda 21%, and 2 (4%) were biclonal. Immunofixation of the urine was positive in 97% (kappa 80%, lambda 17%, indeterminate 3%) of those tested. The size of the urine M protein ranged from unmeasurable to 1.4 g/24h (median 0.04 g/24h). Serum albumin ranged from 2.5 to 4.3 g/dL (median 3.6). Five patients (10%) had an albumin value < 3 g/dL. Ten (26%) had a reduction of 1 uninvolved immunoglobulin, while 8 (21%) had a reduction of both IgG and IgA immunoglobulins. Lymphoplasmacytic infiltration of the bone marrow ranged from 3% to 80%, (median 30%). Three (6%) had less than 10% infiltration, while 13 (27%) had 50% or greater infiltration. The 48 patients were followed for a total of 292 (range 0.5 to 22.6 years; median 3.7) person-years, during which time 33 progressed to symptomatic WM and one to AL amyloidosis. The expected number of WM based on the SEER data was 0.004 cases. Thus, relative risk of progression to WM was increased 7,586-fold (95% CI, 5,083 to 10,373). The median time to progression was 4.6 years. The absolute risk of progression to WM was 6% at 1 year, 39% at 3 years, and 55% at 5 years. The median survival after progression to symptomatic WM was 5.1 years. Seventy-three percent of patients died, indicating a robust follow-up. We evaluated sex, hemoglobin level, size of serum M protein, reduction of uninvolved immunoglobulins, presence of urinary monoclonal light chains, serum albumin level, and the proportion of lymphoplasmacytic infiltration of the bone marrow as risk factors for progression. Significant risk factors for progression with univariate analysis included size of the serum M protein, hemoglobin level, reduction in uninvolved immunoglobulins, and degree of bone marrow lymphoplasmacytic cell infiltration. Multivariate modeling revealed that the size of the M protein and the degree of bone marrow infiltration were the most important risk factors. We conclude that smoldering WM is a distinct clinical entity that needs to be differentiated from IgM MGUS and symptomatic Waldenstrom's Macroglobulinemia.

Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma: Clinical and Molecular Characterization of a Subset with Worse Outcome.

Background and Objectives: Primary cutaneous anaplastic large cell lymphoma (pcALCL) has an overall favorable prognosis. However, we have previously suggested that patients with extensive limb involvement may have a worse outcome (J Am Acad Dermatol 49:1049, 2003). The primary objective was to assess the potential prognostic factors in pcALCL, in particular the role of extensive regional single-limb disease (ERSL-D), defined as presentation with or progression to T2b or T2c involvement of a single limb, or T3b involvement of > 3 contiguous body regions. Our secondary objectives were to study the gene expression profiles and treatment responses of our patients with pcALCL that may correlate with clinical outcome.Patients and Methods: This was a retrospective study involving 48 patients with pcALCL diagnosed and managed at Stanford from 1990–2005. The potential prognostic factors for overall and disease-specific survivals (OS and DSS) were analyzed using the KM method and univariate and multivariate Cox regression. Cox regression was also used to identify risk factors for progresson to extracutaneous disease. Gene expression profiles were studied using cDNA microarrays.Results: The OS and DSS rates of the entire cohort were 76% and 85% at 5 yrs and 70% and 85% at 10 yrs, respectively. Our univariate analysis demonstrated age, ERSL-D, and progression to extracutaneous disease (as a time-dependent variable) as significant prognostic factors for OS, while ERSL-D and progression to extracutaneous disease were significant for DSS. Sex, presence of spontaneous regression, and lesion site were not significantly assoicated with OS or DSS. Patients with T1 (solitary skin lesion) disease had an overall more favorable OS and DSS compared to those with T2 (regional skin involvement) and T3 (generalized skin involvement) disease, although the differences were not statisticlly significant. In our multivariate analysis, age (HR 1.83, 95% CI 1.02–3.26) and progression to extracutaneous disease (HR 6.42, 95% CI 1.39–29.68) remained significant for OS, while ERSL-D (HR 29.31, 95% CI 1.72–500.82) and progression to extracutaneous disease (HR 13.12, 95% CI 1.03–167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a significant risk factor for progression to extracutaneous disease (HR 10.20, 95% CI 1.84–56.72). Microarray studies of 14 samples from 3 ERSL-D and 7 classic pcALCL patients were performed. The patients with ERSL-D and classic pcALCL formed distinct, separate clusters. Classic pcALCL showed concurrent upregulation of epidermal genes analogous to normal skin, while ERSL-D lacked this signature. Genes upregulated in ERSL-D (after subtraction of epidermal genes) included STAT5A, IL2Rα, HIPK2, WDR10 and those down-regulated included RXRA. These gene profiling data suggest that targeting IL2R (denileukin diftitox) or STAT5 (HDAC inhibitors) may be appropriate in ERSL-D while therapeutic resistance to bexarotene may be linked to lack of RXRA gene expression.Conclusion: Our data suggest that patients with ERSL-D have a worse clinical outcome associated with a distinct gene expression profile. More aggressive and targeted treatments may be indicated in this subgroup.

