Christian Jehn

Biomarkers of depression in cancer patients

Inflammation and perturbation of the hypothalamic‐pituitary‐adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin‐6 (IL‐6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients.

Association of IL-6, Hypothalamus- Pituitary-Adrenal Axis Function, and Depression in Patients With Cancer

Background: Evidence suggests that cytokines (IL-6) and alteration of the hypothalamic—pituitary—adrenal (HPA) axis play a crucial role in the etiology of depression. Patients with cancer show elevated prevalence rates for depression. The objective of this cross-sectional study was to investigate the associations between these abnormalities and depression. Methods: Plasma concentrations of IL-6 and cortisol were measured in cancer patients with (N = 31) and without depression (N = 83). The relative diurnal variation of cortisol (cortisol VAR), expressed in percentage, was calculated. Results: There was a significant difference in median plasma concentration of IL-6 between the patients with depression and those without (18.7 vs 2.7 pg/mL; P < .001). Relative cortisol VAR was decreased in depressed patients as compared with patients without depression (11.72% vs 60.6%, P = .037). A positive correlation between the depressive symptoms and IL-6 concentration was found (r = 0.469, P < .001). Negative correlations were found between cortisol VAR versus depressive symptoms and cortisol VAR versus IL-6 (r = -0.6, P < .001 and r = -0.52, P < .001, respectively). IL-6 (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.2; P = .006) and cortisol VAR (OR = 1.3; 95%CI = 1.0-1.4; P = .02) are independently associated with depression. Conclusions: Depression in cancer is associated with increased plasma IL-6 concentrations and dysfunction of the HPA axis.

Influence of comorbidity, age and performance status on treatment efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory elderly patients with metastatic colorectal cancer

BACKGROUND We investigated the influence of comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status and age on the efficacy and safety profile of cetuximab and irinotecan in elderly irinotecan-pretreated patients with mCRC. METHODS 497 patients with mCRC were entered in the database of this non-interventional study (NIS). Comorbid conditions were recorded. RESULTS A total of 247 and 250 patients aged <65 and >65 years, respectively, with a median age of 66 y were documented; 78% of the patients showed a reduced ECOG status. Grade III/IV toxicities occurred in 18% of patients without any difference between age groups although older patients had more comorbidities with a higher Charlson Comorbidity Index (CCI) (p = 0.002). Skin rash was strongly related to response (p = 0.006). Age, line of therapy, ECOG, gender and CCI had no influence on response. The objective response rates were similar: 38.1% for age <65 years versus 36.4% for age >65 years (p = 0.57). Progression-free survival (PFS) did not differ between patients 18-65 years (6.0 months) and patients >65 years (6.2 months; p = 0.99). Only PS had a negative impact on PFS (hazard ratio (HR): 0,499; 95% confidence interval (CI) 0.34-0.72; p=0.002), whereas the presence of skin toxicity (grade>1) influenced PFS and response rate (RR) positively (HR: 2.04; 95% CI, 1.6-2.6; p<0.001). CONCLUSIONS Only PS and age had a negative influence on PFS irrespective of CCI or age. There were no significant differences in response rate and safety profile for elderly patients when treated with cetuximab and irinotecan. Comorbidities and age had no influence on efficacy or toxicity.

Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long-term outcome

For patients with refractory acute myeloid leukemia (AML), allogeneic stem cell transplantation (alloSCT) represents the only curative approach. We here analyzed the long‐term outcome of 131 consecutive patients with active AML, which was either primary refractory or unresponsive to salvage chemotherapy, transplanted at our center between 1997 and 2013. After a median follow‐up of 48 months for the surviving patients, disease‐free survival (DFS) at 5 yr post alloSCT was 26% (94% CI: 17–35). Relapses, most of which occurred within the first 2 yr from transplant, were the predominant cause of treatment failure affecting 48% (95%CI: 40–58) of patients, whereas non‐relapse mortality was 26% (95%CI: 20–36) at 5 yr and thereafter. A marrow blast count ≥20% before alloSCT was an independent prognosticator associated with an inferior DFS (HR: 1.58, P = 0.027), whereas the development of chronic graft‐versus‐host disease (cGvHD) predicted an improved DFS (HR 0.21, P < 0.001) and a decreased relapse incidence (HR: 0.18, P = 0.026), respectively. These results indicate that alloSCT represents a curative treatment option in a substantial proportion of patients with refractory AML. A pretransplant blast count <20% before alloSCT and the development of cGvHD are the most important predictors of long‐term disease control.

Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression.

BACKGROUND Increased IL-6 and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. The objective was to assess the influence of BDNF and IL-6 on cognitive function and depression in patients with cancer. METHODS Serum BDNF and plasma IL-6 were measured in patients with metastatic cancer. Diagnosis of depression was established according to DSM-IV criteria. Cognitive function was assessed by the Verbal Learning and Memory Test (VLMT). RESULTS A total of 59 patients were recruited in this study. Only IL-6 levels were significantly elevated in patients with clinical depression (35.7 vs. 6.9 pg/ml; p<0.001). There were no differences in hemoglobin levels (p=0.3) or BDNF levels (p=0.16). Patients with clinical depression showed significant impairment of short-term memory (STM) (24.4 vs. 37.5; p=0.01), but not of long-term memory (LTM) (3.9 vs. 2.8; p=0.3). STM was dependent on the level of BDNF and younger age (b=0.60; p=0.001; b= -0.63; p=0.003, respectively). IL-6 was not only strongly associated with depression, but was an independent predictor of BDNF level as well (b= -0.50; p=0.01). LTM was associated only with a good KPS (b=0.47; p=0.037). Hemoglobin levels and the prior number of chemotherapy lines were not predictive of memory performance. CONCLUSIONS Low BDNF is associated with cognitive impairment, STM, in patients with cancer, however no influence on depression could be found. IL-6 is strongly associated with depression and an independent predictor of BDNF levels.

