Endocrine dysregulation in aneurysmal subarachnoid haemorrhage.

INTRODUCTION: Aneurysmal Subarachnoid haemorrhage (aSAH) is one of the most common causes of neurocritical care admission. Consistent evidence has been suggestive of endocrine dysregulation in aSAH. This review aims to provide an up-to-date presentation of the available evidence regarding endocrine dysregulation in aneurysmal subarachnoid haemorrhage. METHODS: A comprehensive literature search was performed using PubMed database. All available evidence related to endocrine dysregulation in hypothalamic-pituitary hormones, adrenal hormones and natriuretic peptides after aSAH, published since 2010, were reviewed. RESULTS: There have been reports of varying prevalence of dysregulation in hypothalamic-pituitary and adrenal hormones in aSAH. The cause of this dysregulation and its pattern remain unclear. Hypothalamic-pituitary and adrenal dysregulation have been associated with higher incidence of poor neurological outcome and increased mortality. Whilst there is evidence that long-term dysregulation of these axes may also develop, it appears to be less frequent than the acute-phase dysregulation and transient in pattern. Increased levels of catecholamines have been reported in the hyper-acute phase of aSAH with reported inconsistent correlation with the outcomes and the complications of the disease. There is growing evidence that of a causal link between the endocrine dysregulation and the development of hyponatraemia and delayed cerebral ischaemia, in the acute phase of aSAH. However, the pathophysiological mechanism and pattern of endocrine dysregulation which could be causally associated with these complications still remain debatable. CONCLUSION: The evidence, mainly from small observational and heterogeneous in methodology studies, is suggestive of adverse effects of the endocrine dysregulation on the outcome and the incidence of complications of the disease. However, the cause of this dysregulation and a pathophysiological mechanism that could link its presence with the development of acute complications and the outcome of the aSAH remain unclear. Further research is warranted to elucidate the clinical significance of endocrine dysregulation in subarachnoid haemorrhage.

Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers.

PURPOSE: Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect "immunocompetent" seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. METHODS: This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ, interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. RESULTS: During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. CONCLUSIONS: Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome.

Yeast central nervous system infection in a critically ill patient: a case report.

INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.

Coronary flow reserve is associated with tissue ischemia and is an additive predictor of intensive care unit mortality to traditional risk scores in septic shock.

BACKGROUND: Reduced coronary velocity flow reserve (CFR) is associated with poor outcome in patients with cardiovascular disease. We investigated whether CFR is associated with tissue ischemia and acidosis, impaired myocardial deformation and adverse outcome in patients with septic shock. METHODS: In 70 mechanically-ventilated patients with septic shock, we examined: a) S' and E' mitral annular velocities using tissue Doppler imaging (TDI), b) CFR of the left anterior descending artery after adenosine infusion using transesophageal Doppler echocardiography and c) lactate, pyruvate and glycerol in tissue by means of a microdialysis (MD) catheter inserted into the subcutaneous adipose tissue as markers of tissue ischemia and acidosis. SOFA and APACHE II prognostic scores and mortality in the intensive care unit (ICU) were recorded. RESULTS: Reduced CFR, S' and E' as well as increased E/E' correlated with increased SOFA, APACHE II and MD lactate to pyruvate ratio (p<0.05 for all correlations). Impaired TDI markers also correlated with increased MD glycerol (p<0.05). Reduced CFR correlated with decreased E' (p<0.05). CFR was 1.8 ± 0.42 in non-survivors (n=34) versus 2.08 ± 0.44 in survivors (p=0.007). A CFR<1.90 predicted mortality with sensitivity of 70% and specificity of 69% (area under the curve 77%; p=0.003). CFR had an additive value to APACHE (chi-square change: 4.358, p=0.03) and SOFA (chi-square change: 3.692, p=0.04) for the prediction of mortality. CONCLUSION: Tissue ischemia and acidosis is a common pathophysiological link between decreased CFR and impaired LV myocardial deformation in septic shock. CFR is an additive predictor of ICU mortality to traditional risk scores in septic shock.

L-asparaginase fatal toxic encephalopathy during consolidation treatment in an adult with acute lymphoblastic leukemia.

