Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study.

Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes ≥ A2 within the first year post-TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher-grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies.

Association of human cytomegalovirus DNAaemia and specific granzyme B responses in lung transplant recipients.

In lung transplant recipients (LTRs), human cytomegalovirus (HCMV) DNAaemia could be associated with HCMV disease and reduced allograft survival. In the present study we analysed whether or not HCMV-specific granzyme B (Grz-B) responses indicating CD8(+) T cell cytotoxicity exert an impact on HCMV DNAaemia and relate to specific interferon (IFN)-γ secretion. HCMV-specific Grz-B responses were quantitated by enzyme-linked immunosorbent assay (ELISA) in 70 samples from 39 HCMV seropositive LTRs who were prospectively investigated for HCMV DNA plasma levels and IFN-γ kinetics using a standardized CD8(+) T cell assay (QuantiFERON®-CMV assay). In all LTRs who were protected from HCMV DNAaemia by early and persistent IFN-γ responses, Grz-B responses were also detected. In LTRs who developed episodes of HCMV DNAaemia, the Grz-B responses which were detected prior to viral DNA detection differed significantly in patients who experienced episodes with high (exceeding 1000 copies/ml) and low plasma DNA levels (P = 0·0290, Fisher's exact test). Furthermore, the extent of Grz-B release prior to viral DNAaemia correlated statistically with the detected levels of IFN-γ (P < 0·0001, Spearman's rank test). Of note, simultaneous detection of Grz-B and IFN-γ secretion was associated significantly with protection from high HCMV DNA plasma levels during the subsequent follow-up (P = 0·0057, Fisher's exact test), and this association was stronger than for IFN-γ detection alone. We conclude that, in addition to IFN-γ responses, Grz-B secretion by CD8(+) T cells is essential to control HCMV replication and a simultaneous measurement of IFN-γ and Grz-B could contribute to the immune monitoring of LTRs.

Prospective analysis of human cytomegalovirus DNAemia and specific CD8+ T cell responses in lung transplant recipients.

In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV-specific CD8+ T cell responses, which were longitudinally assessed using a standardized assay. Sixty-seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T cell tests performed per patient. HCMV-specific CD8+ T cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fisher's exact test), and were absent before HCMV disease. In HCMV-seropositive LuTRs, high-level DNAemia requiring preemptive therapy occurred more frequently when HCMV-specific CD8+ T cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fisher's exact test). Thus, our data indicate that HCMV-specific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation.

Clinical ex vivo lung perfusion--pushing the limits.

Ex vivo lung perfusion (EVLP) provides the ability to evaluate donor lungs before transplantation. Yet, limited prospective clinical data exist with regard to its potential to recondition unacceptable donor lungs. This paper summarizes the results of a prospective study of lung transplantation using only initially unacceptable donor lungs, which were improved by EVLP for 2-4 h. From March 2010-June 2011, 13 lungs were evaluated ex vivo. Median donor PaO(2) at FiO(2) 1.0/PEEP5 was 216 mmHg (range 133-271). Four lungs, all with trauma history, showed no improvement and were discarded. Nine lungs improved to a ΔPO(2) higher than 350 mmHg. Median PvO(2) at final assessment in these lungs was 466 mmHg (range 434-525). These lungs were transplanted with a median total ischemic time of 577 min (range 486-678). None of the patients developed primary graft dysfunction grades 2 or 3 within 72 h after transplantation. One patient with secondary pulmonary hypertension was left on a planned prolonged extracorporeal membrane oxygenation postoperatively. Median intubation time was 2 days. Thirty-day mortality was 0%. During the observation period, 119 patients received standard lung transplantation with comparable perioperative outcome. EVLP has a significant potential to improve the quality of otherwise unacceptable donor lungs.

Human cytomegalovirus infection in lung transplant recipients triggers a CXCL-10 response.

Human cytomegalovirus (HCMV) causes significant morbidity in lung transplant recipients (LTRs). The clinical effects of HCMV replication are determined partly by a type 1 T-helper cell (Th1) response. Because the chemokine interferon-inducible protein of 10 kilodaltons (IP-10, CXCL-10) induces a Th1 response, we investigated whether HCMV triggers IP-10 in LTRs. The IP-10 concentration and HCMV DNA load were determined in 107 plasma and 46 bronchoalveolar lavage fluid (BALF) samples from 36 LTRs. Initial HCMV detection posttransplantation was significantly associated with increased plasma IP-10, regardless of whether the patients showed HCMV DNAemia (p = 0.001) or HCMV replication only in the allograft (p < 0.0001). In subsequent episodes of HCMV detection, plasma IP-10 increased regardless of whether HCMV was detected in blood (p = 0.0078) or only in BALF (p < 0.0001) and decreased after successful antiviral therapy (p = 0.0005). Furthermore, levels of HCMV DNA and IP-10 correlated statistically (p = 0.0033). Increased IP-10 levels in HCMV-positive BALF samples were significantly associated with severe airflow obstruction, as indicated by a decrease in forced expiratory volume in one second (FEV1). Our data indicate that HCMV replication in LTRs evokes a plasma IP-10 response and that, when an IP-10 response is observed in BALF, it is associated with inflammatory airway obstruction in the allograft.