Prognostic Factors and Optimal Treatment Strategy for Intrahepatic Nodular Recurrence After Curative Resection of Hepatocellular Carcinoma

Intrahepatic recurrence is a major problem after curative resection of hepatocellular carcinoma. However, the most effective treatments for patients with intrahepatic recurrence still remain unclear. In addition, the selection of various treatment modalities such as repeat resection, local ablation therapy, and transarterial chemoembolization is only applicable to patients with intrahepatic nodular recurrence. Of 353 patients who underwent curative resection, 97 patients with intrahepatic nodular recurrence were retrospectively studied. The prognostic factors for survival after recurrence and treatment modalities were analyzed. The patients were divided into two groups, a control group and a progression group, according to their response to initial treatment for recurrent tumors. The 1-, 3-, and 5-year overall survival rates after recurrence in patients with intrahepatic nodular recurrence were 91.0%, 71.0%, and 37.5%, respectively. Multivariate analysis revealed that early recurrence (< or =12 months), Child-Pugh class B or C at diagnosis of recurrence, and serum albumin level of < or =3.5 g/dL at diagnosis of recurrence were poor prognostic factors for survival after recurrence. With regard to the response to the initial treatment, time to recurrence of < or =12 months was found to be the only statistically significant risk factor for progression of disease in multivariate analysis. Time to recurrence, which usually corresponds with the cellular origin of recurrence, seems to be more important when determining the prognosis of patients with recurrent disease and treatment response than treatment modality. Therefore, different treatment methods should be selected according to the time to recurrence of intrahepatic nodular recurrence.

Long-term Intraocular Pressure Fluctuations and Risk of Conversion from Ocular Hypertension to Glaucoma

To investigate whether long-term intraocular pressure (IOP) fluctuations are a risk factor for conversion from ocular hypertension to glaucoma. Observational cohort study. The study included 252 eyes of 126 patients with ocular hypertension observed untreated as part of the Diagnostic Innovations in Glaucoma Study. At baseline, ocular hypertensive eyes had elevated IOP, normal visual fields (VFs) on standard automated perimetry, and normal optic discs as evaluated by stereophotograph assessment. Glaucoma conversion was defined as development of reproducible VF loss or optic disc damage. Analyses included all IOP measurements from the baseline visit to time of progression (for converters) and last follow-up (for nonconverters). Mean IOP and IOP fluctuation were calculated as the arithmetic mean and standard deviation (SD), respectively, of all available IOP measurements per eye. Univariable and multivariable Cox regression analyses were used to evaluate the association between IOP fluctuation and time to progression. Multivariable models adjusted for age, mean IOP, central corneal thickness, vertical cup-to-disc ratio, and pattern SD. Forty eyes of 31 subjects developed glaucoma during follow-up. Mean IOPs during follow-up were 25.4+/-4.2 mmHg for the eyes that converted to glaucoma and 24.1+/-3.5 mmHg for the eyes that did not. Corresponding values for IOP fluctuation were 3.16+/-1.35 mmHg and 2.77+/-1.11 mmHg, respectively. Intraocular pressure fluctuation was not a risk factor for conversion to glaucoma both in univariable analysis (hazard ratio [HR], 1.30 per 1 mmHg higher; 95% confidence interval [CI], 0.76-1.96; P = 0.092) and in multivariable analysis (adjusted HR, 1.08 per 1 mmHg higher; 95% CI, 0.79-1.48; P = 0.620). Mean IOP during follow-up was a significant risk factor for progression both in univariable analysis (HR = 1.16 per 1 mmHg higher; 95% CI, 1.04-1.31; P = 0.010) and in multivariable analysis (adjusted HR, 1.20 per 1 mmHg higher; 95% CI, 1.06-1.36; P = 0.005). Long-term IOP fluctuations do not appear to be significantly associated with the risk of developing glaucoma in untreated ocular hypertensive subjects.

