[NON-ALCOHOLIC FATTY PANCREATIC DISEASE (NAFPD) AND THE METABOLIC SYNDROME: INITIATING FACTOR OR ADDITIONAL COMPONENT?].

Nonalcoholic fatty pancreatic disease (NAFPD) integrates the spectrum of chronic clinical and morphological pancreatic changes: steatosis and nonalcoholic steatopancreatitis. NAFPD prevalence in USA was 27.8%, in China--12.9-16%. According to our data, 51.8% of patients with chronic pancreatitis was diagnosed MS. Association NAFPD with MS has been confirmed in most studies, the presence of any components of MS increases the prevalence NAFPD by 37 %. In the NAFPD pathogenesis is important not only excessive intake of free fatty acids (FFA), which leads to the pancreatic parenchyma inflammation and fibrosis, but also "glucolipotoxicity" (i.e., the combined toxicity of hyperglycemia and increased FFA level) for ß-cells. It is shown that NAFPD is an initial index ofectopic fat deposition, and the earlier manifestation of MS than NAFLD. Most likely, a stage (or degree) of the MS is usefully to determine as the pancreatic status--its exo- and endocrine functions, and fat deposition. This approach will allow us to develop new therapeutic approaches not only to treatment but also to the primary prevention of metabolic syndrome.

[Genetic aspects of pancreatic cancer].

The purpose of the review--to analyze the basic data on modifiable and genetic risk factors of pancreatic cancer (PC). PC is the most fatal disease that kills about 95% of patients. Among the known risk factors for PC only for smoking, obesity, and family history a positive association with the PC risk in meta-analyzes confirmed. The PC etiology remains unclear, more than 90% of patients acquire it sporadically. Currently, the most significant genes for PC include KRAS2, p16/CDKN2, TP53, SMAD4/DPC4. Mutations in the KRAS noted in 90% of cases of pancreatic ducts adenocarcinoma. p16/CDKN2A mutation is accompanied by a 38-fold increased risk of PC compared with the general population. TP53 mutations are associated not only with carcinogenesis but also PC metastasis, as well as SMAD4/DPC4 mutations. Study of the role of genetic aspects in the PC development is necessary both to identify individuals with high PC risk, as well as for the development of gene-specific treatments, such as inhibitors of proteins, histone deacetylase, and histone acetyltransferase (vorinostat, belinostat, entinostat, panobinostat, curcumin) are in clinical trials.

[Pancreatitis, pancreatic cancer and obesity: hypothesis and facts].

THE PURPOSE OF THE REVIEW: Analyze the basic data on the role of obesity in the pathogenesis of pancreatic cancer (PC) and the modern mechanisms of this association. RECENT LITERATURE DATA: In the European Union and in Russia incidence of pancreatic diseases increases, such pancreatic cancer (PC) ranks 10th among cancer diseases. Obesity is a risk factor for not only of severe acute pancreatitis, but also PC at that independently of diabetes. In a meta-analysis the PC risk in obese increased by 47%, while the person with a central obesity have a higher PC risk compared to those with a peripheral type of obesity (odds ratio = 1,45, 95% CI: 1,02-2,07), but association between BMI and PC risk in this Japanese population may be different from that in Western populations, sometimes inversely. The link between obesity and PC is explained by insulin resistance and hyperinsulinemia: was proved a direct correlation between the level of circulating C-peptide and PC, low levels of serum adiponektin and leptin increase the PC risk. There are also genetic risk factors for PC: a statistically significant interaction between IVS1-27777C> and IVS1-23525A>T genotypes of the FTO gene with obesity and the PC risk: AA genotype in patients with BMI < 25 kg/m2 reduced PC risk by 22%-28% (p < 0,0001), and with BMI ≥ 25 kg/m2 was associated with 54%-60% increased PC risk (p < 0,0015). Lifestyle factors (smoking, consumption of saturated fats, etc.) increase the PC risk.

Collapsibility of the relaxed pharynx and risk of sleep apnoea.

