ON THE ORIGIN OF LUNG CANCER DEVELOPMENT.

In the review on the issues of histogenesis of lung cancer (LC), the significant results of experimental, pathological, immunohistochemical and molecular-biological studies are presented. However, until now, no data has been obtained that would allow scientists to come to an unambiguous decision about the origin and development of this disease. The question remains not yet fully understood, since researchers discuss the origin of LC development in a hypothetical form. This situation poses the task of further in-depth scientific research, which would make it possible to clarify the unambiguous origin of LC development, and, therefore, would allow solving the problem of its early diagnosis and create grounds for screening programs, which is of high scientific and clinical significance.

Histogenesis of central lung cancer: cytological investigation.

AIM: To study the features of the bronchial mucosa lesion in relation to centrally growing lung cancer (LC) according to diagnostic fibrobronchoscopy in comparison with the results of cytomorphological data to determine the possible origin of tumor growth (histogenesis). PATIENTS AND METHODS: The data of fibrobronchoscopy and cytological findings based on the materials of 75 patients with a clinical diagnosis of LC were studied and compared. By the sum of the numerous cytomorphological features of epithelial cells and their components, the cells of the cylindrical epithelium and LC of various histological types were identified. The cells in bronchial smears and bronchial lavage were stained by Pappenheim and Papanicolau. Diagnostic material was examined by light microscopy. RESULTS: We have found that in a part of the patients (49%), the tumors with exophytic growth in the bronchus are covered with a cylindrical epithelium, which indirectly indicates the origin of cancer growth under the epithelial layer. In cytological preparations of 51% patients, cancer cells were found, which confirms the tumor invasion into the bronchial mucosa. In 48 (64%) patients, fibrobronchoscopy revealed that the examined bronchus was compressed from 50% to pinpoint width, evidencing that tumor growth develops from the outside, peribronchially. CONCLUSION: The obtained data indirectly confirm the development of central LC from type II pneumocytes, which are found in the glands of the submucous membrane of the bronchus. However, it does not exlude the development of this type of LC from the basal cell of the bronchial epithelium.

[Factors affecting the survival of patients with peritoneal carcinomatosis of colorectal origin]. / Faktory prognoza vyzhivaemosti bol'nykh, operirovannykh po povodu peritoneal'nogo kartsinomatoza pri rake tolstoi kishki.

One of the main problems in the treatment of peritoneal carcinomatosis (PC) in colorectal cancer (CRC) is the adequate selection of patients for cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AIM: To determine the predictive factors of overall (OS) and disease-free survival (DFS) in CRC patients with PC after CS with HIPEC. MATERIAL AND METHODS: From 2010 to 2018 years 102 patients with CRC and PC were included in the study. The cytoreduction was complete (CC0, according to Sugabaker scale) in 96 (94.2%) cases. The age median of patients was 65 years. There were 63 (62%) women. In 81 (79%) patients, the PC was synchronous. The median level of CEA was 8.5 ng/ml. The median peritoneal carcinomatous index (PCI) was 3 (1-23). RESULTS: The median of follow-up was 18 (11; 33) months. The median of DFS and OS were 13 (9;31) and 32 (17; n/d) months, respectively. Multifactorial Cox-regression analysis showed the localization of the primary tumor in the right colon (OR=1.66; 95% CI 1.1-2.5; p=0.013) and the level of the PCI (OR = 1.08; 95% CI 1.024-1.15; p=0.008) were independent negative factors of OS. CONCLUSION: The CS and HIPEC in patients with CRC with PC allowes to achieve five-year survival in a part of patients, especially with low PCI. Identifying adverse prognostic factors preoperatively can help in selecting patients for CS in the future.

[Reinforcement of staple line of colorectal anastomosis for leakage prevention: a systematic review and metaanalysis]. / Rol' ukrepleniia kolorektal'nogo anastomoza dlia profilaktiki ego nesostoiatel'nosti: sistematicheskii obzor literatury i metaanaliz.

