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Little is known about quality of care for patients with myelodysplastic syndromes (MDS), or patient and provider factors that influence quality. We identified Medicare enrollees diagnosed with MDS between 2006 and 2011, and analysed linked claims for performance on two widely-accepted quality measures: diagnostic bone marrow cytogenetic testing (diagnostic quality) and pre-treatment iron assessment for patients receiving an erythropoiesis-stimulating agent (ESA; treatment quality). A total of 4575 patients met the criteria for diagnostic quality measurement, and 3379 for treatment quality measurement. In the diagnostic cohort, 74% had a claim for marrow cytogenetic testing 3 months before to 3 months after diagnosis. In multivariate models, younger age (P < 0·001), treatment at a higher-volume MDS centre (P < 0·001), and claims for pancytopenia (P < 0·001) were all associated with higher levels of testing. A borderline result was observed for diagnostic year, with improvement over time (P = 0·06). In the treatment cohort, 56% had evidence of pre-ESA iron assessment, with higher rates for later years of diagnosis (P < 0·001), higher household income (P = 0·03), and those treated at higher-volume centres (P = 0·01). In this large cohort of patients with MDS, quality of care was suboptimal overall, but worse in several specific subgroups. These data suggest that targeted educational and/or process-focused interventions are warranted., (© 2016 John Wiley & Sons Ltd.)

Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0·004) corresponded to a hazard ratio of 3·48 [95% confidence interval: (1·42-8·53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0·026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2·0 [0·7-5·6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction., (2011 Blackwell Publishing Ltd.)

Waldenström macroglobulinaemia is a low-grade, lymphoplasmacytic lymphoma that is responsive to rituximab. We report the role of a minor response in predicting overall outcomes. We extended follow-up of a previously described cohort (n = 69) treated with 4 weekly doses of rituximab and observed durable responses (median time to progression, 30 months; 5-year survival rate, 66%). Patients achieving a minor response [25-50% immunoglobulin M (IgM) reduction] appeared to do as well as those achieving an objective response (>50% IgM reduction), which suggests that more aggressive or intensive therapy for minor responders is not required. Future studies of Waldenström macroglobulinaemia should report minor responses because they are associated with clinically meaningful benefits. This trial was registered at http://www.clinicaltrials.gov as #NCT00005609.

The phenotype of peripheral blood mononuclear cells (PBMC) was examined in 13 healthy volunteers, 26 HTLV-I carriers, and 58 ATL patients (22 smouldering, five chronic, 24 acute, and seven lymphoma type). The percentage of CD4+, CD25+, CD28+ and CD45RO+ cells in the PBMC of the chronic and acute type patients was significantly higher than that of the volunteers, whereas the percentage of CD8+ and CD45RA+ cells in these patients was significantly low. The histogram for CD45RO fluorescence intensity (FI) revealed two patterns: pattern A consisted of CD45RO+ cells with high FI (CD45ROhigh) and intermediate FI (CD45ROint). Pattern B consisted exclusively of CD45ROhigh. Pattern A was evident in all volunteers. The percentage of subjects showing pattern B was increased in an order that reflected disease progression. In the patients with pattern A, the CD45ROint cells were CD4+ and CD8-, and the FI of CD2, CD3, and Fas within the CD45ROint cells appeared to be lower than that within the CD45ROhigh cells. The acute type patients with pattern A had a significantly longer survival curve than that of these patients with pattern B. These results suggest that the presence of CD45ROint cells may be related to protection against disease progression in HTLV-I-infected individuals.

