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Background: Little is known about the extent of impairments in work and activities of daily life (ADL) in patients with psoriasis, and the influence of contextual factors such as disease-related characteristics and treatment. Therefore, this study aimed to assess these impairments in patients with psoriasis who started using biologicals/small molecule inhibitors.Methods: Using data from the prospective BioCAPTURE registry, we collected patient, disease, and treatment parameters, as well as work/ADL impairments at baseline, 6 and 12 months. Changes in impairment parameters and correlations between impairment and patient/disease characteristics were assessed using generalized estimating equations.Results: We included 194 patients in our analysis. After biological initiation, disease activity decreased significantly (PASI 11.2 at baseline versus 3.9 at 12 months, p < 0.001). Work-for-pay in this cohort was lower than in the Dutch general population (53% versus 67%, p = 0.01). In patients who had work-for-pay, presenteeism improved over time (5% at baseline versus 0% at 12 months, p = 0.04). Up to half of the patients reported impairments in ADL, which did not change over time. Associations between impairments and contextual factors varied, but all impairments were associated with worse mental/physical general functioning.Conclusion: Patients with psoriasis using biologicals are less likely to have work-for-pay. Treatment improves the work productivity of employed patients, but we were unable to detect changes in ADL performance.

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Real-world evidence, directly comparing the effectiveness of interleukin (IL)17-inhibitors, IL23-inhibitors, tumour necrosis factor alpha (TNF-α)-inhibitors and an IL12/23-inhibitor in psoriasis, is scarce. The aim of this study was to directly compare the first-year effectiveness of biologic therapies for psoriasis, corrected for confounders. This prospective, multicentre cohort study assessed BioCAPTURE data on etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, and guselkumab in 1,080 treatment episodes of 700 patients with psoriasis. The course of the mean absolute Psoriasis Area and Severity Index (PASI) and the proportion of patients who achieved PASI90/PASI75 were compared using linear mixed models and mixed logistic regression models respectively, corrected for baseline PASI, biologic naivety, and weight. Patients treated with adalimumab, ustekinumab, secukinumab, ixekizumab, or guselkumab all had a significantly lower mean PASI after 12 months compared with etanercept, and significantly higher overall odds of reaching PASI90 than those treated with etanercept. Patients treated with ixekizumab or guselkumab also had higher probabilities of reaching PASI90 than adalimumab, ustekinumab, and secukinumab. Relative to randomized controlled trials, the proportions of patients who reached PASI90/75 were lower in this real-world study.

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A dose reduction strategy for adalimumab, etanercept and ustekinumab in patients with psoriasis who have stable and low disease activity has recently been compared with usual care in the CONDOR study (CONtrolled DOse Reduction) of biologics in patients with psoriasis with low disease activity. The aim of the current study was to perform a cost-utility analysis with a 12-month time horizon alongside this trial, using prospectively measured healthcare costs and quality-adjusted life years, based on Short-Form Six-Dimension utilities. Bootstrap analys-es were used to calculate the decremental cost-utility ratio and the incremental net monetary benefit. The dose reduction strategy resulted in a mean cost saving of €3,820 (95th percentile -€3,099 to -€4,509) per patient over a period of 12 months. There was an 83% chance that dose reduction would result in a reduction in quality adjusted life years (mean -0.02 (95th percentile -0.06 to 0.02). In conclusion, dose reduction of biologics resulted in substantial cost savings with an acceptable reduction in quality of life.

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Importance: Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible. Objective: To investigate whether dose reduction (DR) of biologics in patients with stable psoriasis is noninferior to usual care (UC). Design, Setting, and Participants: This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied. Interventions: Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose. Main Outcomes and Measures: The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index [DLQI] and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for ≥3 months), and proportion of patients with successful dose tapering. Results: Of 120 patients (mean [SD] age, 54.0 [13.2] years; 82 [68%] male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range [IQR], 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred. Conclusions and Relevance: In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues. Trial Registration: ClinicalTrials.gov Identifier: NCT02602925.