Large intraocular pressure fluctuations: a risk factor for glaucoma progression

Abstract Purpose: We are aware of the detrimental effects of peaks of intraocular pressure (IOP) above the normal range. However, we have observed that many of our patients continue to experience glaucomatous progression despite their mean IOP being below what the physician considers an adequate target IOP for that individual. We studied the risk associated with diurnal IOP variations in open angle glaucoma. Methods: The patients who were enrolled in the study used the Zeimer self‐tonometer to measure IOP over a period of 5 days. The readings were taken upon waking, noon, mid‐afternoon, dinnertime and bedtime. Visual fields over the 10‐year duration of the study were reviewed for progression. We performed statistical analyses on these readings to study the relative risk of disease progression. Results: Baseline office IOP had no predictive value (relative hazard: 0.98). The IOP range over multiple days was a significant risk factor for progression even after adjusting for office IOP, age, race and visual field damage at baseline (relative hazard ratio 5.76). 88% of patients in the upper 25 percentile of IOP fluctuation, and 57% of patients in the lower 25th percentile of IOP fluctuation, progressed within 8 years Conclusions: In this presentation, corroborating studies, common IOP fluctuations and proposed mechanisms for IOP fluctuations will be presented. Ways to control IOP spikes will be discussed and pharmacotherapy options will be explored.Diurnal fluctuations in IOP present a greater risk of visual‐field loss to the patient with glaucoma compared to mean IOP. By monitoring IOP more closely and by prescribing medication that offers the best control of IOP with the least amount of fluctuation, ophthalmologists can offer their patients the best therapy for glaucoma.

Analysis of incidence and risk factors for progression in patients with intracranial steno-occlusive lesions by serial magnetic resonance angiography

Objectives Conventional angiography and transcranial Doppler ultrasonography have usually been used for serial observation of cerebral atherosclerotic diseases. This study used magnetic resonance (MR) angiography to monitor serial changes in steno-occlusive lesions of the major intracranial arteries to elucidate the incidence of progression and investigate the risk factors for progression. Patients and Methods The 151 consecutive patients, 78 males and 73 females aged 42–92 years (mean 71.1 ± 10.2 years), were followed up by serial MR angiography for 5–34 months (mean 14.4 ± 5.78 months). Progression was defined as increased stenosis or occlusion, or new stenotic lesion. Age, sex, duration of MR angiography follow up, hypertension, diabetes mellitus, hyperlipidemia, hyperuricemia, current smoking, and atrial fibrillation were chosen as risk factors for multiple logistic analysis. Results Twenty-three of the patients (15.2%) had progression, caused by total occlusion in 10, increased stenosis in 10, and new stenosis in 3, 15 patients had regression, and 113 patients had no change. Diabetes (odds ratio: 6.771, p value: 0.0004) and current smoking (odds ratio: 7.574, p value: 0.0019) were determined as significant risk factors for progression. Conclusions Patients with intracranial steno-occlusive lesion and either diabetes or smoking habit should be carefully followed up by serial MR angiography.

Role of Central Corneal Thickness on Baseline Parameters and Progression of Visual Fields in Open Angle Glaucoma

To evaluate the relationship of central corneal thickness (CCT) to baseline visual field parameters and visual field progression in patients with primary open-angle glaucoma (POAG). Charts of consecutive patients with POAG were reviewed to obtain visual field data. Visual field was measured by standard threshold static perimetry. Variables analyzed included mean deviation (MD) and pattern standard deviation (PSD). A total of 121 eyes examined over 4 years were evaluated. A significant negative relationship between CCT and PSD (correlation coefficient: -0.02, p<0.05) was found. Analyses comparing CCT to change in PSD and MD (visual field progression) were statistically not significant. Patients with thinner corneas initially present with a greater visual field defect, indicating that thin corneas may contribute to advanced glaucomatous damage at the time of diagnosis. However, CCT does not seem to be a significant risk factor for progression of the disease.

Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma

Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear. We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease. During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups. The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.