OBJECTIVE: To evaluate the influence of reinforcement of staple line of colorectal anastomosis on the incidence of leakage. MATERIAL AND METHODS: A systematic review was performed in accordance with the PRISMA recommendations. Statistical analysis was carried out in the Review Manager 5.3 software. RESULTS: This trial included four original articles published in 2011-2018. There were 493 patients. Reinforcement of anastomosis was made in 232 (47%) cases, colorectal anastomosis was not reinforced in 261 (53%) patients. Anastomotic leakage rate was 5.6 and 11.1% in both groups, respectively (OR 0.55, CI 0.13-2.33; p=0.42). Transabdominal reinforcement reduced leakage rate by 10.2% (OR 0.18, CI 0.06-0.55; p=0.002) while transanal reinforcement was ineffective (OR 1.66, CI 0.38-7.19; p=0,5). Incidence of preventive stoma was similar (OR 0.3, CI 0.07-1.22; p=0.09), but it was possible to abandon preventive stoma in 18% of cases after anastomotic reinforcement. CONCLUSION: A small number of studies dedicated to anastomosis reinforcement resulted controversial data.

[Risk factors of postoperative complications in patients with synchronous colorectal cancer liver metastases]. / Faktory, assotsiirovannye s razvitiem posleoperatsionnykh oslozhnenii u bol'nykh s sinkhronnymi metastazami kolorektal'nogo raka v pecheni.

AIM: Univariate and multivariate analysis of various risk factors and morbidity in patients with synchronous colorectal cancer (CRC) liver metastases. MATERIAL AND METHODS: Prospective data of 173 patients with synchronous CRC liver metastases have been analyzed from January 2013 to February 2017 at the Ryzhikh State Coloproctology Research Center. RESULTS: In multivariate analysis significant risk factors of morbidity were age ≤61 years, the largest liver metastasis ≥ 2.1 cm (odds ratio (OR) 2.99; 95% CI 1.4-6.5), number of liver metastases >1 (OR 2.5; 95% CI 1.1-5.5), bilobar liver injury (OR 2.5; 95% CI 1.3-4.8), blood loss (OR 1.001; 95% CI 1.0001-1.002). Model for prediction of complications was constructed (AUC 0.79). CONCLUSION: Simultaneous surgery is not risk factor of complications. Probability of complications is increased in advanced tumor and consequently more traumatic surgery. Predictive model is useful for prognosis of complications and describes surgical experience of State Coloproctology Research Center.

[Meta-analysis of management of colorectal anastomotic leakage]. / Meta-analiz metodov lecheniia nesostoiatel'nosti kolorektal'nogo anastomoza.

AIM: To identify the most effective management of colorectal anastomosis failure via analysis of available literature sources. RESULTS: Systematic review included 20 original trials. Effectiveness of redo interventions for colorectal anastomosis failure including open, laparoscopic, minimally invasive techniques (transanal drainage, endoscopic vacuum therapy, endoscopic drainage) was described. Anastomotic failure rate was 6.5%. Medication was effective in 57% (95% CI 34-77%) of cases. Redo open surgery was applied in 43% (95% CI 23-66%) of patients. Postoperative mortality was 21-27%. Redo laparoscopic procedure was performed in 61% (95% CI 50-70%) of cases for anastomotic failure after previous laparoscopy, incidence of conversion was 12% (95% CI 4-28%). Transanal drainage was effective in 85% (95% CI 61-94%) of cases, endoscopic vacuum therapy - in 82% (95% CI 74-87%), healing of anastomosis without need for colostomy was achieved in 16% (95% CI 9-26%) of cases. Endoscopic clipping for colorectal anastomotic defect was effective in 73.3-77% of cases. CONCLUSION: Redo surgery for anastomotic failure is associated with advanced mortality and need for permanent colostomy. Laparoscopic approach reduces incidence of complications after redo surgery and followed by better functional outcomes. Minimally invasive procedures are advisable for colorectal anastomosis failure without need for redo surgery. However, effectiveness of these methods is controversial due to few reports and no comparative trials.

[HEMIHEPATECTOMY FOR RESECTABLE HEPATIC METASTASIS FROM COLORECTAL CANCER WITH POOR PROGNOSIS].