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BACKGROUND AND PURPOSE: Among patients with an acute ischaemic stroke secondary to large-vessel occlusion, the hypoperfusion intensity ratio (HIR) [time to maximum (TMax) > 10 volume/TMax > 6 volume] is a strong predictor of infarct growth. We studied the correlation between HIR and collaterals assessed with digital subtraction angiography (DSA) before thrombectomy. METHODS: Between January 2014 and March 2018, consecutive patients with an acute ischaemic stroke and an M1 middle cerebral artery (MCA) occlusion who underwent perfusion imaging and endovascular treatment at our center were screened. Ischaemic core (mL), HIR and perfusion mismatch (TMax > 6 s minus core volume) were assessed through magnetic resonance imaging or computed tomography perfusion. Collaterals were assessed on pre-intervention DSA using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scale. Baseline clinical and perfusion characteristics were compared between patients with good (ASITN/SIR score 3-4) and those with poor (ASITN/SIR score 0-2) DSA collaterals. Correlation between HIR and ASITN/SIR scores was evaluated using Pearson's correlation. Receiver operating characteristic analysis was performed to determine the optimal HIR threshold for the prediction of good DSA collaterals. RESULTS: A total of 98 patients were included; 49% (48/98) had good DSA collaterals and these patients had significantly smaller hypoperfusion volumes (TMax > 6 s, 89 vs. 125 mL; P = 0.007) and perfusion mismatch volumes (72 vs. 89 mL; P = 0.016). HIR was significantly correlated with DSA collaterals (-0.327; 95% confidence interval, -0.494 to -0.138; P = 0.01). An HIR cut-off of <0.4 best predicted good DSA collaterals with an odds ratio of 4.3 (95% confidence interval, 1.8-10.1) (sensitivity, 0.792; specificity, 0.560; area under curve, 0.708). CONCLUSION: The HIR is a robust indicator of angiographic collaterals and might be used as a surrogate of collateral assessment in patients undergoing magnetic resonance imaging. HIR <0.4 best predicted good DSA collaterals.

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The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients >/=the age of 60 (median 63; range 60-73) years, undergoing AuSCT with that of 382 patients <60 (median 52; range 30-59) years. The two groups were similar except that older patients had a higher beta(2)-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4-9) and 1-year treatment-related mortality (TRM) was 9% (6-13) in patients <60 years, compared with 5% (2-10) and 8% (4-14), respectively, in patients >/=60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT >12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.

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PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

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Peripheral blood stem cell grafts from patients with lymphoma are often contaminated with neoplastic cells. Administration of a lymphoma-specific monoclonal antibody before collecting stem cells may be one way of reducing the contamination. Similarly, an antibody after transplantation at a time of minimal residual disease may increase the efficacy of the procedure. The objective of this study was to determine the safety of using rituximab as both an in vivo purging agent and a posttransplantation adjuvant. Eligible patients with lymphoma received 375 mg/m2 rituximab intravenously IV) on day 1, 2.5 g/m2 cyclophosphamide IV on day 4, and 10 microg/kg per day filgrastim starting on day 5 and continuing until completion of leukapheresis. Patients subsequently received a standard preparative regimen and then received 375 mg/m2 rituximab IV 7 days after platelet independence was achieved. Twenty-five patients (14 men, 11 women; median age, 51 years) were enrolled. Of the 25 patients, 23 received transplants after at least 2.0 x 10(6) CD34+ cells/kg were harvested. As determined with a sensitive polymerase chain reaction assay, 6 of 7 stem cell products tested were free of tumor contamination. All patients engrafted promptly, and the rituximab infusions were well tolerated. Transient neutropenia of uncertain etiology occurred in 6 patients a median of 99.5 days post-transplantation. An additional patient developed progressive pancytopenia. Rituximab used as an in vivo purging agent and adjuvant immunotherapy with peripheral blood stem cell transplantation for non-Hodgkin's lymphoma is a well-tolerated regimen. However, the ultimate determination of efficacy will require the results of ongoing studies.

