Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study.

BACKGROUND & AIMS: Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS: AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N = 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS: A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P = .066), 4 mg BID (46.3%; P = .059), and 4 mg QD (43.9%; P = .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P = .020), 24.4% (P = .013), and 24.4% (P = .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION: Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. CLINICALTRIALS: gov number, NCT03675477.

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies.

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects. Continuous efforts led to the discovery of a series of diverse compounds with the most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule and antibody-based targeting of CAIX/CAXII in cancer.

PD-1/PD-L1 and DNA Damage Response in Cancer.

The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor's susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.

[Assessment of the selected, late phase of angiogenesis factors' concentration in colorectal cancer patients]. / Ocena stezenia wybranych czynników poznego etapu angiogenezy u chorych na raka jelita grubego.

UNLABELLED: Angiogenesis is a process of new blood vessels creating based on existing already vascularisation. This composed and multistage mechanism, which is responsible for growth of the tissues and organs, plays a crucial role in neoplasia. The exact role of particular cells, cytokines and extracellular matrix in cancerogenesis is still discussing. An identification of it is the key to searching the antiangiogenic substances breaking simultaneously neoplastic proliferation. THE AIM OF THE STUDY was to compare the angiopoietin-1(Ang-1), angiopoietin-2 (Ang-2) and Tie-2 receptor (rec. Tie-2) concentrations in the serum of colorectal cancer patients with concentrations of these factors in the serum of healthy people. Moreover the aim of the study was to assess the correlation between the concentrations of these factors and stage of clinical neoplasm progression. MATERIAL AND METHODS: The study included 35 patients hospitalized in the Department of General Surgery due to confirmed by histopatological examination colorectal cancer, between 2006 to 2007. The group of examined patients consisted of 9 women and 26 men with ages between 39 to 81 (average 67.20+/-8.85). The control group consisted of 11 healthy people. The examinations relied on the 10 ml of blood sampling from all the patients, in fasting state, one day before the operation. 10 ml of blood, in the healthy group was also sampled in fasting state. Afterwards all blood samples, 30 minutes after collecting, were centrifuged with velocity 6000 rotation per minute. The gaining serum was freezed in temperature -80 degrees C. The concentrations of Ang-1, Ang-2 and rec.Tie-2 were measured with ELISA method. RESULTS: Among examined patients with colorectal cancer, the statistically significant, higher concentration of Ang-2 in comparison with control group was revealed (6239.7+/-3482.3 pg/ml vs. 2954.9+/-9624.2 pg/ml). The concentration of Ang-2 among the patients from III and IV group according to the clinical and pathomorfological progression classification was statistically significant, higher than in I and II group of the patients (III: 8668,8+/-4938.57 pg/ml; IV: 9002.1+/-5380.92 pg/ml vs. I: 4672.3+/-1808.7 pg/ml; II: 5284.8+/-3204.2 pg/ml). The concentration of Ang-1 and rec. Tie-2 in blood of all the patients with colorectal cancer didn't statistically differ from the control group (Ang-1: 42339.9+/-20197.2 pg/ml vs. 48976.4+/-2284.5 pg/ml; rec.Tie-2; 14.4+/-5.1 vs. 16.8+/-6.2 ng/ml). CONCLUSIONS: The concentration of Ang-2 in the colorectal patients was statistically higher than in the control group. The increase concentration of Ang-2 correlated with the stage of colorectal cancer's clinical progression. The higher concentration of Ang-2 may eventually become a helpful marker in diagnostic and assessment of colorectal cancer's clinical progression stage.

[Paliative procedures in cholangiocarcinomas--experience of 5 centers]. / Zabiegi paliatywne w raku pecherzyka i/lub dróg zólciowych--doswiadczenia 5 osrodków.