The present study measured hypotonic pharyngeal collapsibility in subjects not known to have obstructive sleep apnoea (OSA), and assessed the variables that affect collapsibility and the relationship with OSA. The critical value of positive end-expiratory pressure (P(crit)) was measured under the hypotonic condition of anaesthesia in 227 subjects who underwent elective surgery. The risk of OSA in this population was estimated using the Berlin questionnaire. The mean P(crit) for all subjects was positive (above atmospheric), ranging from 0.69 (95% confidence interval (CI) -7.39-8.77) to 4.0 (CI -4.82-12.82) cmH(2)O for subjects with low and high prevalence of OSA, respectively. P(crit) < or = -5 cmH(2)O was only found in 3.1% of the study subjects. In the general population, P(crit) was similar in males and females and correlated positively with increasing age, while a correlation with neck circumference was found only in males. P(crit )accounted for only 12.25% of the variability in OSA risk score. In conclusion, subjects with high critical value of positive end-expiratory pressure are at an increased risk for developing obstructive sleep apnoea. However, the human pharynx is prone to collapse and occludes in most people in the absence of neuromuscular support. Therefore, in most subjects, the level of neuromuscular activity may ultimately determine the occurrence of sleep apnoea.

Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma.

Allogeneic SCT is an effective therapy for lymphoma. Reduced-intensity conditioning (RIC) reduces non-relapse mortality (NRM) associated with myeloablative conditioning but relapse rates are high when performed in active disease. This study was designed to explore the safety and outcome of ibritumomab tiuxetan (Zevalin) combined with RIC in patients with advanced lymphoma. The study included 12 patients, median age 54 years (37-62), with a median of four prior treatments (2-6) and active disease documented on PET-CT. Zevalin 0.4 mCi/kg was given on day -14 and fludarabine combined with BU (n=6) or melphalan (n=6) was started on day -6. GVHD prevention was tapered 3 months after SCT to augment the graft-versus-lymphoma effect. All patients engrafted, a median of 14 days after SCT. Eighty-three percent achieved CR/PR. With a median follow-up of 21 months (12-37), 2-year PFS is 33%. Only three patients relapsed; cumulative incidence 25%. NRM was 42%, predominantly due to acute GVHD. Zevalin-RIC is feasible with consistent engraftment, acceptable organ toxicity, but high rates of acute GVHD. The low incidence of relapse suggests augmented anti-lymphoma effect. Zevalin-RIC merits further study. Better results may be achieved in patients earlier in disease course and with longer duration of immune-suppression.

Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan.

Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft-versus-host disease grade II-IV in 33 and 53%, respectively (P=0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.

[Vessel-platelet and coagulation components of hemostasis in patients with chronic tubulointerstitial nephritis].

AIM: To study vessel-platelet and coagulation parts of hemostasis system, their correlation with clinical characteristics and activity of chronic tubulointerstitial nephritis (CTIN). MATERIAL AND METHODS: 128 patients 15 to 65 years of age with CTIN were included in the study. The diagnosis was confirmed morphologically in 42 patients. The patients were divided into subgroups by activity of the disease at the moment of examination (active and inactive CTIN), by arterial pressure (normotensive and hypertensive patients), intact and low renal function, by duration of the disease (up to 60 months, 61-120 months, more than 120 months). Complex study of hemostasis system was carried out by a set of standard techniques. RESULTS: CTIN runs with activation of vessel-platelet hemostasis characterised by a decrease in platelets count (p < 0.001), persistent platelet hyperaggregation and activation (p < 0.001). Severity of platelet aggregative activity is related with endothelial affection manifesting with high level and activity of Willebrand factor (p < 0.001). The most typical changes of coagulation in CTIN were acceleration of activated partial thrombin time (p < 0.001) closely related with activation of thrombocytic hemostasis and background thrombinemia the presence of which was confirmed by elevated blood level of soluble fibrin-monomeric complexes (SFMC). THE CONCLUSION: Hypercoagulation, suppression of fibrinolytic plasma activity, increase of SFMC and fibrinogen levels in the blood as well as detected enhancement of platelet aggregation testify to a latent course of renal intravascular blood coagulation in CTIN. Hemostasis system activation in CTIN helps assessment of the disease activity.

