Prognosis and incidence of immunological and oncological complications after direct-acting antiviral therapy for chronic hepatitis C.

Background and study aims: The long-term comprehensive prognosis of chronic hepatitis C after direct-acting antiviral (DAA) therapy is unclear. This study aimed to investigate the prognosis and incidence of immunological and oncological complications after DAA therapy. Patients and methods: The study included a total of 1461 patients who received DAA therapy in our university hospital and affiliated hospitals between September 3, 2014 and September 30, 2018. Results: The incidence rates of total malignancies in overall or female patients after DAA therapy were significantly greater than expected in the corresponding general population. The same was true for lung malignancies. Predictive risk factors associated with the occurrence and recurrence of hepatic malignancies after DAA therapy in patients with sustained virological response were cirrhosis and insulin use, protein induced by vitamin K absence or antagonist-II level, and albumin-bilirubin score, respectively. Eight (0.5%) patients were diagnosed with autoimmune diseases after starting DAA therapy. Importantly, the attending physician considered a possible causal relationship between DAA therapy and these autoimmune diseases in five cases (four rheumatoid arthritis and one membranoproliferative glomerulonephritis). The 5-year overall survival rate was 91.6%. The most frequent primary cause of death was malignancy in 41 (60.2%) patients, including 25 with hepatic malignancies. Lung and colorectal cancers were the next most common. Conclusions: Given that the incidence of total and lung cancers might increase and DAA-related autoimmune diseases might emerge after DAA therapy, we should be alert for the development of these diseases as well as hepatic malignancies.

Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites : a multicenter retrospective propensity score-matched cohort study.

Background: The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics. Patients and methods: The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups. Results: After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows: age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937). Conclusions: Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

A change in the timing for starting systemic therapies for hepatocellular carcinoma: the comparison of sorafenib and lenvatinib as the first-line treatment.

Aim: The aim of this retrospective multicenter study was to evaluate the differences in the timing for starting systemic therapies as the first-line treatment for hepatocellular carcinoma (HCC). Methods: A total of 375 patients with HCC treated with sorafenib from May 2009 to March 2018 and 56 patients treated with lenvatinib from March 2018 to November 2018 at our affiliated hospitals were included in this study. Results: The median ages of the sorafenib and lenvatinib groups were 71.0 (interquartile range [IQR]: 64.0-77.0) and 73.5 (IQR: 68.0 -80.0) years old, and 300 (80.0%) and 42 (75.0%) patients were men, respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate and advanced in 39 patients (10.4%), 133 patients (35.5%) and 203 patients (54.1%) in the sorafenib group and 1 patient (1.8%), 17 patients (30.4%) and 38 patients (67.9%) in the lenvatinib group, respectively. In the analysis of intermediate HCC, patients who satisfied the criteria of TACE failure/refractoriness (P=0.017), those with ALBI grade 1 (P=0.040), and those with a serum AFP level < 200 ng/ml (P=0.027) were found more frequently in the lenvatinib group than in the sorafenib group, with statistical significance. The objective response rate (ORR) of lenvatinib was 34.8% in the overall patients and 46.7% in the intermediate-stage HCC patients, which was significantly higher than sorafenib (P=0.001, P=0.017). Conclusions: The emergence of lenvatinib has encouraged physicians to start systemic chemotherapy earlier in intermediatestage HCC patients.

Novel diagnostic and therapeutic techniques for surveillance of dysplasia in patients with inflammatory bowel disease.

The risk for developing dysplasia and colorectal cancer in patients with longstanding inflammatory bowel disease (IBD) involving the colon is well documented. Random biopsies during white-light, standard-definition colonoscopy (33 to 50 biopsies) with or without dye spraying chromoendoscopy has been the recommended strategy in North America to detect dysplastic lesions in IBD. However, there are several limitations to this approach including poor physician adherence, poor sensitivity, increased procedure time and considerable cost. The new generation of high-definition endoscopes with electronic filter technology provide an opportunity to visualize colonic mucosal and vascular patterns in minute detail, and to identify subtle flat, multifocal, polypoid and pseudopolypoid neoplastic and non-neoplastic lesions. The application of these new technologies in IBD is slowly being adopted in clinical practice. In addition, the advent of confocal laser endomicroscopy provides an opportunity to explore real-time histology, thus redefining the understanding and characterization of the lesions in IBD. There is emerging evidence that serrated adenomas are also associated with longstanding IBD colitis and may be recognized as another important contributing factor to colorectal cancer development. The circumscribed neoplastic lesions can be treated using endoscopic therapeutic management such as mucosal resection or, especially, endoscopic submucosal dissection. This may replace panproctocolectomy in selected patients. The authors review the potential of these techniques to transform endoscopic diagnosis and therapeutic management of dysplasia in IBD.

Endoscopic indications for endoscopic mucosal resection of laterally spreading tumours in the colorectum.

BACKGROUND: Laterally spreading tumours (LSTs) in the colorectum are usually removed by endoscopic mucosal resection (EMR) even when large in size. LSTs with deeper submucosal (sm) invasion, however, should not be treated by EMR because of the higher risk of lymph node metastasis. AIMS: To determine which endoscopic criteria, including high magnification pit pattern analysis, are associated with sm invasion in LSTs and clarify indications for EMR. METHODS: Eight endoscopic criteria from 511 colorectal LSTs (granular type (LST-G type); non-granular type (LST-NG type)) were evaluated retrospectively for association with sm invasion, and compared with histopathological findings. RESULTS: LST-NG type had a significantly higher frequency of sm invasion than LST-G type (14% v 7%; p<0.01). Presence of a large nodule in LST-G type was associated with higher sm invasion while pit pattern (invasive pattern), sclerous wall change, and larger tumour size were significantly associated with higher sm invasion in LST-NG type. In 19 LST-G type with sm invasion, sm penetration determined histopathologically occurred under the largest nodules (84%; 16/19) and depressed areas (16%; 3/19). Deepest sm penetration in 32 LST-NG type was either under depressed areas (72%; 23/32) or lymph follicular or multifocal sm invasion (28%; 1/32 and 8/32, respectively). CONCLUSIONS: When considering the most suitable therapeutic strategy for LST-G type, we recommend endoscopic piecemeal resection with the area including the large nodule resected first. In contrast, LST-NG type should be removed en bloc because of the higher potential for malignancy and greater difficulty in diagnosing sm depth and extent of invasion compared with LST-G type.