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Donor leukocyte infusion (DLI) has well-documented activity in CML, but the role of DLI in other diseases is less well defined. To evaluate the strategy in multiple myeloma (MM) we evaluated 25 MM patients from 15 centers who were treated with DLI. Patients with persistent or recurrent disease after allogeneic BMT received DLI from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). Chemotherapy was given before DLI in three patients. Two of 22 patients responded completely to DLI alone and three patients responded to the combination of DLI and chemotherapy. Nine patients who had not had sufficient disease control after DLI were given additional DLIs; five of these patients had either complete (two) or partial (three) responses. Thirteen of 25 evaluable patients developed acute GVHD and 11 of 21 evaluable patients developed chronic GVHD; all responders developed GVHD. No patients developed post-DLI pancytopenia. Four patients had responses which lasted >1 year after DLI, three patients had responses which lasted <1 year, and three patients had ongoing responses but with follow-up <1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders.

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Outbreaks of vancomycin-resistant enterococci (VRE) are well described. The presence of mutants of VRE, such as vancomycin-dependent enterococci (VDE), in individual patients has been documented, but their potential to spread nosocomially has not been known. We present the first cluster of patients who acquired VDE nosocomially. Five bone marrow transplantation patients were infected or colonized by a genotypically indistinguishable multiantibiotic-resistant strain of Enterococcus faecium. Vancomycin dependence in 3 of the 5 isolates was demonstrated. All cluster patients had received protracted prophylactic treatment with vancomycin (mean, 22.6 days), and specimens from >/=2 body sites were repeatedly culture-positive for the outbreak strain. The outbreak was controlled with aggressive infection control strategies, and prophylactic antibiotic policies were revised. Awareness of the potential for nosocomial spread of multiantibiotic-resistant VDE is vital for the care of immunocompromised patients, especially those receiving prophylactic antibiotics.

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From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD. In this trial, cyclosporine 1 mg/kg/day was given from the day of bone marrow reinfusion until the completion of the interferon and gamma-interferon. Gamma-interferon at 0.025 mg/m2 every other day was started when the total white cell count was >200 cells/ml for 2 consecutive days and continued for a total of 10 doses after ABMT. The preparative regimens were busulfan and cyclophosphamide, or cyclophosphamide with total body irradiation. All patients received 4HC-purged marrow grafts. Median age was 45 years (range 19-68). The diagnoses included chemo-resistant non-Hodgkin's lymphoma (10), acute lymphoblastic leukemia (two), chemo-resistant Hodgkin's disease (two), acute myeloid leukemia (one), and multiple myeloma (one). Median absolute neutrophil count recovery was 25.5 days (range 19-46 days). Median platelet count recovery was 40.5 days (range 28-279 days). There were nine deaths, two were related to transplant toxicity (infection), while the other seven were due to relapse. Event-free survival with a median of 964 days (range 19-1441 days of follow-up was 44%. In conclusion, treatment with cyclosporine, and gamma-interferon after ABMT was well tolerated and did not impair engraftment. Further studies with a larger number of patients are required to document any beneficial anti-tumor effect of autologous GVHD induction after ABMT.