Fluctuation of Intraocular Pressure and Glaucoma Progression in the Early Manifest Glaucoma Trial

To investigate whether increased fluctuation of intraocular pressure (IOP) is an independent factor for glaucoma progression. A cohort of patients was followed up in a randomized clinical trial. Two hundred fifty-five glaucoma patients from the Early Manifest Glaucoma Trial (EMGT; 129 treated and 126 control patients). Study visits, conducted every 3 months, included ophthalmologic examinations, IOP measurements, and standard automated perimetry, with fundus photography every 6 months. Intraocular pressure values were included only until the time of progression in those eyes that showed such progression. Individual mean follow-up IOP and IOP fluctuation, calculated as the standard deviation of IOP at applicable visits, were the variables of main interest. Cox regression with time-dependent variables was used to evaluate the association between IOP fluctuation and time to progression, both with and without IOP mean in the models. These analyses also controlled for other significant variables. Glaucoma progression, as defined by a predetermined visual field criterion, worsening of the disk, assessed by an independent disc reading center, or both. Median follow-up time was 8 years (range, 0.1-11.1 years). Sixty-eight percent of the patients progressed. When considering mean follow-up IOP and IOP fluctuation in the same time-dependent model, mean IOP was a significant risk factor for progression. The hazard ratio (HR) was 1.11 (95% confidence interval [CI], 1.06-1.17; P<0.0001). Intraocular pressure fluctuation was not related to progression, with an HR of 1.00 (95% CI, 0.81-1.24; P = 0.999). These results confirm our earlier finding that elevated IOP is a strong factor for glaucoma progression, with the HR increasing by 11% for every 1 mmHg of higher IOP. Intraocular pressure fluctuation was not an independent factor in our analyses, a finding that conflicts with some earlier reports. One explanation for the discrepancy is that our analyses did not include postprogression IOP values, which would be biased toward larger fluctuations because of more intensive treatment. In contrast, in this EMGT report, no changes in patient management occurred during the period analyzed.

Six-Year Progression of Retinopathy and Associated Risk Factors in African American Patients With Type 1 Diabetes Mellitus

To report the 6-year progression of diabetic retinopathy (DR) and associated risk factors among African American patients with type 1 (insulin-dependent) diabetes mellitus. Participants from the New Jersey 725 included 483 African American patients with type 1 diabetes who underwent reexamination as part of a 6-year follow-up. Evaluations included a structured clinical interview, ocular examination, 7 stereoscopic fundus photographs, and blood pressure measurements. Severity of DR was determined via masked grading of fundus photographs. Biological evaluation included blood and urine assays. During the 6-year period, 56.1% of patients at risk showed progression of DR; 15.0% showed progression to proliferative DR; and 15.9% developed macular edema. A baseline high glycosylated hemoglobin level and systemic hypertension were significant risk factors for progression of DR, progression to proliferative DR, and incidence of macular edema. Progression to proliferative DR was significantly associated with baseline older age, renal disease, and severity of DR. The incidence of macular edema was significantly associated with baseline older age, low socioeconomic status, severity of DR, and total serum cholesterol level. Six-year progression of DR is high in African American patients with type 1 diabetes. Improving glycemic and blood pressure control may reduce the ocular morbidity of diabetes in African Americans.

A study on comparative efficacy of anti tubercular chemoprophylaxis with 2 different regimens: 2 months of rifampicin and pyrazinamide and 6 months of daily isoniazid and rifampicin in HIV infected tuberculin reactors

Human immune-virus (HIV) infection is the most significant risk factor for progression of latent mycobacterium tuberculosis (MTB) infection to active tuberculosis. Tuberculosis reactivation among human immunodeficiency virus (HIV) infected cases can be prevented by anti tubercular chemoprophylaxis. This randomized controlled study compared the efficacy of 2 months of daily rifampicin and pyrazinamide and 6 months of daily rifampicin and isoniazid drug regimes in preventing active tuberculosis in HIV seropositives. It is observed that 2 months of daily rifampicin in combination with pyrazinamide is not only efficacious as that of 6 months of daily rifampicin and isoniazid combination in preventing active tuberculosis in HIV seropositives but has the advantage of better compliance, lesser side effects and prolonged post prophylactic preventive effect.

Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine and Melphalan (FM) Reduced Intensity Conditioning (RIC) for High-Risk AML/MDS.