The current study aimed at improvement of treatment effects for patients with resectable metastases of colorectal cancer in the liver with a poor prognosis. Overall 437 patients were enrolled with metastatic colorectal cancer in the liver exhibiting at least one adverse factor of long-term prognosis: multiple metastases, bilobar liver metastases, large metastases, the presence of extrahepatic metastases, etc. Combined treatment was performed for 339 (78%) patients: combined treatment with adjuvant systemic chemotherapy (163 patients), combined treatment with perioperative systemic chemotherapy (54 patients), or combined treatment of perioperative regional chemotherapy (122 patients). Surgical treatment was performed in 66 (15%) patients. The remaining group of 32 (7%) patients with resectable metastases who received only systemic chemotherapy was considered separately. All liver resections were extensive due to the widespread metastases. The complication rate stood at 56%. Mortality among operated patients was 4%. Postoperative mortality and complications as well as the intraoperative blood loss were not statistically different in two groups. Adding bevacizumab to preoperative chemotherapy did not increase blood loss. After combined treatment with adjuvant chemotherapy a 5-year survival was 26 ± 4% that significantly outperforming a 5-year survival rate after surgery (17 ± 5%), after just drug treatment a 5-year survival has not been reached, and also after combined treatment with perioperative systemic chemotherapy (13 ± 5%) and not statistically significant exceeded a 5-year survival after combined treatment with perioperative regional chemotherapy (20 ±5%). Thus our study demonstrates the benefits of combined treatment with adjuvant systemic chemotherapy for resectable metastases of colorectal cancer in the liver with a poor prognosis. For initially unresectable metastases with extrahepatic manifestations of the disease treatment should be begun with systemic chemotherapy. To liver resection in the latter cases there are resorted only after the transfer of patients in operable condition.

Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors.

Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. We investigated the modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors.

Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat.

Many neuropeptides regulate feeding and arousal; the ventral tegmental area (VTA) is likely to be one site where they act. We used whole-cell patch-clamp and single-unit extracellular recordings to examine the effects of such neuropeptides on the activity of VTA neurons. Substance P (SP; 300 nM) increased the firing rate of the majority of VTA dopaminergic and gamma-aminobutyric acid (GABA)ergic neurons, and induced oscillations in two dopaminergic cells. Corticotropin-releasing factor (CRF; 200 nM) excited the majority of VTA cells directly, whereas neuropeptide Y (NPY; 300 nM) directly inhibited a subset of dopaminergic and GABAergic cells. Consecutive application of several neuropeptides revealed that all the neurons were excited by at least one of the excitatory neuropeptides SP, CRF or/and orexins. Alpha-melanocyte-stimulating hormone had no effect on dopaminergic cells (at concentrations of 500 nM and 1 microM) and affected only a small proportion of GABAergic neurons. Ghrelin (500 nM), agouti-related peptide (1 microM); cocaine and amphetamine-related transcript (500 nM) and leptin (500 nM and 1 microM) did not modulate the firing rate and membrane potential of VTA neurons. Single-cell reverse transcription polymerase chain reaction analysis showed that all NPY receptors were present in VTA neurons, and all but one cell expressed NPY and/or at least one NPY receptor. CRF was expressed in 70% of dopaminergic VTA cells; the expression of CRF receptor 2 was more abundant than that of receptor 1. These findings suggest a link between the ability of neuropeptides to promote arousal and their action on VTA neurons.

Deficits in cortico-striatal synaptic plasticity and behavioral habituation in rats with portacaval anastomosis.

Hepatic encephalopathy is characterized by disturbances of motor and cognitive functions involving the basal ganglia. So far no standards for assessment of neuropsychiatric abnormalities (disorders of sleep, mood, anxiety and personality) in subclinical hepatic encephalopathy have been defined. Using an animal model of mild (subclinical) hepatic encephalopathy we investigated now striatum-related behaviors and cortico-striatal synaptic plasticity in rats 2 months after introduction of a portacaval shunt and sham-operated matched controls. In a novel open field portacaval shunt rats displayed less locomotor activity; unlike controls they also showed no habituation to the field and no recall of the field environment after 24 h, indicative of cognitive deficit. The elevated-plus maze test indicated no differences in fear/anxiety in the portacaval shunt animals. Tetanic stimulation of cortical afferents in magnesium-free solution evoked an N-methyl-D-aspartate-dependent long-term potentiation in sham-operated animals. In portacaval shunt animals long-term potentiation was significantly impaired. Histamine, a potent modulator of cortico-striatal transmission, induced a larger long-term depression of field potentials in control compared with portacaval shunt rats. In conclusion, a combination of electrophysiological and behavioral approaches has revealed functional changes in cortico-striatal transmission. These data are relevant for understanding the mechanisms of motor and cognitive dysfunctions in hepatic encephalopathy patients and for the development of precise psychometric tests, evaluating cognitive deficits in subclinical hepatic encephalopathy.