The Hodgkin lymphoma International Study for Individual Care (HoLISTIC) Consortium's A-HIPI model, developed in 2022 for advanced-stage classical Hodgkin lymphoma (cHL), predicts survival within 5 years amongst newly diagnosed patients. This study validates its performance in the Brazilian Hodgkin lymphoma registry. By 2022, the Brazilian HL registry included 1357 cHL patients, with a median 5-year follow-up. Probabilities for 5-year progression-free survival (PFS) and overall survival (OS) were calculated using A-HIPI-model equations. Discrimination (Harrell C-statistic/Uno C-statistic) and calibration measures assessed external validation and calibration. Lab values beyond the allowed range were excluded, mirroring the initial A-HIPI analysis. A total of 694 advanced-stage cHL patients met the original inclusion criteria (age 18-65 years, Stage IIB-IV). Median age was 31 years; 46.3% were females. Stage distribution was IIB (33.1%), III (27.4%), IV (39.5%). Bulky disease in 32.6%. Five-year PFS and OS were 68.4% and 86.0%, respectively. Harrell C-statistics were 0.60 for PFS and 0.69 for OS, and Uno C-statistics were 0.63 for PFS and 0.72 for OS. Calibration plots demonstrated well-calibrated predictions with calibration slopes of 0.91 and 1.03 for 5-year OS and PFS, respectively. Despite differing patient, clinical characteristics, and socioeconomic factors, the baseline prediction tool performed well in the Brazilian cohort, demonstrating adequate discrimination and calibration. This supports its reliability in diverse settings., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

A shared decision on the most appropriate agent for the treatment of cancer-associated thrombosis should consider the following factors, which should be reassessed as patients continue along their cancer care pathway: risk of bleeding; tumour site; suitability of oral medications; potential for drug-drug interactions; and patient preference and values regarding choice of drug. Continuing anticoagulation beyond 6 months in patients with cancer-associated venous thromboembolism and active cancer is recommended., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Summary: Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)‐based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy‐related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30‐ and 90‐day mortality between DR and non‐DR patients. Furthermore, DR did not affect median relapse‐free survival (RFS) [DR, 14.5 (95% confidence interval, 9.0–41.7) months; non‐DR, 15.0 (12.3–19.3)] with an adjusted difference in five‐year restricted mean survival time (Δ5y‐RMST) of 0.2 (−8.4 to 8.8) months nor median OS (DR, 17.0 [11.9 to 45.5] months; non‐DR, 17.5 [14.8 to 20.5]) with an adjusted Δ5y‐RMST of 0.8 (−5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject. [ABSTRACT FROM AUTHOR]

Summary: Older patients with cancer often receive treatment regimens based on their age without considering other objective factors that may influence outcomes. Assessment of frailty can identify older patients who are robust and therefore more likely to benefit from intensive treatment, or conversely, frail and might instead be offered alternative approaches. However, such assessment requires specialised training and dedicated clinical resources. Alternative quantitative biomarkers associated with frailty are lacking. Here, we asked if expression signatures of 74 immune cell, ageing, and senescence‐related messenger RNAs in purified peripheral blood T cells could identify associations with clinical frailty in patients with haematological malignancies. We studied 69 patients between the ages of 36 and 92 years (median 76 years) with leukaemia, lymphoma, or multiple myeloma, across two institutions. Expression of four genes (aryl hydrocarbon receptor [AHR], CD27, CD28, and interleukin‐2 receptor subunit alpha [IL2RA; CD25]) in T cells was associated with frailty, independent of age. An expression‐based regression model had 76% sensitivity and 90% specificity to assign a patient as robust. These data identify measurable peripheral blood correlates of clinical frailty and suggest biomarkers for future prospective assessment. [ABSTRACT FROM AUTHOR]

Summary: Cancer‐associated venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. Treatment of cancer‐associated VTE comes with a heightened risk of anticoagulant‐related bleeding that differs by choice of anticoagulant as well as by patient‐ and disease‐specific risk factors. Available data from randomized controlled trials and observational studies in cancer‐associated VTE suggest that direct oral anticoagulants are effective, continuing anticoagulation beyond six months is indicated in those with active cancer and that patients who develop 'breakthrough' thrombotic events can be effectively treated. We review the evidence that addresses these key clinical questions and offer pragmatic approaches in individualizing care. While significant investigative efforts over the past decade have made impactful advances, future research is needed to better define the factors that contribute to anticoagulant‐related bleeding and VTE recurrence, in order to aid clinical decision‐making that improves the care of patients with cancer‐associated VTE. [ABSTRACT FROM AUTHOR]