RIC with FM has extended the use of HSCT to patients otherwise not eligible for this treatment. Longer follow-up and larger number of patients now allow for more robust evaluation of risk factors and outcomes. Herein are the results of such an evaluation.Patients and Methods: We evaluated outcomes of 112 patients with high-risk AML/MDS treated from August 1996 to December 2003 with FM (fludarabine 100–180 mg/m2 and melphalan 100–180 mg/m2) and unmanipulated HSCT. Eligibility included age >54 yrs. or comorbidity precluding an ablative preparative regimen. Disease status at HSCT was relapsed/refractory (n=43, 38.4%), primary induction failure (n=32, 28.6%), untreated (n=7, 6.3%) or complete remission (CR, n=30, 26.8). Cytogenetic risk was intermediate (n=59, 53%), high (n=47, 42%), low (n=3, 2.5%) or unknown (n=3, 2.5%). Donors were HLA matched related (MRD; n=59) or unrelated (UD; n=53). GVHD prophylaxis was tacrolimus based in all but one patient. Anti-thymocyte-globulin was added in 31 UD HSCT. Stem cell sources were bone marrow (n=56) or peripheral blood (n=57). Median age was 55 (range 22–74). Evaluated were the following variables and their influence on disease progression and overall survival: - age, donor type, duration of first CR, disease status at transplant (categorized as CR, No CR with (NoCR/CB) and without circulating blasts (NoCR/NoCB)), cytogenetics, acute and chronic GVHD (time dependent variables), and blood counts on day 30 (lymphocytes, monocytes and platelets). We used a Cox's regression analysis.Results: Median time of follow up among survivors (n=43) was 28.4 mo (3.3–88.9). CR rate at day 30 post transplant was 87% (n=97), 8 patients died early and 7 did not respond. 25 (26%) of 97 patients progressed after day 30. All but 3 patients relapsed within the first year post HSCT, and only one relapsed more than 2 years after HSCT. In a landmark analysis, disease status at transplant was the only significant risk factor for progression among these 97 patients (HR of 3.7 for the NoCR/CB group compared to the CR group). 69 of 112 patients died with a median survival of 4.6 mo. Seven deaths (10% of all deaths) were observed more than 2 yrs. after HSCT, due to GVHD (n=3), infection (n=2), relapse (n=1) and unknown causes (n=1). Two-year OS and PFS was 44% and 69% respectively. Disease status at HSCT and grade II-IV aGVHD were the only significant predictors of OS on univariate and multivariate analysis. Blood counts on day 30 were associated with disease status at transplant, donor type and aGVHD. Their independent effect on outcome could not be evaluated given sample size.Conclusion: A significant portion of older patients with high-risk AML/MDS may achieve long-term PFS, but early relapses are the major cause of treatment failure in this context.Prognostic factors for event-free and overall survivalVariablesMultivariate analysis for disease progressionDisease statusnEvents (n)HR95% CIp2-yr PFSCR3061.057% (39–72)NoCR/NoCB4171.10.4–3.20.946% (30–60)NoCR/CB26123.71.4–9.80.00122% (9–38)Multivariate analysis for overall survival (OS)Disease statusHR95% CIp2-yr OSCR30121.066% (48–80)NoCR/NoCB49291.80.9–3.50.0640% (26–53)NoCR/CB34282.81.4–3.50.00223% (11–37)gd II-IV aGVHD2.81.8–4.6<0.001CB=circulating blasts

The Natural History of Smoldering (Asymptomatic) Multiple Myeloma.

Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were > 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%.Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein < 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells < 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p < 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p < 0.001) and reduction of uninvolved immunoglobulins (p < 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.

The management of primary rhegmatogenous retinal detachment not involving the fovea

To establish the likelihood of, and risk factors associated with, progression of 'macula-on' retinal detachment. A multi-centre prospective observational study of patients with acute retinal detachment, not involving the fovea, was conducted over a 6-month period. Data collected included duration of symptoms, visual acuity, presence of posterior vitreous detachment, retinal drawings and subretinal fluid (SRF) distance from the fovea at a minimum of two time points. A total of 82 data sets from 15 institutions were analysed. Of 82 cases 11 (13%) demonstrated progression of fluid. Mean progression in those cases which progressed was 2.3 disc diameters (dd) and the average rate of progression was 1.80 dd/day. Binary regression analysis failed to reveal any statistically significant risk factors for progression. Multiple regression analyses were made to identify risk factors. With distance of SRF from fovea at operation as a function, distance of SRF at presentation was the only statistically significant risk factor. In all, 26% of patients underwent surgery out-of-hours. A total of 83% patients achieved a 6-week best-corrected vision of 6/9 or better. Most retinal detachments in this study did not progress within the first few days. The distance of SRF from the fovea at presentation was the only statistically significant risk factor for progression to foveal detachment.

Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study

To examine the long-term influence of pregnancy on the development and progression of microvascular complications in Type 1 diabetes. In the EURODIAB Prospective Complications Study (PCS), 793 women potentially child bearing at baseline completed the follow-up (7.3 years) and 163 (21%) gave birth during the follow-up period. We compared risk factors [mean levels of age, duration of diabetes, HbA(1c), systolic blood pressure (SBP) and proportion giving birth] between those that did or did not develop microvascular complications during the follow-up period. For the 425 childless women at baseline, 102 gave birth during follow-up. HbA(1c) was a significant risk factor for progression to microalbuminuria but age, duration of diabetes, systolic blood pressure or giving birth were not. Duration of diabetes and high HbA(1c) were significant risk factors for progression to proliferative retinopathy, whereas giving birth was not. Similar results were obtained for progression to any form of retinopathy. Giving birth was not significantly related to the incidence of neuropathy. Similar results were obtained for women with children at baseline giving birth during follow-up (n = 61/368). In this European study, having a first or another pregnancy did not seem to be a risk factor for long-term progression of any microvascular complication. This is in accordance with the findings of the Diabetes Control and Complications Trial (DCCT).

Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy

Before highly active antiretroviral therapy (HAART) became available, cytomegalovirus was a major cause of opportunistic infection in HIV-infected patients and was associated with accelerated progression to AIDS and death. We have investigated whether cytomegalovirus viraemia remains a significant risk factor for progression of HIV disease and death in the era of HAART. 374 patients whose CD4-cell count had ever been below 100 per microL were enrolled in a prospective study. Serial blood samples were tested for cytomegalovirus by PCR. Rates of new cytomegalovirus disease, new AIDS-defining disorders, and death were calculated over a median follow-up of 37 months after stratification according to baseline and most recent cytomegalovirus PCR status at any point during follow-up. Of 2969 PCR assays, 375 (12.6%) were positive for cytomegalovirus DNA. 259 (69.3%) patients were persistently negative for cytomegalovirus by PCR; 15 were persistently positive; and 100 were intermittently positive and negative. In multivariate models, cytomegalovirus PCR-positive status as a time-updated covariate was significantly associated with increased relative rates of progression to a new AIDS-defining disorder (2.22 [95% CI 1.27-3.88] p=0.005) and death (4.14 [1.97-8.70] p=0.0002). Detection of cytomegalovirus in blood by PCR continues to identify patients with a poor prognosis, even in the era of HAART. Randomised controlled clinical trials of drugs active against cytomegalovirus are needed to investigate whether this virus is a marker or a determinant of HIV disease progression.

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

SummaryBackgroundWe investigated the temporal progression of the clinical, radiological, and virological changes in a community outbreak of severe acute respiratory syndrome (SARS).MethodsWe followed up 75 patients for 3 weeks managed with a standard treatment protocol of ribavirin and corticosteroids, and assessed the pattern of clinical disease, viral load, risk factors for poor clinical outcome, and the usefulness of virological diagnostic methods.FindingsFever and pneumonia initially improved but 64 (85%) patients developed recurrent fever after a mean of 8.9 (SD 3.1) days, 55 (73%) had watery diarrhoea after 7.5 (2.3) days, 60 (80%) had radiological worsening after 7.4 (2.2) days, and respiratory symptoms worsened in 34 (45%) after 8.6 (3.0) days. In 34 (45%) patients, improvement of initial pulmonary lesions was associated with appearance of new radiological lesions at other sites. Nine (12%) patients developed spontaneous pneumomediastinum and 15 (20%) developed acute respiratory distress syndrome (ARDS) in week 3. Quantitative reverse-transcriptase (RT) PCR of nasopharyngeal aspirates in 14 patients (four with ARDS) showed peak viral load at day 10, and at day 15 a load lower than at admission. Age and chronic hepatitis B virus infection treated with lamivudine were independent significant risk factors for progression to ARDS (p=0.001). SARS-associated coronavirus in faeces was seen on RT-PCR in 65 (97%) of 67 patients at day 14. The mean time to seroconversion was 20 days.InterpretationThe consistent clinical progression, shifting radiological infiltrates, and an inverted V viral-load profile suggest that worsening in week 2 is unrelated to uncontrolled viral replication but may be related to immunopathological damage.Published online May 9, 2003 http://image.thelancet.com/extras/03art4432web.pdf

