CD19+CD21low B cells and CD4+CD45RA+CD31+ T cells correlate with first diagnosis of chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for National Institutes of Health-defined cGVHD patients (n = 163) in comparison to time-matched HCT recipients who never experienced cGVHD (n = 64), analyzed from day 100 after HCT. In logistic regression analysis, CD19(+)CD21(low) B cells (P = .002; hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.53 to 7.17) and CD4(+)CD45RA(+)CD31(+) T cells (P < .001; HR, 3.88; 95% CI, 1.88 to 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD, independent of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B cells (P = .008; HR, 3.00; 95% CI, 1.33 to 6.75) and CD4(+)CD45RA(+)CD31(+) T cells (P = .017; HR, 2.80; 95% CI, 1.19 to 6.55). CD19(+)CD21(low) B cells were found to have the highest discriminatory value with an area under the receiver operating curve of .77 (95% CI, .64 to .90). Our results demonstrate that CD19(+)CD21(low) B cells and CD4(+)CD45RA(+)CD31(+) T cells are significantly elevated in patients with newly diagnosed cGVHD.

CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS), pathognomonic for chronic graft-versus-host disease (cGVHD) of the lung, is a progressive and often fatal complication after allogeneic hematopoietic cell transplantation (HCT). Biomarkers for the prediction and diagnosis of BOS are urgently needed to improve patients' prognosis. We prospectively evaluated B-cell subpopulations and B-cell activating factor (BAFF) in 136 patients (46 BOS, 41 no cGVHD, 49 cutaneous cGVHD) to define novel biomarkers for early diagnosis of National Institutes of Health-defined BOS diagnosed a median of 11 mo after HCT. Patients with newly diagnosed BOS had significantly higher percentages of CD19(+)CD21(low) B cells (25.5 versus 6.6%, P < .0001), BAFF (7.3 versus 3.5 ng/mL, P = .02), and BAFF/CD19(+) ratio (0.18 versus 0.02 ng/10(3) CD19(+) B cells, P 5 .007) compared with patients without cGVHD. The area under the receiver operating curve for CD19(+)CD21(low) B cells was 0.97 (95% confidence interval, 0.94-0.99) and a cutoff point >9% was optimal for diagnosing BOS in patients with first drop of pulmonary function tests with a sensitivity of 96% and a negative predictive value of 94%. Thus, elevated levels of CD19(+)CD21(low) B cells are a potential novel biomarker for HCT patients at risk for developing BOS at an early stage and could allow improvement of patient outcome.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia.

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 106L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 106/L) and class-switched (7 vs 35 vs 42 × 106/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Allogeneic disparities in immunoglobulin-like transcript 5 induce potent antibody responses in hematopoietic stem cell transplant recipients.

In hematopoietic stem cell transplant (HSCT) recipients, the recognition of polymorphic antigens by the donor-derived immune system is an important mechanism underlying both graft-versus-host disease and graft-versus-leukemia (GVL) effect. Here we show that a subset of HSCT recipients (13.9%, n = 108) have antibodies directed to surface molecules of dendritic cells. We have used one such serum in conjunction with retroviral expression cloning to identify the highly polymorphic surface molecule immunoglobulin-like transcript 5 (ILT5) as one of the targets of dendritic cell-reactive antibodies. ILT5 reactive antibodies were found in 5.4% of HSCT patients but not in solid organ transplantation recipients, patients with collagen diseases, multiparous women, or polytransfused or healthy persons. We show that ILT5-specific antibodies can mediate killing of ILT5-bearing cells and furthermore demonstrate ILT5 expression in some leukemic cells, indicating that it might be a target for GVL effects. Thus, our results represent the first description of potent allogeneic antibody responses to a non-major histocompatibility complex cell surface molecule in hematopoietic stem cell transplanted patients and warrant further studies to elucidate the role of antibodies to polymorphic cell surface molecules in GVL and graft-versus-host responses.

Use of Natural Family Planning (NFP) and Its Effect on Couple Relationships and Sexual Satisfaction: A Multi-Country Survey of NFP Users from US and Europe.

PURPOSE: Birth control is a persistent global health concern. Natural family planning (NFP) comprises methods to achieve or avoid pregnancy independent of mechanical or pharmacological intervention. The sympto-thermal method (STM) of NFP employs daily observation of cervical fluids and measurement of basal body temperature. This multi-country study was undertaken to describe the characteristics of STM users, understand their perceptions of NFP, and its perceived impact on relationships. METHODS AND RESULTS: Questionnaires for women and men were developed in German and translated to English, Polish, Italian, Czech, and Slovak by native speakers. A total of 2,560 respondents completed the online questionnaire (37.4% response). Participants were married (89%) and well educated, and their self-perceived financial status was described as "good" or "very good" by 65% of the respondents. Forty-seven percent had previously used contraceptives. Ninety-five percent of women and 55% of men said using NFP has helped them to know their body better. Large majorities of men (74%) and women (64%) felt NFP helped to improve their relationship while <10% felt use of NFP had harmed their relationship. Most women (53%) and men (63%) felt using NFP improved their sex life while 32% of women and 24% of men felt it was unchanged from before they used NFP. Seventy-five percent of women and 73% of men said they are either "satisfied" or "very satisfied" with their frequency of sexual intercourse. CONCLUSION: This survey demonstrates STM of NFP is a well-accepted approach to family planning across several Western cultures. It is consistently viewed as being beneficial to couples' self-knowledge, their relationship, and satisfaction with frequency of sexual intercourse.