Gene expression profiling predicts relapse-free and overall survival in newly diagnosed myeloma patients treated with novel therapies In addition, the LR FISH/HR GEP had a relapse rate at 12 months of 30% (3/12 patients) I versus i 0% in patients with LR GEP/HR FISH (0/8 patients; B Table b IA B ) b . Patients with HR GEP/HR FISH demonstrated reduced RFS and OS when compared to LR GEP/FISH with HR GEP being the best predictor of early RFS. For example, patients with HR GEP had a death rate due to multiple myeloma (MM) of 21% (HR GEP/HR FISH), 25% (HR GEP/LR FISH), 0% (LR GEP/HR FISH) and 6% (LR GEP/LR FISH) ( I P i = 0-03; B Table b IB B ) b . [Extracted from the article]

Summary: Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno‐occlusive disease (VOD), remains a multi‐organ system complication following haematopoietic cell transplantation (HCT). When SOS/VOD is accompanied by multi‐organ dysfunction, overall mortality rates remain >80%. However, the definitions related to the diagnosis and grading of SOS/VOD after HCT are almost 25 years old and require new and contemporary modifications. Importantly, the pathophysiology of SOS/VOD, including the contribution of dysregulated inflammatory and coagulation cascades as well as the critical importance of liver and vascular derived endothelial dysfunction, have been elucidated. Here we summarise new information on pathogenesis of SOS/VOD; identify modifiable and unmodifiable risk factors for disease development; propose novel, contemporary and panel opinion‐based diagnostic criteria and an innovative organ‐based method of SOS/VOD grading classification; and review current approaches for prophylaxis and treatment of SOS/VOD. This review will hopefully illuminate pathways responsible for drug‐induced liver injury and manifestations of disease, sharpen awareness of risk for disease development and enhance the timely and correct diagnosis of SOS/VOD post‐HCT. [ABSTRACT FROM AUTHOR]

Summary: For patients with untreated hepatic veno‐occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi‐organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide‐treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post‐HCT benefitted from defibrotide. [ABSTRACT FROM AUTHOR]

Summary: Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life‐threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient‐ and disease‐related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro‐inflammatory and pro‐apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post‐HCT conditions, including veno‐occlusive disease/sinusoidal obstruction syndrome, graft‐versus‐host disease, transplant‐associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT‐related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT. [ABSTRACT FROM AUTHOR]

Summary: Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T‐IND study was similar to previous reports. [ABSTRACT FROM AUTHOR]

The management of Waldenström macroglobulinaemia ( WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide ( DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88 WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate ( ORR) was 87%. The median progression-free survival ( PFS) and time-to-next-therapy ( TTNT) were 32 (95% confidence interval [ CI]: 15-51) and 50 (95% CI: 35-60) months, respectively. In the previously untreated cohort ( n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23-not reached [ NR]) and NR (95% CI: 37- NR), respectively. Twenty-five (86%) of 29 genotyped patients harbored MYD88L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well-tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients' MYD88 status. [ABSTRACT FROM AUTHOR]

Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes ( MDS). We investigated the predictive value of these factors on overall survival ( OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia ( CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System ( IPSS-R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age-adjusted IPSS-R, frailty (Hazard ratio 2·7 (95% confidence interval [ CI] 1·7-4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1-2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS-R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. Trial Registration: Identifier: NCT02537990. [ABSTRACT FROM AUTHOR]

Sinusoidal obstruction syndrome ( SOS), also called veno-occlusive disease of the liver, is one of the most relevant complications of endothelial origin that appears early after haematopoietic cell transplantation ( HCT). Despite its relatively low incidence and the fact that most cases of SOS resolve spontaneously, the cases that evolve to multi-organ failure ( MOF; severe SOS) have a mortality rate higher than 80% and represent one of the major clinical problems after HCT. For this reason, transplantation teams must have a pre-established policy regarding preventive measures in high-risk patients, strict daily control of weight and fluid balance during HCT, homogeneous diagnostic criteria, appropriate complementary studies for a correct differential diagnosis and measures to prevent and manage hepatorenal syndrome; in addition they must also be ready to start early treatment with defibrotide in patients with a possible severe SOS. Due to the lack of definitive evidence to enable the establishment of general recommendations in the management of SOS, this review analyses all of these aspects based on the author's personal experience. [ABSTRACT FROM AUTHOR]

The article presents guidelines on the management and diagnosis of Waldenström macroglobulinaemia. Topics discussed include screening for hepatitis B viruses, assessing bone marrow aspirate and trephine biopsy and conducting studies for anti-myelin-associated glycoprotein (MAG) serology and nerve conduction. Other topics discussed include not using rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP-R) as primary therapy and using plasma exchange for patients.

