High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.

Treatment with (90)Y- and (177)Lu-DOTATOC in patients with metastatic neuroendocrine tumors

BACKGROUND: Treatment with (90)Y- or (177)Lu-DOTATOC has recently been introduced in the palliative treatment of somatostatin receptor-expressing neuroendocrine tumors (NETs). The aim of the study was to present clinical experience with (90)Y- and (177)Lu-DOTATOC therapy in the management of NET. METHODS: To prove suitability for treatment each patient underwent scanning with (111)In-DTPAOC or (68)Ga-DOTATOC positron emission tomography/computed tomography. All patients received [(90)Y-DOTATOC] as initial treatment. In case of disease relapse the treatment was repeated. To avoid side effects of repeated [(90)Y] applications, a switch to [(177)Lu-DOTATOC] was carried out. Clinical, biochemical, and radioimaging responses were documented. RESULTS: Twenty patients with metastatic nonresectable NETs (15 pancreas NETs, 2 midgut NETs, 1 gastrinoma, 1 paraganglioma, 1 NET of unknown primary origin) were included. In 8 patients the treatment was repeated more than once (mean, 3 times; range, 2-5 times). After [(90)Y] treatment moderate toxicity was observed in 8 patients. No serious adverse events were documentable. After restaging, a partial remission was found in 5 patients, stable disease in 11 patients, and tumor progression in 4 patients. CONCLUSIONS: Peptide receptor-targeted radionuclide therapy is a promising, safe, and feasible approach in the palliative therapy of patients with NET.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

The role of circumferential fiberotomy in enhancing orthodontic stability

Objectives: Circumferential septal fiberotomy (CSF) following orthodontic treatment has been propagated to improve stability and prevent relapse of tooth alignment. The hypothesis of no difference between performed CSF and controls was tested. Methods: In 9 consecutively admitted patients at the end of orthodontic tooth alignment, the lower arch-wire was removed. CSF was performed from the mandibular canine to the central incisor on a randomly chosen side, while the contra-lateral side served as unsurgerized control. At baseline and every 4 weeks up to 6 months, study casts were taken and 1) analyzed using the Irregularity Index (II)according to Little and 2)photographed, traced and superimposed digitally. The translational and rotational movements of teeth as well as gingival parameters were analyzed as well. Results: By using the II and by superimposing the tracings, no statistically significant differences were found between the test (CSF) and control sides for any parameters. Moreover, CSF did not impinge on the gingival tissues. Conclusion: Since CSF did not improve stability of orthodontically aligned teeth nor prevent relapse during the healing pahse of up to 6 months, CSF should not be recommended following orthodontic therapy.

Predicting asthma control and exacerbations: chronic asthma as a complex dynamic model

PURPOSE OF REVIEW: Predicting asthma episodes is notoriously difficult but has potentially significant consequences for the individual, as well as for healthcare services. The purpose of this review is to describe recent insights into the prediction of acute asthma episodes in relation to classical clinical, functional or inflammatory variables, as well as present a new concept for evaluating asthma as a dynamically regulated homeokinetic system. RECENT FINDINGS: Risk prediction for asthma episodes or relapse has been attempted using clinical scoring systems, considerations of environmental factors and lung function, as well as inflammatory and immunological markers in induced sputum or exhaled air, and these are summarized here. We have recently proposed that newer mathematical methods derived from statistical physics may be used to understand the complexity of asthma as a homeokinetic, dynamic system consisting of a network comprising multiple components, and also to assess the risk for future asthma episodes based on fluctuation analysis of long time series of lung function. SUMMARY: Apart from the classical analysis of risk factor and functional parameters, this new approach may be used to assess asthma control and treatment effects in the individual as well as in future research trials.

Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results

All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 x 10(9)/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 x 10(9)/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 x 10(9)/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials

BACKGROUND: We evaluated the ability of CA15-3 and alkaline phosphatase (ALP) to predict breast cancer recurrence. PATIENTS AND METHODS: Data from seven International Breast Cancer Study Group trials were combined. The primary end point was relapse-free survival (RFS) (time from randomization to first breast cancer recurrence), and analyses included 3953 patients with one or more CA15-3 and ALP measurement during their RFS period. CA15-3 was considered abnormal if >30 U/ml or >50% higher than the first value recorded; ALP was recorded as normal, abnormal, or equivocal. Cox proportional hazards models with a time-varying indicator for abnormal CA15-3 and/or ALP were utilized. RESULTS: Overall, 784 patients (20%) had a recurrence, before which 274 (35%) had one or more abnormal CA15-3 and 35 (4%) had one or more abnormal ALP. Risk of recurrence increased by 30% for patients with abnormal CA15-3 [hazard ratio (HR) = 1.30; P = 0.0005], and by 4% for those with abnormal ALP (HR = 1.04; P = 0.82). Recurrence risk was greatest for patients with either (HR = 2.40; P < 0.0001) and with both (HR = 4.69; P < 0.0001) biomarkers abnormal. ALP better predicted liver recurrence. CONCLUSIONS: CA15-3 was better able to predict breast cancer recurrence than ALP, but use of both biomarkers together provided a better early indicator of recurrence. Whether routine use of these biomarkers improves overall survival remains an open question.

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.

Soft tissue profile changes following mandibular advancement and setback surgery an average of 12 years postoperatively

PURPOSE: The aim of this study was to assess long-term changes in position of soft tissue landmarks following mandibular advancement and setback surgery. MATERIALS AND METHODS: Twenty-seven patients (14 women, 13 men; mean age, 36 years) who had undergone either mandibular advancement (15 patients) or setback surgery (12 patients), were available for a long-term follow-up an average of 12 years postoperatively. In all of these cases, lateral cephalometric radiographs taken immediately before operation, at 1 week, 14 months, and 12 years postoperatively, were studied. RESULTS: During the 14 months postoperatively, soft tissue chin and mentolabial fold followed its underlying hard tissue in all patients. A continuous skeletal relapse was observable 12 years after mandibular advancement, but soft tissue chin moved more in an anterior direction. After mandibular setback, soft and hard tissue landmarks remained almost unchanged. Over the entire observation period, a thickening of soft tissue at pogonion was generally seen, and particularly a thickening of the whole chin in the setback group. All patients showed a significant lengthening and thinning of the upper lip. In all except 2 males, the patient's body weight increased markedly. CONCLUSION: In contrast to the immediate postoperative stage, soft tissue changes observed an average of 12 years after the primary operation do not directly follow the movements of the underlying skeletal structure. The soft tissue profile changes observed over such a long term seem to be influenced not only by the underlying skeletal structure but also by other factors such as weight gain and aging process.

Stability of soft tissue profile after mandibular setback in sagittal split osteotomies: a longitudinal and long-term follow-up study

PURPOSE: The aim of the study was to conduct a long-term prospective follow-up on the stability of soft tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal fixation to set back the mandible. PATIENTS AND METHODS: Seventeen consecutive patients (6 females, 11 males) were re-examined 12.7 years (T5) after surgery. The precedent follow-ups included: before surgery (T1), 5 days (T2) after surgery, 6.6 months (T3) after surgery, and 14.4 months after (T4) surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner program (Dentofacial Software, Toronto, Canada). The x-axis for the system of coordinates ran through Sella (point 0) and the line NSL -7 degrees. RESULTS: The net effect of the soft tissue chin (soft tissue pogonion) was 79% of the setback at pogonion. At the lower lip (labrale inferior) it was 100% of the setback at lower incisor position. Point B' followed point B to 99%. Labrale inferior and menton' also showed a significant backward, as well as a downward, movement (T5 to T2). Gender correlated significantly (P = .004) with the anterior displacement of point B' and pogonion' (P = .012). The soft tissue relapse 12.7 years after BSSO setback surgery at point B' was 3% and 13% at pogonion'. CONCLUSION: Among the reasons for 3-dimensional long-term soft tissue changes of shape, the surgical technique, the normal process of human aging, the initial growth direction, and remodeling processes must be considered. Growth direction positively influenced the long-term outcome of setback surgery in female compared with male patients because further posterior movement of the mandibular soft tissue occurred.