PATIENT: Male, 51 FINAL DIAGNOSIS: Encephalopaty toxic Symptoms: Confusion • disorientation • drowsiness • fever MEDICATION: L-asparaginase Clinical Procedure: - Specialty: Oncology. OBJECTIVE: Unknown ethiology. BACKGROUND: Novel therapies have improved survival in malignancies of lymphoid origin. This improvement, however, has been at the cost of chemotherapy-related toxicities. L-asparaginase is frequently included in combination chemotherapies for acute lymphoblastic leukemia. Its use is frequently limited by significant adverse effects, such as coagulation abnormalities and cerebrovascular complications. L-asparaginase-associated encephalopathy is most often observed during the induction phase of chemotherapy and usually carries a favorable prognosis. CASE REPORT: We describe the profile of an adult with acute lymphoblastic leukemia treated with L-asparaginase, who developed toxic leukoencephalopathy during the second phase of consolidation treatment. He presented with decreased level of consciousness, which progressed to deep coma and finally brain death. MRI disclosed extensive lesions, consistent with toxic encephalopathy. CONCLUSIONS: Even mild neurological symptoms should raise suspicion of these possibly fatal chemotherapy related toxicities.

Association of ERCC1 SNPs with outcome in platinum-treated patients with advanced urothelial cancer: a Hellenic Cooperative Oncology Group study.

AIM: The association between two polymorphisms of ERCC1 and treatment outcomes after platinum-based chemotherapy in patients with advanced urothelial cancer (UC) was examined. MATERIALS & METHODS: Genotyping of 19007C>T and 8092C>A polymorphisms was determined by PCR amplification and RFLP in 113 advanced UC patients, treated with platinum-based chemotherapy. RESULTS: Seventy eight patients (69%) were carriers of the 19007T polymorphic allele: 51 (45%) heterozygotes and 27 (24%) homozygotes. Fifty three (47%) patients were carriers of the 8092A polymorphic allele: the frequencies of C/A and A/A genotypes were 37% and 10%, respectively. The T/T genotype was independently associated with prolonged median cancer-specific survival (not-reached vs 14.8 months; p = 0.026). There was no interaction between T/T or any other genotype with the type of platinum derivative (cisplatin/carboplatin). CONCLUSION: 19007C>T, especially in its homozygotic state, but not 8092C>A polymorphism, could be a useful prognostic marker in advanced UC treated with platinum-based chemotherapy.

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis.

BACKGROUND: The aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer. METHODS: Patients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-ß1 and VEGF-A were measured at baseline and during treatment. RESULTS: Among 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3-4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS. CONCLUSIONS: This trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. ( REGISTRATION NUMBER: ACTRN12610000270011).

Serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels.

PURPOSE: The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels. MATERIALS AND METHODS: An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls. RESULTS: The patients had higher adiponectin (10.9 ± 6.1 µg/mL vs 6.0 ± 2.9 µg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted. CONCLUSIONS: Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis.

Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression.

UNLABELLED: The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation. BACKGROUND: Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer. METHODS: A total of 595 patients with high risk, [corrected] early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2). RESULTS: CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively). CONCLUSIONS: The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2(+) disease.

Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents.

Multiple myeloma (MM) comprises 1% of all malignancies and 13% of hematological malignancies in the Caucasian population. Yearly incidence is 4/100,000 in the US and is higher in blacks and males [1]. The pathogenesis of the disease is relatively unknown; several chromosomal abnormalities have been related to the development of the disease,but none is characteristic of MM. Cyclin-D1 is a protein encoded by the CCND1 (bcl-1) gene on chromosome 11q13, and is an important regulator of G1 to S phase progression.

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents.

The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.

Renal impairment is not an independent adverse prognostic factor in patients with multiple myeloma treated upfront with novel agent-based regimens.

Abstract Renal impairment (RI) is a common presenting complication of multiple myeloma associated with significant morbidity and early mortality, while it has been associated with inferior survival in patients treated with conventional regimens. We assessed the impact of RI in 203 unselected consecutive patients treated upfront with novel agents (thalidomide, lenalidomide, bortezomib). RI was assessed by the estimated glomerular filtration rate (eGFR). RI (eGFR <60 mL/min) was present in 93 (45.8%) of patients at diagnosis and was associated with advanced age, advanced International Staging System (ISS) stage, poorer performance status, hypercalcemia, urine Bence-Jones proteinuria, anemia and thrombocytopenia. Myeloma response rates were similar for patients with or without RI. In univariate analysis RI was associated with shorter survival and a higher rate of early death (7% vs. 3.5%); however, when adjusted for other prognostic factors, RI was not independently associated with survival. In conclusion, in unselected newly diagnosed patients treated with novel agent-based therapies, RI is not independently associated with inferior survival, probably due to the significant activity of novel agents even in the context of RI.

