Successful treatment of Epstein–Barr virus–associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder,with ibrutinib and third-party Epstein–Barr virus–specific T cells

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein–Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).     

Prolonged Duration of Therapy Is Associated With Improved Survival in Patients Treated for Relapsed/Refractory Multiple Myeloma in Routine Clinical Care in the United States

Background

In clinical trials, an extended therapy duration has been associated with better outcomes in patients with newly diagnosed multiple myeloma (NDMM). However, data on how the therapy duration affects the outcomes for patients with relapsed/refractory multiple myeloma (RRMM) are limited. We conducted a large, retrospective study in the United States to evaluate the effect of the duration of second-line therapy on overall survival.

Hormone replacement therapy,mammographic density,and breast cancer risk: a cohort study

Purpose

Hormone replacement therapy (HRT) use increases breast cancer risk and mammographic density (MD). We examine whether MD mediates or modifies the association of HRT with the breast cancer.

Methods

For the 4,501 participants in the Danish diet, cancer and health cohort (1993–1997) who attended mammographic screening in Copenhagen (1993–2001), MD (mixed/dense or fatty) was assessed at the first screening after cohort entry. HRT use was assessed by questionnaire and breast cancer diagnoses until 2012 obtained from the Danish cancer registry. The associations of HRT with MD and with breast cancer were analyzed separately using Cox’s regression. Mediation analyses were used to estimate proportion [with 95% confidence intervals (CI)] of an association between HRT and breast cancer mediated by MD.

Results

2,444 (54.3%) women had mixed/dense breasts, 229 (5.4%) developed breast cancer, and 35.9% were current HRT users at enrollment. Compared to never users, current HRT use was statistically significantly associated with having mixed/dense breasts (relative risk and 95% CI 1.24; 1.14–1.35), and higher risk of breast cancer (hazard ratio 1.87; 1.40–2.48). Association between current HRT use and breast cancer risk was partially mediated by MD (percent mediated?=?10%; 95% CI 4–22%). The current HRT use-related breast cancer risk was higher in women with mixed/dense (1.94; 1.37–3.87) than fatty (1.37; 0.80–2.35) breasts (p value for interaction?=?0.15).

Conclusions

MD partially mediates some of the association between HRT and breast cancer risk. The association between HRT and breast cancer seems to be stronger in women with dense breasts.

     

Postoperative hydrocephalus in cranial base surgery

The incidence of postoperative hydrocephalus and factors relating to it were analyzed in 257 patients undergoing cranial base surgery for tumor resection. A total of 21 (8%) patients developed postoperative hydrocephalus, and all required shunting, Forty-two (17%) patients developed cerebrospinal fluid (CSF) leak that required placement of external drainage systems (ventriculostomy or lumbar drain, or both); 10 (23%) of these 42 patients eventually needed shunt placement to stop the leak because of hydrocephalus. Prior craniotomy, prior radiation therapy, and postoperative CSF infection were also associated with an increased risk of developing hydrocephalus (48% versus 6%, 19% versus 8%, and 14% versus 7%, respectively). Prior radiation and postoperative CSF infection increased the risk of CSF leak in patients with hydrocephalus (30% versus 18% and 30% versus 9%, respectively). CSF leak and hydrocephalus commonly occurred in patients who underwent resection of a glomus tumor. In conclusion, 8% of patients who underwent cranial base surgery for tumors developed de novo hydrocephalus; half of them also had CSF leak in addition to hydrocephalus; and all required shunt placement for CSF diversion.     

The XIIIth Banff Conference on Allograft Pathology: The Banff 2015 Heart Meeting Report: Improving Antibody‐Mediated Rejection Diagnostics: Strengths,Unmet Needs,and Future Directions

The 13th Banff Conference on Allograft Pathology was held in Vancouver, British Columbia, Canada from October 5 to 10, 2015. The cardiac session was devoted to current diagnostic issues in heart transplantation with a focus on antibody‐mediated rejection (AMR) and small vessel arteriopathy. Specific topics included the strengths and limitations of the current rejection grading system, the central role of microvascular injury in AMR and approaches to semiquantitative assessment of histopathologic and immunophenotypic indicators, the role of AMR in the development of cardiac allograft vasculopathy, the important role of serologic antibody detection in the management of transplant recipients, and the potential application of new molecular approaches to the elucidation of the pathophysiology of AMR and potential for improving the current diagnostic system. Herein we summarize the key points from the presentations, the comprehensive, open and wide‐ranging multidisciplinary discussion that was generated, and considerations for future endeavors.     

Impact of Allograft Injury Time of Onset on the Development of Chronic Lung Allograft Dysfunction After Lung Transplantation

The impact of allograft injury time of onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late‐onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single‐center study, 1894 transbronchial biopsy samples from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD), and organizing pneumonia (OP). The association between the time of onset of each injury pattern and CLAD was assessed by using multivariable Cox models with time‐dependent covariates. Bronchoalveolar lavage (BAL) CXCR3 ligand concentrations were compared between early‐ and late‐onset injury patterns using linear mixed‐effects models. Late‐onset DAD and OP were strongly associated with CLAD: adjusted hazard ratio 2.8 (95% confidence interval 1.5–5.3) and 2.0 (1.1–3.4), respectively. The early‐onset form of these injury patterns did not increase CLAD risk. Late‐onset LB and acute rejection (AR) predicted CLAD in univariable models but lost significance after multivariable adjustment for late DAD and OP. AR was the only early‐onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late‐onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.     

Evaluation of a muscle pump‐activating device for non‐healing venous leg ulcers

This evaluation involves an innovative muscle pump‐activating device (geko™) as an adjunctive therapy with best practices for non‐healing venous leg ulcers (VLUs). Stimulating the common peroneal nerve (at the fibular head), the geko™ device creates a response that acts as foot and calf muscle pumps, increasing venous, arterial and microcirculatory flow. The aim was to evaluate and determine if the geko™ is effective in this population and if it should be added to the medical supply formulary. In all, 12 patients with 18 recalcitrant VLUs (defined as less than 30% reduction in wound size in 30 days with best practices) in two community settings in Ontario consented to the evaluation and were treated with the geko™ for up to 20 weeks. A total of 44% of wounds healed, and 39% decreased in size. One patient non‐adherent with the geko™ and best practices had deterioration in his or her wounds. With the patients as their own control, the mean weekly healing rate with the geko™ was 9·35% (±SD 0·10) compared to 0·06% (±SD 0·10) prior to baseline, which was statistically significant (P < 0·01). Three patients not in optimal therapy increased compression due to decreased pain, further enabling healing. This study was not a randomised investigation, although the patients acted as their own controls. A pragmatic evaluation reflects the reality of the community sector; in spite of best practices or evidence‐based care, therapy is not uniformly applied, with some participants unable to tolerate or indeed comply with optimal compression therapy. Rash occurred under the devices in 7 of 12 (58%) patients. One patient stopped the device due to rash, while another had to take breaks from using the device. Subsequently, the manufacturer (FirstKind Ltd) has developed a new device and protocol specific to the requirements of wound therapy to minimise this response. This small case series demonstrated the highly significant effectiveness of the geko™ device in these hard‐to‐heal VLUs. Further evaluations to determine dose and patient selection criteria are underway.