Stability of the hard and soft tissue profile after mandibular advancement in sagittal split osteotomies: a longitudinal and long-term follow-up study

The aim of the study was to conduct a long-term follow-up investigation of the stability of hard and soft tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal (RIF) fixation to advance the mandible. Sixteen consecutive patients (12 females and 4 males, mean age 21.4 years) were available for re-examination 12.7 years (T5) after surgery. The preceding follow-ups were before (T1), and 5 days (T2), 7.3 months (T3), and 13.9 months (T4) after surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner program. The x-axis for the system of co-ordinates ran through sella (point zero) and the line NSL -7 degrees. Thus, the program determined the x- and y-values of each variable and the usual angles and distances. Statistical analysis was carried out using Wilcoxon's matched-pair signed-ranks test with Bonferroni adjustments. The relationships between the examined variables were analysed by Spearman rank correlation coefficients. The backward relapse at point B (T5) was 2.42 mm, or 50 per cent, and at pogonion 3.21 mm, or 60 per cent of the initial advancement. The mean net effect at T5 on the labial fold (soft tissue point B) was 94 per cent of the advancement at point B. For the soft tissue chin (soft tissue pogonion), it was 119 per cent of the advancement at pogonion. The net effect on the lower lip (labrale inferior) was 55 per cent of the advancement at incision inferior. The amount of the surgical advancement of the mandible was correlated with the long-term relapse in point B. Among possible reasons for this relapse are the initial soft tissue profile, the initial growth direction, and the remodelling processes of the hard tissue.

Stability of hard tissue profile after mandibular setback in sagittal split osteotomies: a longitudinal and long-term follow-up study

The aim of the study was to conduct a long-term follow-up on the stability of the hard tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal fixation (RIF)to set back the mandible and to compare it with that of mandibular advancement performed by the same team of surgeons and with the same examination protocol. Seventeen consecutive patients (6 females and 11 males) could be re-examined 12.7 years (T5) after surgery. The previous examinations were before surgery (T1), 5 days (T2), and 6.6 (T3) and 14.4 (T4) months after surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner software program. The x-axis for the system of co-ordinates ran through sella (point zero) and the line nasion-sella-line minus 7 degrees. The program determined the x- and y-values of each variable and the usual angles and distances. The effects of treatment were determined with Wilcoxon matched pairs, signed ranks test, with Bonferroni adjustment, and the relationship between variables with Spearman rank correlation coefficient. Relapse at point B was 0.94 mm or 15 per cent and at pogonion 1.46 mm or 21 per cent of the initial setback at T5. Relapse was mainly short-term (T4-T2), 13 per cent for point B and 17 per cent for pogonion. Gender correlated significantly with relapse (T5-T2) at point B (P = 0.002) and pogonion (P = 0.021), i.e. females in contrast to males showed further distalization of the mandible instead of relapse. No correlations were seen for age or the amount of surgical setback. The long-term results in mandibular setback patients were more stable when compared with the mandibular advancement patients examined previously. The initial soft tissue profile, the initial growth direction, and the remodelling processes of the hard tissues must be considered as reasons for long-term relapse. Growth direction positively influenced the long-term results in females: further distalization of the mandible occurred.