Increased serum lactate dehydrongenase should be included among the variables that define very-high-risk multiple myeloma.

BACKGROUND: In patients who have symptomatic multiple myeloma (MM), a high serum lactate dehydrogenase (LDH) level is associated with features of advanced disease, adds prognostic value to the international staging system (ISS) and predicts for inferior survival. However, it has not been clearly defined what the impact of this abnormality is for patients treated upfront with novel agent-based regimens. PATIENTS AND METHODS: To address this issue we analyzed 203 consecutive unselected patients with symptomatic MM who received upfront treatment with novel agents in a single center. RESULTS: The median overall survival for patients with normal LDH was 54 months but in patients with increased LDH levels it was 21 months (P = .003), whereas increased serum LDH was associated with a higher probability of early death. Multivariate analysis confirmed that an increased LDH level is independently associated with poor survival. Furthermore, increased LDH levels could identify subgroups of patients within ISS-2 and ISS-3 with even worse outcome. CONCLUSION: We conclude that serum LDH is a simple, inexpensive, and readily available blood test that may be included among the variables that define very-high-risk MM.

Short progression-free survival predicts for poor overall survival in older patients with multiple myeloma treated upfront with novel agent-based therapy.

OBJECTIVES: To assess the importance of the quality of response and of early relapse in unselected elderly patients with myeloma treated upfront with novel agents. METHODS: We analyzed 135 unselected transplant-ineligible patients older than 65 yr who were treated upfront with novel agent-based regimens in a single center. RESULTS: On intent to treat, 81% of patients achieved a response (28% sCR/CR, 23% VGPR, and 30% PR). Median progression-free survival (PFS) for patients who achieved sCR/CR was 31 vs. 20 months for VGPR and 23 months for PR (P = 0.048). Median overall survival (OS) for patients with sCR/CR was 62 months, 53 months for VGPR and 38 months for patients with PR (P = 0.028). Early relapse (PFS < 12 months) was more common in patients with PR (39% vs. 21% for VGPR vs. 3% for sCR/CR). Patients who relapsed or progressed < 12 months from initiation of treatment had a median OS of 15.4 months compared with 53 months (P < 0.001) for patients who had a PFS > 12 months despite the fact that after relapse or progression most patients were treated again with novel agents. In multivariate analysis, short PFS was the most significant adverse prognostic factor affecting OS, associated with a 7.25-fold (P < 0.0001) increase in the risk of death. CONCLUSION: In newly diagnosed patients over 65 yr, treated upfront with novel agents achievement of CR and a PFS ≥ 12 months is associated with improved outcome. Patients who fail to respond or experience early relapse after primary therapy with novel agent-based regimens should be encouraged to participate in clinical trials of novel agents and combinations.

Burkitt's lymphoma in pregnancy with bilateral breast involvement: case report with review of the literature.

BACKGROUND: Burkitt's lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far. CASE REPORT: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable. CONCLUSIONS: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach.

Endometrial cancer: what is new in adjuvant and molecularly targeted therapy?

Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after staging surgery. The prognosis of patients with metastatic disease remains disappointing with only one-year survival. Progestins represent an effective option, especially for those patients with low-grade estrogen and/or progesterone receptor positive disease. Chemotherapy using the combination of paclitaxel, doxorubicin, and cisplatin is beneficial for patients with advanced or metastatic disease after staging surgery and potentially for patients with early-stage disease and high-risk factors. Toxicity is a point in question; however, the combination of paclitaxel with carboplatin may diminish these concerns. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Our increased knowledge of the molecular aspects of endometrial cancer biology has paved the way for clinical research to develop novel targeted antineoplastic agents (everolimus, temsirolimus, gefitinib, erlotinib, cetuximab, trastuzumab, bevacizumab, sorafenib) as more effective and less toxic options. Continued investigation into the molecular pathways of endometrial cancer development and progression will increase our knowledge of this disease leading to the discovery of novel, superior agents.