A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia

Introduction

Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in ‘unfit’ (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.

Methods

For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.

Results

In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).

Conclusion

G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.

Funding

F. Hoffmann-La Roche Ltd.

     

A granulocyte reactive monoclonal antibody, 1G10, identifies the Gal beta 1-4 (Fuc alpha 1-3)GlcNAc (X determinant) expressed in HL-60 cells on both glycolipid and glycoprotein molecules

1G10, a monoclonal IgM antibody that identifies a differentiation antigen on human granulocytes and a subpopulation of monocytes, was found to react specifically with glycosphingolipids bearing the Gal beta 1-4(Fuc alpha 1-3)GlcNAc hapten (X determinant). This carbohydrate determinant was found on both glycolipid and glycoprotein molecules isolated from HL-60 cells (a promyelocytic leukemia cell line). Thus, this highly conserved carbohydrate-defined determinant previously described on mouse embryonic and mouse and human carcinoma cells is also expressed as a tissue-specific differentiation antigen on normal human granulocytes.     

Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis

Background

Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined.

Methods

Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis.

Results

One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08–15.31) and lesion volume (OR 3.14, 95%CI: 0.73–13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42–282.00 and OR 15.97, 95%CI: 1.62–157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94–24.05 and OR 40.69, 95%CI: 2.55–649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates.

Conclusion

Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value.

Key Points

? CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis.? Predictive capability exceeds galactomannan, blood counts, and lesion count.? Any progression between day 7 and day 14 constitutes a high-risk scenario.

     

Adult Living Liver Donors have Excellent Long‐Term Medical Outcomes: The University of Toronto Liver Transplant Experience

Right lobe living donor liver transplantation is an effective treatment for selected individuals with end‐stage liver disease. Although 1 year donor morbidity and mortality have been reported, little is known about outcomes beyond 1 year. Our objective was to analyze the outcomes of the first 202 consecutive donors performed at our center with a minimum follow‐up of 12 months (range 12–96 months). All physical complications were prospectively recorded and categorized according to the modified Clavien classification system. Donors were seen by a dedicated family physician at 2 weeks, 1, 3 and 12 months postoperatively and yearly thereafter. The cohort included 108 males and 94 females (mean age 37.3 ± 11.5 years). Donor survival was 100%. A total of 39.6% of donors experienced a medical complication during the first year after surgery (21 Grade 1, 27 Grade 2, 32 Grade 3). After 1 year, three donors experienced a medical complication (1 Grade 1, 1 Grade 2, 1 Grade 3). All donors returned to predonation employment or studies although four donors (2%) experienced a psychiatric complication. This prospective study suggests that living liver donation can be performed safely without any serious late medical complications and suggests that long‐term follow‐up may contribute to favorable donor outcomes.     

Esophageal achalasia and pregnancy: own observations in 43 patients and a review of the literature

Introduction

Little is known concerning the interaction of achalasia and pregnancy and about an optimal time and type for treatment. Achalatic women of our collective of patients with at least one pregnancy in their history resulting in confinement or miscarriage were invited for a structured interview.

Materials and methods

43 of 109 female patients were included. Questionnaire contained questions on symptoms, type of symptoms, whether patients could link a specific event with outbreak of disease. Date of primary diagnosis and individual therapies were double checked against our documentation as well as duration of complaints and kind of therapy. Patients were asked about their obstetric history, whether and how symptoms had changed, and during which pregnancy week symptoms have occurred. Temporal correlation of the diagnosis of achalasia and pregnancy was investigated.

Results

There was no relationship between pregnancy and onset of achalasia. Risk of subfertility, undernourishment, premature birth, or miscarriage does not seem to be increased in achalasia. Health condition often worsened significantly during pregnancy, mainly in the first trimester and particularly in the untreated patients.

Conclusions

It is advisable to clarify the diagnosis if symptoms suspicious of an achalasia are present before a planned pregnancy. In case of manifest achalasia, surgical treatment should be performed before pregnancy and the improvement in the state of health should be anticipated, as, otherwise, a considerable deterioration of the symptoms during pregnancy may occur. Scientific impact of our observations is very limited and prospective clinical trials are required.

     

Effect of therapy on keratin polypeptide profiles of psoriatic epidermis

The sodium lauryl (dodecyl) sulfate polyacrylamide gel electrophoresis (SLS PAGE) patterns of keratin polypeptides were followed in 29 patients with psoriasis who were treated with middle wavelength ultraviolet (UV) radiation (UV B), oral methoxsalen, and long wavelength UV radiation (PUVA), or systemic antipsoriatic therapy. The keratin patterns from the Malpighian layer reverted to normal in several weeks, while those of the stratum corneum keratin reverted more slowly, often after clinical clearance of the lesions. These data may indicate that therapy should not be discontinued until there is production of normal stratum corneum polypeptides.     

Stent placement in patients with acute subarachnoid haemorrhage: when is it justified?

Purpose

Endovascular stents are widely used for the elective treatment of cerebral aneurysms. Acute stenting is performed in the management of dissections, pseudo-aneurysms, broad-based aneurysms or as a ‘bail out’ measure after coil migration. The purpose of this study is to review the safety of using stents in acute subarachnoid haemorrhage.

Methods

The stent registry of our institution was reviewed for procedures in patients with acute subarachnoid haemorrhage. Imaging studies were reviewed on the hospital’s PACS system and the patients’ notes were retrieved to assess complications and clinical outcomes. Procedures were analysed according to the type of stent, treatment indication, antiplatelet regime, complications and outcomes.

Results

Between 2008 and 2016, 51 stents were placed during 50 stenting procedures in 49 patients with acute subarachnoid haemorrhage. This included 24 patients with saccular aneurysms, 10 with blister aneurysms, 10 dissections and five fusiform aneurysms. Stents were deployed in ‘bail out’ situations on eight occasions. In six cases, flow-diverting stents were used. Eighteen patients (37%) in the cohort suffered a stroke. Nine patients (18%) suffered persistent clinical deficits as a result of the stenting procedure, all but one of which occurred within 24 h. Two patients had a transient ischaemic episode, and there was evidence of asymptomatic ischaemia on imaging in four cases (8%). Five patients died, three (6%) as a result of procedural complications. Twelve patients (25%) required a further embolisation procedure.

Conclusion

The use of stents in acute subarachnoid haemorrhage incurs a considerable complication risk and should be reserved for exceptional circumstances.