Tuberculosis and HIV in the Eastern Mediterranean Region

Tuberculosis [TB] is an important public health problem in the Eastern Mediterranean Region of the World Health Organization. Every year the disease kills 136, 000 people and affects 630, 000 more. HIV is the most significant risk factor for progression from subclinical infection with Mycobacterium tuberculosis to active TB. Although the HIV/AIDS threat in the Region appears to be relatively modest and so far there has been no evidence of an impact of HIV on TB epidemiology in the Region, there is a need to jointly address HIV infection and TB more effectively. In this paper the TB situation in the Region and the measures being taken to combat it are outlined. The impact of HIV infection on TB and the repercussions this could have on theTB situation in the Region are also discussed. Actions that are needed to tackle this double burden are suggested.

The urologist view of BPH progression: results of an international survey.

To assess the opinion amongst the international urological community on whether benign prostatic hyperplasia (BPH) is a progressive disease. A 15-item questionnaire was distributed to the mailing list of the publication European Urology Today as well as being accessed through the website of the European Association of Urology (EAU). The survey included questions on: whether BPH was a progressive disorder; what evidence there was to support this, including clinical parameters that could be identified; risk factors for progression; and prevention of progression. A total of 472 completed questionnaires from 47 countries were evaluated. Overall, the urologists surveyed agreed that BPH was a progressive disease, and that some patients were more prone to this than others. Increased post-void residual urine, reduced flow rate, increased urinary symptoms and urodynamic evidence of obstruction were considered to be the most significant risk factors for progression. Half of the urologists surveyed considered that current medical therapies could prevent progression of BPH, while a significant proportion thought that surgery was an effective preventative measure. BPH, although a benign disease, has a considerable impact on the patient's quality of life. Its progressive nature and the identification of risk factors for progression warrant further investigation. In the future, there is likely to be a shift in the paradigm from treatment of BPH complications to include the prevention of BPH progression.

Determinants of retinopathy progression in type 1 diabetes mellitus

PURPOSE: To determine the risk factors for retinopathy progression in type 1 (insulin-dependent) diabetes mellitus in a prospective cohort study. SUBJECTS AND METHODS: Subjects were 485 participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18 to 56 years with type 1 diabetes mellitus (duration of 1 to 15 years) and no or only mild retinopathy. Retinopathy progression, assessed by seven-field stereoscopic fundus photography, was defined as worsening by two or more levels on a standardized grading scale at the end of follow-up (median, 41 months). RESULTS: The relative risks for retinopathy progression according to successively greater quintiles of total glycosylated hemoglobin level at baseline, after adjusting for age, diabetes duration, sorbinil assignment, and other variables, were 1.0, 2.0, 1.6, 3.7, and 4.4 ( P trend <0.0001). Risk increased with greater baseline diastolic blood pressure: 1.0 for <70 mm Hg, 1.2 for 70 to 79 mm Hg, and 1.8 for ≥80 mm Hg ( P for trend = 0.04). Diastolic blood pressure was a significant risk factor for progression in participants with mild baseline retinopathy ( P for trend <0.02) but not in those without retinopathy at entry. Systolic blood pressure, by comparison, was not associated with progression. Baseline total cholesterol level was a marginally significant predictor of retinopathy progression when examined as a categorical variable (relative risks for increasing quartiles; 1.0, 1.6, 1.8, 1.9; P for trend = 0.03) but not when it was examined as a continuous variable or when hypercholesterolemic patients were compared with those with normal levels. Furthermore, when cholesterol levels were updated in subsequent visits, it was not a significant predictor of progression, and low density lipoprotein (LDL) cholesterol levels did not predict progression no matter how analyzed. Smoking was not associated with progression of retinopathy. CONCLUSIONS: Levels of hyperglycemia and diastolic blood pressure predicted progression of retinopathy in type 1 diabetes mellitus. We found only a suggestion of an association between total cholesterol level (but not of LDL cholesterol level) and progression of retinopathy; resolution of this issue will require additional studies with larger sample sizes and longer follow-up.