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55-66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m(2), n=5) or melphalan (100-150 mg/m(2), n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.

Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy: the continuing diagnostic challenge.

A 64 year old man receiving long term amiodarone treatment presented with dyspnea, cough, and weight loss. Radiographs and computed tomography showed a lung mass with associated multiple pulmonary nodules. Biopsies of the pulmonary mass showed foamy histiocytes without malignant cells. However, findings on FDG-PET scan were consistent with a malignant tumour. These findings on computed tomography and PET scan and the unusually late resolution of the pulmonary lesions after withdrawal of amiodarone treatment posed a challenging diagnostic problem.

Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation.

In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.

Mobilized peripheral blood grafts include more than hematopoietic stem cells: the immunological perspective.

Although stem cell mobilization has been performed for more than 20 years, little is known about the effects of mobilizing agents on apheresis composition and the impact of graft cell subsets on patients' outcome. With the increasing use of plerixafor and the inclusion of poor mobilizers in autologous transplant procedures, new parameters other than CD34(+) stem cell dose are emerging; plerixafor seems to mobilize more primitive CD34(+)/CD38(-) stem cells compared with G-CSF, but their correlation with stable hematopoietic engraftment is still obscure. Immune recovery is as crucial as hematopoietic reconstitution, and higher T and natural killer cells infused within the graft have been correlated with better outcome in autologous transplant; recent studies showed increased mobilization of immune effectors with plerixafor compared with G-CSF, but further data are needed to clarify the clinical impact of these findings. In the allogeneic setting, much evidence suggests that mobilized T-cell alloreactivity is tempered by G-CSF, probably with the mediation of dendritic cells, even though no clear correlation with GVL and GVHD has been found. Plerixafor is not approved in healthy donors yet; early data suggest it might mobilize a GVHD protective balance of immune effectors, but further studies are needed to define its role in allogeneic transplant.

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies.

Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease.

Assessment of the coagulation profile in hemato-oncological patients receiving ATG-based conditioning treatment for allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is increasingly used in pre-allogeneic stem cell transplantation (allo-SCT) conditioning regimens to prevent graft rejection and graft-versus-host disease. However, ATG was also found to be associated with increased incidence of thrombosis during organ transplantation. In the present study, we tested the coagulation status of 21 patients with hematologic malignancies undergoing allo-SCT who received ATG-based (11 patients) or non-ATG-based (10) conditioning treatment. We assessed several thrombophilia markers as well as circulating total and endothelial microparticles (TMP/EMP) and soluble CD40 ligand (CD40L). No significant difference in the mean values of prothrombin time, partial thromboplastin time, fibrinogen, antithrombin, protein C, protein S, thrombin-antithrombin III complex, homocysteine levels, prevalence of genetic thrombophilia markers and levels of EMP, TMP or CD40L was observed between the ATG-treated and ATG-untreated patients, as well as before and after conditioning in each group separately. Platelet counts decreased significantly in ATG-treated patients; however, this decrease was not associated with clinical or laboratory evidence of disseminated intravascular coagulation. No patient developed thromboembolic event or veno-occlusive liver disease. Our results suggest that allo-SCT is not associated with increased hypercoagulability and addition of ATG to conditioning regimen has no significant procoagulant effect.

[Recording nocturnal erections following injuries and insurance claims: cost-effectiveness].