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Chronic graft-versus-host disease (GVHD) is the most common late complication of allogeneic bone marrow transplantation (BMT). The sclerodermatous form of the disease is often refractory to standard treatment modalities. Based on reports of response to etretinate, a synthetic retinoid, among patients with scleroderma, we have added etretinate to the treatment regimen of 32 patients with refractory sclerodermatous chronic GVHD. This case series is comprised mainly of patients who had chronic GVHD of long duration (median of 30 months before the initiation of etretinate). Most had failed to respond to three or more agents before etretinate treatment was started. Clinical response was assessed after 3 months of therapy. Five patients did not complete a 3-month trial. Among the 27 patients evaluable for response, 20 showed improvement including softening of the skin, flattening of cutaneous lesions, increased range of motion, and improved performance status. Four showed no response after 3 months of therapy and 3 had progression of their sclerosis. Overall, etretinate has been fairly well tolerated in our patients, with skin breakdown and/or ulceration leading to its discontinuation in 6 patients. We believe the results in our patients are encouraging and suggest that further evaluation of etretinate in the treatment of sclerodermatous chronic GVHD is warranted.

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Although T cell depletion of allografts used in BMT has reduced GVHD, it has been associated with inferior engraftment and an increased risk of relapse. We have found that T cell depletion by counterflow centrifugal elutriation (CCE) also results in depletion of CD34+ stem cells. In order to determine if the discarded CD34+ cells would improve engraftment, we undertook a phase II trial of allogeneic BMT in which 110 patients (median age 43) with a variety of hematologic malignancies received CD34+ stem cell augmented, elutriated marrow grafts. The T cell-depleted grafts were tightly controlled and contained a mean of 4.3 x 10(7) mononuclear cells/kg, 3.3 x 10(6) CD34+ cells/kg, 1.5 x 10(5) CFU-GM/kg and 5.5 x 10(5) CD3+ T cells/kg. Median time to engraftment of granulocytes (>500/microl) was 16 days and of platelets (>50000/microl) was 25 days, comparable to that seen with unmanipulated marrow. No mixed hematopoietic chimerism was observed that was not associated with disease relapse. The four patients (3.6%) who failed to engraft were all at high risk because of prior donor transfusions or underlying marrow disorders. The incidence of GVHD was dependent on the duration of cyclosporin A (CsA) immunosuppression. In patients who received CsA for > or = 80 days, the incidence of clinically significant acute GVHD (>stage 1) and extensive, chronic GVHD was 5% and 11%, respectively. Peritransplant (< or = 100 day post-BMT) mortality for this group of patients was 15%. Event-free survival in selected subsets of patients compared favorably to previous studies in which patients received unmanipulated marrow allografts.

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T cell depletion (TCD) performed by elutriation has decreased the incidence of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation (BMT). However, as with all forms of TCD, patients may experience graft failure (10%), delayed engraftment, and mixed chimerism. Because 66%-75% of the CD34+ cells coseparate with the small lymphocytes, which are removed by elutriation, we designed a phase I trial in HLA-identical siblings to determine if the readdition of these previously lost small CD34+ cells would improve elutriation's engraftment kinetics. CD34+ cells were isolated from the small cell fraction of 10 consecutive donor grafts and infused into the recipients along with the TCD graft. The positively selected product had a mean T cell content of 1.2 x 10(5)/kg and was 80% CD34+, doubling the CD34+ content of the graft. All patients engrafted promptly with a median time to 500 neutrophils/mm3, untransfused 50,000 platelets/mm3, and discharge from the hospital of 19 (range 10-25), 24 (14-52), and 24 (18-29) days, respectively. Acute GvHD occurred in 2 patients, and no patient had chronic GvHD. Augmenting stem cell dose may be an efficient and safe alternative for overcoming TCD-associated delayed engraftment and graft failure, rather than increasing immunosuppression.

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Graft-versus-host disease (GVHD) continues to be a major obstacle to the success of allogeneic bone marrow transplantation. Furthermore, several clinical strategies being employed at this time in the field of bone marrow transplantation have had an impact on GVHD. In addition to the usual division of topics such as pathophysiology, and acute and chronic GVHD, papers dealing with the impact on GVHD created by allogeneic peripheral blood cell transplantation, donor leukocyte infusions, and unrelated bone marrow transplantation are considered separately.