UNLABELLED: Cholangiocarcinomas have been often met in daily practice. Biliar tract neoplasmas are the most important group in adenomas and papillomas. There is the medical and social problem with cancer patients because they call doctor too late when cancer changes reach a high level and only paliative procedures are recommended. In the most cases the prothesis implanted by ERCP and surgical digestive bypasses are applied. AIM OF THE STUDY: was to evaluate some therapeutic methods in paliative treatment applied in patients with biliary tract cancer. MATERIAL AND METHODS: From 01.2003 to 12.2007 (5 years experience) in 4 departments of general surgery and departments of digestive tract diseases the medical treatment of 430 patients with biliary tract cancer was analyzed. All patients were divided into 3 groups: G1--prosthesis by ERCP; G2--percutaneously, transhepatic drainage of biliary tract; G3--surgical digestive bypass. RESULTS: G1 techniques were applied in 75 patients, G2 in 14 cases and G3 in 74 cases. In the last group of patients the following procedures have been performed: triple bypass (TB) in 45 cases (62%), choledochoduodenostomy (ChD) in 7 cases (9%), gastroenterostomy (GE) in 10 patients (13%) and laparotomy with Kehr drainage in 12 patients (16%). The number of complications in G1 group was observed in 31%, in G2--42%, and in G3--63%. 30 days death rate was 14% in G1, 28% in G2 and 18% in G3. Over 12 months survival rate was in G1, 3 months in G2 and 15 months in G3. Differences are statistically sagnificant (p < 0.05). CONCLUSIONS: From all applied methods of paliative treatment the best results were noticed in surgical digestive bypass and implantation of prosthesis by ERCP. After surgical treatment survival rate was higher, but the number of complications was higher in relation to another methods.

[The burnout syndrome among doctors and nurses]. / Zespól wypalenia zawodowego u lekarzy i pielegniarek.

UNLABELLED: The burnout syndrome is a complex of symptoms which are related to psychological, behavioral and physiological man's functioning. Recently, the spread of a burnout syndrome significantly increases. As Polish examinations show it is a serious danger among nurses and doctors. THE AIM OF THE STUDY: To estimate the presence and the level of the burnout syndrome intensity among nurses and doctors. The second aim was to confirm the connections between symptoms of a burnout syndrome and the internal locus of control. Material and methods. 55 doctors and 53 nurses who worked full-time in hospitals in tbdi and in Social Assistance House were examined. Questionnaire of burnout syndrome Ch. Maslach (MBI) and Questionnaire of Locus of control--I-E Scale W. Gliszczynska were used. RESULTS: Among doctors and nurses all three factors of burnout syndrome were presented: emotional exhaustion (WE), low level of personal satisfaction from work (ZA) and depersonalization (DP). Nurses in comparison to doctors have a higher level of the emotional exhaustion, a lower level of an involvement in work and a lower level of an internal locus of control. CONCLUSIONS: Executed research supplied the proofs which confirmed a view that the burnout syndrome is most popular among nurses and doctors. Our results indicate that the burnout syndrome escalates among nurses in comparison to doctors and its influence of work functioning is essential.

[The influence of the increasing doses of vitamin C on the concentration of the substance reacting with thiobarbituric acid (TBARS) in mice liver]. / Wplyw wzrastajacych dawek witaminy C na stezenie substancji reagujacych z kwasem tiobarbiturowym (TBARS) w watrobie myszy.

Ascorbic acid is known antioxidant protecting many organs and tissues. In some circumstances can act as prooxidant, particullary when coexists with high concentration of ferrum and copper jons. Condition like that can take place for example in liver. In this research Vitamin C was administered to the mice in increasing dosages, then the concentration of TBARS-prooxidant markers was measured in homogenats of their livers. The outcomes of the research are equivocal.

[The estimation of antioxidative vitamins concetrations in blood plasma of patients with neoplasms of gallblader and biliary tract]. / Ocena stezen witamin antyoksydacyjnych w osoczu krwi chorych z nowotworami pecherzyka i dróg zólciowych.

Gallbladder and biliary tract cancer is a serious clinical problem. In-spite of wide range of new diagnostic and therapeutic methods, the significant improvement of treatment results, has not been noticed so far. The research about prevention methods, seems to be important, among the ways of improvement of the diagnosis and therapy outcomes of these diseases. It is related for example to study about one of the cause of biliary tract carcinogenesis--the imbalance between production of reactive oxygen species (ROS) and their inactivation by the antioxidative barrier. One of the components of this organism protection complex are antioxidative vitamins. The aim of this study was to measure the concentration of antioxidative vitamins (A, C, E, and beta-carotene) in serum, in patients with cancer of gallbladder and and biliary tract, in comparison to the results of healthy volunteers. The study groups comprised of 56 patients, both sexes with acute and chronic cholecystitis and with above-mentioned neoplasmas. The results shoved, that concentration of antioxidative vitamins in serum of patients with gallbladder and biliary tract cancer, was significantly decreased. The outcomes of this research, seem to confirm the participation of antioxidative barrier in inhibition of carcinogenesis of in those important parts of digestive system.

[Treatment of cholecysto- and choledocholithiasis--own experiences]. / Leczenie kamicy dróg zólciowych--doswiadczenia wlasne.