Road accidents, work accidents, or other trauma can cause impotence and are frequently followed by insurance claims. During 1990-97 we examined 230 males with such a complaint. All underwent full polysomnographic recordings in the sleep laboratory for 2 nights, during the course of which NPT (nocturnal penile tumescence) was examined with special equipment. It was assessed by an experienced technician following planned awakenings from REM sleep. In 75 of the 230 subjects (33%), satisfactory erections were observed. In 100 (43%), who experienced at least 3 periods of REM sleep, no erections occurred. These patients were categorized as suffering from organic impotence. In the remaining 55 (24%), the results were inconclusive, with only partial erections or not enough REM sleep periods. Since a man recognized as suffering from impotence may be awarded large monthly payments for life, these examinations, in our opinion, are an important tool to prevent unjustified claims, and can save the state unnecessary expenses.

[Long-term remission of the nephrotic syndrome in renal amyloidosis]. / Dlitel'naia remissiia nefroticheskogo sindroma pri amiloidoze pochek.

The authors presented the results of a clinical study of an atypical course of secondary renal amyloidosis developing in a patient with pulmonary tuberculosis and progressing against a background of chronic post-tuberculosis bronchitis. The disease manifested itself in the acute development of the nephrotic syndrome which could be arrested as a result of tuberculostatic therapy. Clinico-laboratory signs of the disease were absent for 20 yrs., then arterial hypertension and chronic renal failure accompanied by minimum proteinuria, developed. The diagnosis of renal amyloidosis was confirmed by nephrobiopsy. Considerable difficulties arose in differential diagnosis with glomerulonephritis in such a clinical course.

[Myeloma-related nephropathy (incidence, clinical aspects and morphology). Analysis of 95 cases of multiple myeloma]. / Mielomnaia nefropatiia (chastota razvitiia, klinika, morfologiia). Analiz 95 sluchaev mnozhestvennoi mielomy.

The authors provided the results of observations of 95 patients with multiple myeloma (MM). Signs of renal involvement in that period were detected in 79% of the patients. The authors analyzed the frequency of various symptoms of myelogenic nephropathy (MN) and its evolution. The comparison of clinicolaboratory findings and the nature of morphological changes of the renal tissue in the MN patients made it possible to define 3 stages in MN development. When the predominance of renal symptomatology made the diagnosis of MM difficult, puncture nephrobiopsy was recommended. It can be performed in the absence of marked hyperproteinemia and hemostatic disorders.

[Precursor thymus-dependent lymphocytes in variants of chronic glomerulonephritis]. / Prekursornye timuszavisimye limfotsity pri raznykh variantakh khronicheskogo glomerulonefrita.

Altogether 67 patients with chronic glomerulonephritis (CGN) were examined for the content of thymus-dependent precursor lymphocytes (auto-RFC, pre-T-cells). The patients suffering from CGN were characterized by the high content of the young post-thymic T-cells (auto-RFC) and high affinity T lymphocytes carrying a receptor for the Fc fragment of IgM as compared to normal donors. In patients with different clinical patterns of CGN, an analysis was made of the content of precursor thymus-dependent lymphocytes. A relationship was discovered between the content of pre-T-cells and the activity of the nephritic process. The activity of the pathological process was associated with the high content of precursor lymphocytes. The inactive course of nephritis was characterized by a well-defined reduction of the number of precursor cells. This might be regarded as depletion of the amount of precursor lymphocytes.

[The immediate results of using plasmapheresis in patients with chronic glomerulonephritis]. / Blizhaishie rezul'taty primeneniia plazmafereza u bol'nykh khronicheskim glomerulonefritom.

A study was made of the effect produced by a short-term course of plasmapheresis (PA) combined with cytostatic, glucocorticoid and deaggregation therapy on the clinico-laboratory characteristics in 45 patients suffering from chronic glomerulonephritis (CGN). It has been established that PA rapidly normalizes the characteristics such as the level of circulating immune complexes and fibrinogen in the blood, ESR. Exerting no effect on renal function, PA led to a significant lowering of proteinuria and erythrocyturia, with its beneficial effects being preserved after discontinuation of the sessions. The best results were attained in associated CGN and nephrotic syndrome, in mesangioproliferative and mesangiocapillary CGN. The effectiveness of the short-term course of PA in patients with membranous and diffuse fibroplastic CGN turned out questionable.