Multiple GABAA receptor subtypes regulate hippocampal ripple oscillations.

High-frequency oscillations (140-200 Hz) were recorded in behaving rats from the CA1 area of the hippocampus. As generation of these synchronous patterns is assumed to depend on coordinated interneuronal inhibition, we studied the interference of benzodiazepines with the fine structure and occurrence of ripple oscillations. The nonselective GABAA receptor alpha-subunit agonist, diazepam, lowered the frequency of ripple oscillations and reduced their occurrence, amplitude and duration. Zolpidem, an alpha1-subunit selective benzodiazepine elevated ripple duration but acted similar to diazepam in other respects. The nonselective alpha-subunit benzodiazepine antagonist, flumazenil, reduced ripple numbers, amplitude and duration. Wavelet based analysis of the dynamics of intraripple frequency revealed a dramatic decay within a ripple. Only diazepam (1 mg/kg) accelerated this intraripple frequency accommodation. The effects were not due to increased behavioural activity and alertness as evident from vigilance state control. The results suggest a differential role of GABAA receptor subtype specific inhibitory mechanisms in the mediation and fine-tuning of the network synchronization during approximately 200 Hz hippocampal oscillations.

Temporal pattern of hippocampal high-frequency oscillations during sleep after stimulant-evoked waking.

Hippocampal ripple oscillations (140-200 Hz) are believed to be critically involved in the consolidation of memory traces during slow-wave sleep (SWS). We investigated the temporal pattern of ripple occurrence in relation to sleep phases following different types of waking. Amphetamine, the atypical wakening drug modafinil or non-pharmacological sleep deprivation lead to an increased ripple occurrence ("rebound") during the subsequent SWS episode. Waking of the same duration evoked by amphetamine or sleep deprivation led to a ripple rebound of similar extent (approximately 200%). The mean intraripple frequency was also elevated by up to 20 Hz during SWS following all treatments. Ripple amplitude was significantly increased only in experiments with amphetamine. Ripple occurrence but not intraripple frequency clearly correlated with the antecedent waking duration independent of treatment. Recovery of ripple occurrence and frequency to the pretreatment level during SWS depended on SWS duration. At the end of the recovery period paradoxical sleep (PS) acted like waking, elevating ripple occurrence during subsequent SWS episodes. On the other hand, PS decreased ripple occurrence if recovery from the rebound was not yet complete. Thus occurrence and structure of ripple oscillations are regulated by the timing and duration of previous SWS, PS and waking episodes.

[Hippocampal ripple oscillations (200 Hz) in mechanisms of memory consolidation]. / Gippokampal'nye rippl-ostsilliatsii (200 Gts) v mekhanizmakh konsolidatsii pamiati.

A current status of knowledge about high-frequency (140-200 Hz) ripple oscillations in the CA1 hippocampal subfield is summarized and considered in the context of two-stage model of the hippocampal memory processing. A large body of evidence suggests highly-selective recruitment of pyramidal cells and interneurons in the generation of the oscillatory pattern after co-operative sharp-wave-related discharge of CA3 pyramidal neurons. We also discuss a role of transmission via gap junctions in the mechanisms of ripple oscillations as well as their adaptive aminergic (histaminergic) modulation. Patterns of neuronal firing in the hippocampus observed during ripple oscillations reproduce space-dependant neuronal activity from the previous waking period. Together with a data about efficacy of high-frequency stimulation for induction of synaptic modification it points out a role for ripples in the formation of long-term memory. Focal ultra fast ripples (up to 500 Hz) have been shown to participate in the development of temporal lobe epilepsy.