Nab-paclitaxel as alternative treatment regimen in advanced cholangiocellular carcinoma.

BACKGROUND: Advanced cholangiocellular carcinoma has a poor prognosis with limited therapeutic options. Nab-paclitaxel has recently been described to be beneficial in metastatic pancreatic cancer improving overall and progression free survival (PFS). The potential antitumor activity of nab-paclitaxel in cholangiocellular carcinoma is hitherto unknown. METHODS: We retrospectively analyzed an institutional cholangiocellular carcinoma registry to determine the potential biological activity of nab-paclitaxel in advanced intrahepatic cholangiocellular carcinoma. Disease control rate (DCR), PFS and overall survival (OS) upon nab-paclitaxel based treatment, after failure of platinum-containing first-line combination chemotherapy, was assessed. RESULTS: Twelve patients were identified. Five of 12 patients (42%) received nab-paclitaxel as second line, and 7 patients (56%) as third-line treatment. The objective DCR with nab-paclitaxel was 83% (10/12 patients). One patient had a complete remission (CR), two patients had a partial remission (PR) and 7 patients had stable disease (SD). Disease was rated progressive in two patients. In all 12 patients receiving nab-paclitaxel the median time to progression was 6 months (range, 2.1-19.5 months). Median OS after initiation of nab-paclitaxel treatment was 9 months (2.1-28.4 months). The median time of survival after diagnosis of advanced disease was 21.5 months, whereby 3 patients were alive at the date of censoring (04/01/2015). CONCLUSIONS: This is the first report suggesting substantial antitumor activity of nab-paclitaxel in advanced cholangiocellular carcinoma. In this small series, nab-paclitaxel based salvage chemotherapy appears to have a biological activity by controlling the disease and positively affecting survival. Randomized trials in this disease entity and subgroup of patients are urged.

Extracorporeal photophoresis increases sensitivity of monocytes from patients with graft-versus-host disease to HLA-DR-mediated cell death.

BACKGROUND: Graft-versus-host disease (GVHD) remains a cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation, and recent studies indicate that extracorporeal photophoresis (ECP) is useful for treatment of steroid-refractory GVHD although the mechanisms are unclear. Antigen-presenting cells (APCs) such as dendritic cells have a central role in GVHD, and apoptosis of APCs by HLA-DR monoclonal antibody (MoAb) has been documented in vitro and in vivo. Monocytes have been identified as precursors of dendritic cells in vivo and particularly under conditions of inflammation. STUDY DESIGN AND METHODS: This study examined whether ECP altered the survival of peripheral blood monocytes from patients with GVHD, monocyte apoptosis after engagement of HLA-DR antigens with MoAb, and monocyte apoptosis after allointeraction with primary CD4+ T lymphocytes. Samples from patients from two centers were studied. RESULTS: It is reported here that ECP induced apoptosis of monocytes over a period of at least 48 hours. ECP also clearly increased cell death of monocytes after engagement of HLA-DR antigens with MoAb. In contrast, engagement of HLA-DR by allointeraction failed to induce significant cell death of monocytes, and this was unaltered by ECP treatment. CONCLUSION: These data reveal that monocytes from patients with GVHD are sensitive to HLA-DR-mediated apoptosis and that ECP treatment increases sensitivity to both spontaneous and HLA-DR-mediated apoptosis. Therefore, ECP treatment in combination with HLA-DR MoAbs could rapidly deplete monocytes and thereby reduce the contribution of monocyte-derived dendritic cells to GVHD.

Quality of drainage blood: survival of red cells after re-transfusion and content of free hemoglobin and potassium.

Re-transfusion of drainage blood is widely used in orthopedic surgery, but objective evidence of the efficacy of re-transfusion of drainage blood in view of post-transfusion survival of RBC has not been given so far. With this study we wanted to evaluate the efficacy and safety of transfusion of drainage blood collected with HandyVac autotransfusion system. In 7 patients red cells in drainage blood were labeled with biotin and percentage of labeled red cells in circulation were determined immediately after re-transfusion, and during 10 days after surgery. To assess further unwanted side-effects of re-transfusion of drainage blood potassium and free hemoglobin were determined in the collected blood. Ten days after re-transfusion at mean 78.9% of drainage-blood derived RBC were found in circulation. Free hemoglobin in drainage blood ranged from 16.8 to 59.2 mg/dL; potassium in drainage blood ranged from 3.84 to 4.52 mmol/L. Our results suggest that re-transfusion of drainage blood collected with HandyVac autotransfusion system is an efficient procedure that seems to be safe in view of free hemoglobin and potassium in the product.