UNLABELLED: Cholecystolithiasis is a serious problem of contemporary medicine. The most common operations in gastroenterologic surgery are gallbladder operations because of calculosis. The most common complications after gallbladder operations are bleeding from site of the gallbladder and bile leakage, but the most serious complication is a bile ducts injury. THE AIM: The assessment of complications quantity after cholecystectomy due to cholecystolithiasis. Observation of operation's profile changes during last 10 years. MATERIAL AND METHODS: From January 1997 to December 2006 in Department of Surgery in MSWiA Hospital in Lodz and in Departments of Surgery in Leczyca and Piotrkow Trybunalski 6845 cholecystectomy were made including 4215 laparoscopic operations. RESULTS: Complications were observed in 12.6% patients. Suppuration of the wound and postoperative hernias occurred more often after classic operations, in the other hand blood and bile leakage from site of the gallbladder were more often observed after laparoscopic operations. The ratio of complications after classic operations to laparoscopic operations was about 15.4% to 6.1%. Conversion was made in 11.5%. During first 5 years conversion was made in 17.6%, in the next 5 years average number of complications drop to 5.4%. CONCLUSIONS: Nowadays laparoscopic cholecystectomy is a standard procedure in symptomatic and asymptomatic cholecystolithiasis. It's a safe operation, burden with a little amount of complications made during acute as well as chronic course of disease. Laparoscopic technique requires a lot of care and in the event of operator's doubts should be replace with classic operation.

Preparation of patients submitted to thyroidectomy with oral glucose solutions.

UNLABELLED: The AIM OF THE STUDY was to determine postoperative insulin-resistance in patients subject to total thyroidectomy, the prevalence of subjective feelings of hunger immediately before surgery, and the incidence of nausea/vomiting after surgery in patients prepared for elective operations by means of oral glucose solutions. MATERIAL AND METHODS: The study group comprised 115 patients, including 71 patients prepared for surgery by means of oral glucose solutions (12.5% glucose) administered 12 and 3 hours before the procedure, at a dose of 800 and 400 ml. The control group comprised 44 patients prepared for surgery by means of the traditional manner- the last meal was served before 2pm the day before the surgical procedure, while fluids before 10pm. Considering both groups, we evaluated glucose and insulin levels three times, as well as determined the insulin-resistance ratio (HOMA-IR) 24 before, and 12 hours and 7 days after surgery. The incidence of nausea and vomiting after surgery, and the subjective feeling of hunger before surgery were also evaluated. RESULTS: Statistically significant differences considering insulin level and HOMA-IR values were observed during the II and III measurements. The glucose and insulin values, and the HOMA-IR insulin-resistance ratio, showed no statistically significant differences during measurement I. No statistically significant glucose level differences were observed during measurements II and III. A significantly greater subjective feeling of hunger before surgery and nausea/vomiting afterwards were observed in the control group. CONCLUSIONS: The preparation of patients with oral glucose solutions decreases the incidence of postoperative (thyroidectomy) insulin-resistance, and occurrence of nausea/vomiting during the postoperative period.

Assesment of inflammatory response intensity in early postoperative period in patients after hernioplasty operated on with classic stoppa method and videoscopic TEP method.

THE AIM OF THE STUDY was comparison of inflammatory response intensity through estimation of CRP, IL-6 and WBC concentration in blood serum in patients before and after inguinal hernia operations with Stoppa and TEP method. MATERIAL AND METHODS. The study involoved 117 patients operated on inguinal hernia between 2006-2008. The patients were divided into two groups. In the first group (group I - 56) Stopp'a method was used, in the second (group II - 61) TEP method. The patients selection was coincidental. All examined patients were men between 25-75 years old (mean age 54.3). Moreover, the operation's time, state of postoperative wound, the average hospitalization time and intensity of pain were estimated. The observations were directed over two weeks after operation. RESULTS. The inflammatory response estimated with CRP, IL-6 concentration in blood serum was considerably higher in patients operated with Stoppa method. There wasn't observed a relevant difference in increase of white blood cells' concentration in both groups. Moreover, the patients operated on with TEP method experienced lower pain. In group, operated on with Stoppa method, 3 cases of wound healing complications were observed. The operation's time was considerably shorter in the first group. The hospitalization time, was considerably shorter in patients operated on with videoscopic method. CONCLUSIONS. The operation of inguinal hernia with TEP technique in comparison with Stopp'a method is connected with considerably lower inflammatory response of organism, what directly involve with postoperative pain abridgment and reduction of hospitalization time. Moreover it may have influence on frequency of postoperative complications related with wound healing.