Breast Cancer-Associated Thrombotic Microangiopathy

Background: Thrombotic microangiopathy (TMA) is defined as thrombocytopenia and microangiopathic hemolytic anemia. Cancer-associated TMA, a rare but fatal condition, seems an entity distinct from classical thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Patients and Methods: All patients with breast cancer-associated TMA treated at our institution between 2003 and 2008 were analyzed retrospectively. To elucidate pathophysiological mechanisms, we measured the serum activity of the metalloprotease ADAMTS13. Results: 8 patients were identified. All showed bone marrow infiltration of breast cancer as well as thrombocytopenia, schistocytes, and hemolytic anemia. ADAMTS13 activity was mildly decreased in 4/6 patients (20–108%, normal range 30–120%), but none showed severely low levels as is characteristic of classical TTP. 6 patients were treated with anthracycline-containing fractionated chemotherapy, 5/6 patients experienced partial response. Overall survival was 13 months. Fractionated chemotherapy was well tolerated. Conclusions: Cancer-associated TMA has an underlying mechanism different from classical TTP. While bone marrow infiltration might be of major relevance, ADAMTS13 deficiency seems to be an epiphenomenon. Fractionated chemotherapy resulted in higher remission rates and comparatively long survival.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT).

Biweekly Pegylated Liposomal Doxorubicin (Caelyx) in Heavily Pretreated Metastatic Breast Cancer: A Phase 2 Study.

BACKGROUND Pegylated liposomal doxorubicin (PLD) has shown to be as effective as conventional doxorubicin in the treatment of metastatic breast cancer but provides a lower risk of cardiotoxicity. This phase 2 study in heavily pretreated patients with metastatic breast cancer was initiated to evaluate a biweekly instead of a 4-week schedule of PLD in order to obtain a more flexible and tolerable regimen. PATIENTS AND METHODS A total of 25 patients with 2 or more prior lines of chemotherapy for metastatic disease were treated with PLD (25 mg/m2) at 2-week intervals for a maximum of 12 courses. Pretreatment with anthracyclines was allowed as long as the cumulative doxorubicin dose at study entry was below 400 mg/m2. Most patients were pretreated with anthracyclines, taxanes, vinorelbine, alkylating agents, and capecitabine. RESULTS The clinical benefit rate, ie, objective response or stable disease, for at least 6 months was 22.7% for all patients and 22.2% in anthracycline- and taxane-pretreated patients, respectively. Median duration of clinical benefit and median time to progression were 12.5 months (95% confidence interval [CI], 10.1-32.3) and 7 weeks (95% CI, 5.4-8.6), respectively. Median overall survival was 9.6 months (95% CI, 5.4-13.9). One- and 2-year survival rates were 38% and 4%, respectively. Myelosuppression was low, with no grade 3 or 4 neutropenia or thrombocytopenia. Most common nonhematologic toxicities were nausea, alopecia, asthenia, and hand-foot syndrome. The low rate of hematologic toxicity and hand-foot syndrome is clinically noteworthy. CONCLUSION Biweekly PLD is an easily manageable schedule with a favorable toxicity profile. Efficacy was moderate in heavily pretreated patients.

Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate risk karyotype in first complete remission

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long‐term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) vs. delayed remission (DR) in a cohort of 132 AML patients with an intermediate‐risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3‐yr overall survival (OS) and disease‐free survival (DFS) of 76% vs. 54% (P = 0.03) and 76% vs. 53% (P = 0.03). Likewise, 3 yr after alloSCT the cumulative incidence of relapse (CI‐R) was significantly lower in the ER subgroup as compared to patients achieving DR, that is, 10% vs. 35% (P = 0.004), whereas non‐relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, P = 0.002) and a higher CI‐R (HR 3.55, P = 0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate‐risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT.

Synchronous tuberculosis, Epstein-Barr virus-associated lymphoproliferative disorder and cytomegalovirus infection in an allogeneic transplant recipient: a case report

BackgroundAllogeneic stem cell transplant recipients are prone to infections by various organisms. Tuberculosis (TB) represents a rare infectious complication, especially in countries non-endemic for TB.Case reportHere, we report the case of a German patient with exposure to TB decades before he was diagnosed with disseminated TB as well as synchronous Epstein-Barr virus associated lymphoproliferative disorder and cytomegalovirus infection after allogeneic stem cell transplantation for refractory acute myeloid leukemia. Tuberculostatic and virostatic therapy was administered and the patient could be discharged with no apparent signs of infection two weeks after initiation of therapy.ConclusionThis case illustrates the need for awareness of mycobacterial infections in patients from non-endemic regions undergoing stem cell transplantation even if other reasons for fever are present.