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A sample of 437 patients being evaluated for bone marrow transplantation (BMT) completed interviews and questionnaires to assess their psychosocial adjustment. Nearly a third of the patients (31%) showed some degree of depression on the Center for Epidemiologic Studies Depression Scale. Scores on the Profile of Mood States Scale also indicated that these BMT candidates were experiencing a high level of psychological distress. This distress was found to be predicted by low scores on the Self-Rated Karnofsky Performance Scale and on scales measuring mastery and dispositional optimism. The value of assessing the levels of psychological distress and psychosocial resources of patients being evaluated for BMT and for providing necessary psychiatric interventions are discussed.

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PURPOSE: We examined the impact of age on outcomes in patients with cancer undergoing autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: All 506 adult patients who underwent ABMT at the Johns Hopkins Oncology Center between January 1987 and January 1994 were studied. A total of 405 patients were aged 18 to 49 years and 101 were aged > or = 50. The effect of age and other prognostic variables on transplant-related mortality (TRM), relapse, and event-free survival rates were analyzed. RESULTS: Patients aged > or = 50 years has a 2.24-fold increased risk of TRM. Although relapse rates were not different based on age, the increased TRM rate resulted in a slight decrease in overall event-free survival in the older patients. Causes of death were not different by age and were mainly related to preparative regimen toxicity. Length of hospital stay and hospitalization costs were not increased in the older patients. CONCLUSION: While the TRM rate was higher in older patients, relapse rates were not increased. Nearly 25% of older patients were expected to be cured of the disease. These data support the use of ABMT in eligible older patients, at least up to the age of 65.

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A sample of 437 patients completed self-report measures of quality of life and social support while they were being evaluated for bone marrow transplantation (BMT) at The Johns Hopkins Oncology Center. Generally, the candidates showed reasonably high levels of quality of life (QOL) on the Satisfaction with Life Domains Scale (SLDS), their present ranking on the Cantril Self-Anchoring Ladder of Life, and their scores on the Bradburn Positive Affect Scale. The level of QOL of these candidates for transplant was significantly related to their level of social support. Both availability and adequacy of social support for these transplant candidates were found to be significantly related to QOL as measured by the SLDS. Availability of social support as measured by patient membership in religious and other organizations was significantly related to Positive Affect but not Negative Affect. The Family APGAR and Relational Support Scales measures of social support were significantly correlated with both Positive and Negative Affect.

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OBJECTIVE: To determine the number of different radiation schedules used in Ontario to treat women with node-negative breast cancer after lumpectomy and axillary dissection. DESIGN: Retrospective survey. SETTING: Princess Margaret Hospital, Toronto, and regional centres of the Ontario Cancer Treatment and Research Foundation (in Hamilton, London, Ottawa, Windsor and Thunder Bay). PATIENTS: A total of 551 of 1624 consecutive patients with node-negative breast cancer having undergone lumpectomy and axillary dissection who were eligible but did not participate in the Ontario Clinical Oncology Group randomized clinical trial and who received adjuvant breast irradiation between April 1984 and February 1989. OUTCOME MEASURES: Schedules of radiotherapy received. RESULTS: Forty-eight different radiotherapy schedules were identified. Total doses ranged from 4000 to 6600 cGy and the number of fractions from 15 to 30. Several different schedules were preferred: 322 patients (58.5%) received 4000 cGy in 15 or 16 fractions to the whole breast over 3 weeks plus a local boost of 1250 cGy to the primary site in 5 fractions over 1 week; 66 patients (12.0%) received 4000 cGy in 15 or 16 fractions over 3 weeks to the whole breast plus a local boost of 1000 cGy to the primary site in 4 or 5 fractions over 1 week; and 63 patients (11.5%) received 5000 cGy in 25 fractions to the whole breast in 5 weeks, without a boost. CONCLUSIONS: The practice of adjuvant radiotherapy for early breast cancer in Ontario varies. The optimal radiation regimen for patients after lumpectomy should be determined through randomized clinical trials.

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