Stability after bilateral sagittal split osteotomy setback surgery with rigid internal fixation: a systematic review

PURPOSE: The purpose of this systematic review was to evaluate relapse and its causes in bilateral sagittal split setback osteotomy with rigid internal fixation. MATERIALS AND METHODS: Literature research was done in databases such as PubMed, Ovid, the Cochrane Library, and Google Scholar Beta. From the original 488 articles identified, 14 articles were finally included. Only 5 studies were prospective and 9 retrospective. The range of postoperative study records was from 6 weeks to 12.7 years. RESULTS: The horizontal short-term relapse was between 9.9% and 62.1% at point B and between 15.7% and 91.3% at pogonion. Long-term relapse was between 14.9% and 28.0% at point B and between 11.5% and 25.4% at pogonion. CONCLUSIONS: Neither large increase nor decrease of relapse was seen when short-term values were compared with long-term. Bilateral sagittal split osteotomy for mandibular setback in combination with orthodontics is an effective treatment of skeletal Class III and a stable procedure in the short- and long-term. The etiology of relapse is multifactorial: the proper seating of the condyles, the amount of setback, the soft tissue and muscles, remaining growth and remodeling, and gender were identified. Age did not show any correlations. To obtain reliable scientific evidence, further short- and long-term research of bilateral sagittal split osteotomy setback with rigid internal fixation should exclude additional surgery, ie, genioplasty or maxillary surgery, and include correlation statistics.

Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison

Although diarrhoea-associated haemolytic uremic syndrome (HUS) in children is well described, the clinical features of bloody diarrhoea-associated thrombotic thrombocytopenic purpura (TTP)-HUS in adults are not documented. Twenty-one adults, 6.5% of the 322 adults in The Oklahoma TTP-HUS Registry, 1989-2006, have presented with bloody diarrhoea. There were no case clusters. Escherichia coli O157:H7 was identified in five patients, but many patients did not have appropriate studies. The annual incidence was 0.68/10(6), 10-fold less than the incidence of diarrhoea-associated HUS in children in Oklahoma. Two (13%) of 16 patients in whom ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) was measured had <10% activity. Severe neurological abnormalities (67%) and renal failure (62%) were common; seven patients (33%) died; no survivors have relapsed. Compared to the 38 other Oklahoma Registry patients with ADAMTS13 <10%, frequency of severe neurological abnormalities and death was not different; frequency of renal failure was greater; frequency of relapse was less. Compared to 5999 children with sporadic diarrhoea-associated HUS in published reports, frequency of renal failure and relapse was not different; frequency of severe neurological abnormalities and death was greater (P < 0.05 for all differences). Awareness of the continuous occurrence of sporadic bloody diarrhoea-associated TTP-HUS in adults is important for prompt diagnosis and appropriate management.

Current management of thrombotic thrombocytopenic purpura

PURPOSE OF REVIEW: New treatment modalities have become increasingly popular for the treatment of acute thrombotic thrombocytopenic purpura. Widespread availability of ADAMTS13 assays resulted in the increased recognition of patients with hereditary thrombotic thrombocytopenic purpura and specific issues related to acquired ADAMTS13 deficiency. These new aspects with implications on management of thrombotic thrombocytopenic purpura patients are reviewed here. RECENT FINDINGS: Today, plasma exchange with the replacement of fresh frozen plasma is still the treatment of choice in acute thrombotic thrombocytopenic purpura. The finding of circulating anti-ADAMTS13 autoantibodies in the majority of patients constitutes the rationale for the concomitant administration of immunosuppressive drugs. Rituximab seems to have a favorable benefit-risk ratio in plasma-refractory and relapsing thrombotic thrombocytopenic purpura; however, long-term follow-up data are not yet available. Constitutively lacking ADAMTS13 in hereditary thrombotic thrombocytopenic purpura can be supplemented by simple plasma infusions. Severe acquired ADAMTS13 deficiency either at presentation or in remission identifies patients at a particularly high risk of relapse. SUMMARY: Despite progress in understanding the pathophysiology of thrombotic thrombocytopenic purpura, acute bouts as well as relapses still represent serious health threats to patients and rapid initiation of plasma exchange is mandatory. Large randomized clinical trials, however, need to determine whether new treatment modalities are superior to standard plasma exchange.