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haema-tology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) has reviewed the available litera-ture and made recommendations for the diagnosis and management of veno-occlusive disease of the liver following haematopoietic stem cell transplantation (HSCT). This guideline includes recommendations for both prophylaxis and treatment of the condition and includes recommenda-tions for children and adults undergoing HSCT. [ABSTRACT FROM AUTHOR]

The gene expression profiles ( GEPs) of 96 selected genes were analysed by real-time quantitative polymerase chain reaction (q PCR) with a Taq Man low-density array card in isolated tumour plasma cells ( PCs) from 157 newly diagnosed multiple myeloma ( MM) patients. This q PCR-based GEP correctly classified cases following the Translocation-cyclin D classification. Classic prognostic parameters and q PCR-based GEP predicted MM patient outcome and, although multivariate analyses revealed that cytogenetic risk (standard vs. high risk) was the variable that most strongly predicted prognosis, GEP added significant information for risk stratification. Considering only the standard risk cytogenetic patients, multivariate analyses revealed that high β2-microglobulin, low CDKN1A and high SLC19A1 gene expression levels independently predicted a short time-to-progression ( TTP), while high International Staging System stage, low CDKN2B and high TBRG4 gene expression predicted poor overall survival ( OS). A gene expression risk score enabled the division of standard risk patients into two groups with different TTPs (83% vs. 38% at 3 years, P < 0·0001) and OS rates (88% vs. 61% at 5 years; P = 0·003). This study demonstrates that quantitative PCR is a robust, accurate and feasible technique for implementing in the daily routine as a surrogate for GEP-arrays. [ABSTRACT FROM AUTHOR]

Novel treatments for multiple myeloma ( MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population-based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988-96 (conventional therapy), 1997-05 (high dose melphalan and autologous transplant), and 2006-09 (novel agents era). Both relative survival ( RS) and overall survival ( OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997-05 and 2006-09 compared with previous years and a trend to improvement was observed from 1997-05 to 2006-09. For patients aged 65-74 years, RS improved significantly in 2006-09 compared with 1988-96 and 1997-05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65-74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice. [ABSTRACT FROM AUTHOR]

In this review, the key issues that pertain to Waldenström disease are discussed in a concise question-and-answer format. Diagnosis, prognosis, and indications for state-of-the-art therapy are updated. Current therapies presented at the 7th International Workshop for Waldenström Macroglobulinaemia are included. [ABSTRACT FROM AUTHOR]

Single cell network profiling ( SCNP) is a multi-parameter flow cytometry technique for simultaneous interrogation of intracellular signalling pathways. Diagnostic paediatric acute myeloid leukaemia ( AML) bone marrow samples were used to develop a classifier for response to induction therapy in 53 samples and validated in an independent set of 68 samples. The area under the curve of a receiver operating characteristic curve ( AUCROC) was calculated to be 0·85 in the training set and after exclusion of induction deaths, the AUCROC of the classifier was 0·70 ( P = 0·02) and 0·67 ( P = 0·04) in the validation set when induction deaths (intent to treat) were included. The highest predictive accuracy was noted in the cytogenetic intermediate risk patients ( AUCROC 0·88, P = 0·002), a subgroup that lacks prognostic/predictive biomarkers for induction response. Only white blood cell count and cytogenetic risk were associated with response to induction therapy in the validation set. After controlling for these variables, the SCNP classifier score was associated with complete remission ( P = 0·017), indicating that the classifier provides information independent of other clinical variables that were jointly associated with response. This is the first validation of an SCNP classifier to predict response to induction chemotherapy. Herein we demonstrate the usefulness of quantitative SCNP under modulated conditions to provide independent information on AML disease biology and induction response. [ABSTRACT FROM AUTHOR]

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia ( WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M ( IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials. [ABSTRACT FROM AUTHOR]

Deals with the hemostatic effect of desmopressin (DDAVP) in patients with moderate or mild hemophilia A and von Willebrand's disease. Advantage of DDAVP for children; Details on the use of DDAVP in hemorrhagic situations; Mechanism of action of DDAVP.