Peptidergic mechanisms of hyperthermia-evoked convulsions in rats in early postnatal ontogenesis.

This report addresses the verification of the hypothesis that arginine-vasopressin affects the formation of hyperthermia-evoked convulsions in early ontogenesis in rats on days 3, 5, 7, and 9 of postnatal life. The modification of experimental febrile convulsions by PACAP (pituitary adenylate cyclase-activating peptide) was investigated; PACAP is a physiological regulator of the neurosecretion of arginine-vasopressin. Arginine-vasopressin (10 microg/rat) and PACAP (0.01 microg/rat) decreased the latency of generalized tonic-clonic convulsions and the time of truncal generalization of convulsive activity on days 3 and 5 of rat development. Animals given arginine-vasopressin (0.1-10 microg/rat) sowed significant increases in the duration of generalized convulsions to the level of status epilepticus on day 9 of life. Conversely, administration of higher doses of PACAP (0.1 microg/rat) increased the threshold of tonic-clonic convulsions on days 3 and 5 and decreased it on days 7 and 9 of postnatal development. The indirect involvement of PACAP in the mechanisms of experimental febrile convulsions is suggested to act via changes in arginine-vasopressin neurosecretion.

[Peptidergic mechanisms of hypothermia-induced seizures in rats during early ontogenesis]. / Peptidergicheskie mekhanizmy gipertermicheski vyzvannykh sudorog u krys v rannem postnatal'nom ontogeneze.

Arginine-vasopressin reduced the tonic-clonic seizures' latency as well as the duration of the seizures brain-stem generalisation on the 3rd and 5th postpartum days in rats. The reduced latency was also observed after the PACAP38 low doses administration, whereas higher doses diminished and then enhanced the threshold of generalised hyperthermia-induced seizures on the 3rd and 5th days and the 7th and 9th days, resp. The arginine-vasopressin-treated animals had a dramatically enhanced duration of the tonic-clonic seizures up to the epileptic status on the 9th postpartum day. The findings suggest the PACAP involvement in mechanisms of experimental febrile seizures through its effect upon arginine-vasopressin neurosecretion.

[Pituitary adenylate cyclase activating peptide (PACAP)--its polyfunctionality in the mechanisms of brain protection]. / Peptid, aktiviruiushchii adenilattsiklazu gipofiza (PACAP)--polifunktsional'nost' v mekhanizmakh zashchity mozga.

Modern data of molecular and biological properties and physiological role of new pituitary adenylate cyclase activating polypeptide--PACAP--review. PACAP play key role in the embryogenesis of brain, in the protection of brain nerve cells from ischemia-induced death, injuring and apoptosis. New data are discussed concerned with molecular cloning and tissue distribution of receptors for PACAP, gene proPACAP expression in gastrointestinal tract, reproductive organs and nervous system. PACAP increase cytosolic free calcium and modifies the calcium-sensitive K(+)-channels, PACAP protects cultures cortical and hippocampal neurons from glutamate-induced cytotoxicity. The sleep modulation and modification of seizures activity of brain through the secretion of vasopressin or/and through NMDA receptors directly should be include in the program of PACAP "physiological continuum" of functions.

[Surgical treatment of acute biliary pancreatitis]. / Khirurgicheskoe lechenie ostrogo biliarnogo pankreatita.

The analysis of surgical treatment of 126 patients with acute biliary pancreatitis is made. The authors follow an active surgical policy in patients with justified risk of surgery. The operation is carried out in two stages: 1st-radical elimination of pathologic changes of extrahepatic bile ducts, restoration of the passage through the large duodenal papilla (LDP), and 2nd stage is the operation on the pancreas. The indications and contraindications for transduodenal intervention in acute biliary pancreatitis have been determined. The authors think it necessary in destructive forms of acute pancreatitis accompanied by extensive fermentative damage of parapancreatic and retroperitoneal cellular tissue to remove it thoroughly and to drain it widely. The reoperation should be performed not earlier that 12-21 days after the initial operation. Postoperative lethality was 8.7%.