Magnesium deficiency in patients with recent myocardial infarction and provoked coronary artery spasm.

This study sought to clarify the relationship between magnesium (Mg) deficiency and coronary artery spasm provoked by pharmacologic agents in patients with a recent acute myocardial infarction (AMI). Twenty-three consecutive patients suffering from AMI were investigated with a Mg retention test (Mg: 0.1 mmol/kg for 4 h) in both the acute phase (within I week (3+/-2 days) of onset) and the subacute phase (3-4 weeks (24+/-6 days) of the onset). Early coronary arteriography was performed in all patients. Coronary stenosis in the infarct-related artery was less than 90% in all patients in the subacute phase. The spasm provocation test was performed in the subacute phase and coronary spasm was defined as transient subtotal or total occlusion in association with angina or electrocardiographic ST-segment deviation. Coronary artery spasm was provoked in only 13 of the 23 patients. Compared with the control subjects (12 patients without coronary artery disease or coronary spasm), the 24-h Mg retention was significantly higher in patients with AMI (acute phase: 78+/-27%, subacute phase: 66+/-32%, vs control: 48+/-12%, p<0.05). In the subacute phase, the 24-h Mg retention decreased in patients without coronary spasm (43+/-26%), but a high level of Mg retention was still observed in patients with coronary spasm (84+/-25%). There was no difference in the serum concentrations of Mg, calcium and phosphorus between the 2 groups on both phases. In conclusion, both Mg deficiency and provoked coronary artery spasm were noted in more than half of the Japanese patients with a recent AMI, suggesting a close association between Mg deficiency and AMI.

New non-invasive protocol for detection of coronary spastic angina with significant organic stenosis.

OBJECTIVES: This study sought to determine whether a newly-combined test, accelerated exercise following mild hyperventilation (HV) is more beneficial to detect ischaemic evidence in patients with pharmacology-induced coronary artery spasm (CAS) and luminal narrowing of > 75% than classic methods. METHODS AND RESULTS: Forty consecutive patients who all had luminal narrowing of > 75% but < 90% and pharmacology-induced coronary vasospasms of fixed lesions were involved in this study. In these patients, initial HV test, followed by treadmill (TM) exercise test and lastly the newly combined test were performed on three consecutive days. Of the 40 patients, firstly six, secondarily 16 and lastly 32 had positive responses to the HV test, TM exercise test, and newly combined test, respectively. The remaining six patients (15%) had negative results, although the triple sequential tests were performed. Thus, sensitivity of the HV test, the TM exercise test, and the newly combined test was 15% (6/40), 40% (16/40), and 84% (32/38), respectively. Specificity of the three tests were all 100% (46/46). Non-sustained ventricular tachycardia and hypotension were observed in two (5%) patients. However, no serious or irreversible complications were encountered in this study. CONCLUSIONS: We recommend the newly combined protocol rather than the classic tests for the detection of ischaemic evidence in patients with coronary spastic angina and fixed stenosis.

Early stage gastric MALT lymphoma with high-grade component cured by Helicobacter pylori eradication.

A 68-year-old woman was diagnosed with gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type with a high-grade component. Surgical treatment was recommended because of the presence of the high-grade component, but she refused surgery. As an alternative, she received Helicobacter pylori eradication treatment, which successfully induced regression of the lymphoma. She shows no sign of recurrence endoscopically and histologically, as of 29 months after the eradication treatment. Moreover, the B-cell monoclonality and Helicobacter pylori infection demonstrated at diagnosis has disappeared. This is one of the rare cases of gastric lymphoma of the MALT type with a high-grade component cured by Helicobacter pylori eradication alone.

Usefulness of accelerated exercise following mild hyperventilation for the induction of coronary artery spasm : comparison with an acetylcholine Test.

STUDY OBJECTIVES: This study was performed to compare the results of accelerated exercise following mild hyperventilation and a standard acetylcholine (ACh) test for the induction of coronary artery spasm in patients with drug-induced coronary artery spasm. METHODS AND RESULTS: The subjects were 74 patients with angiographically confirmed coronary artery spasm who were examined using accelerated exercise (ie, exercise that was accelerated every minute according to the protocol of Bruce and Horsten) following mild hyperventilation and who were not receiving any medication. ACh was injected in incremental doses of 20 microg and 50 microg into the right coronary artery and incremental doses of 20 microg, 50 microg, and 100 microg into the left coronary artery. Positive coronary spasm was defined as > or =99% luminal narrowing. Accelerated exercise following a mild hyperventilation test was as useful for detecting evidence of ischemia as was an ACh test (48 patients [64.9%] vs 49 patients [66.2%], respectively; not significant). No difference was observed between ischemic changes on ECG as a result of the newly combined method and the occurrence of ACh-induced spasm. ACh-induced coronary vasospasm occurred in 61 patients (82.4%). In the remaining 13 patients, intracoronary administration of ergonovine provoked coronary spasms. No serious irreversible complications were detected as a result of this newly combined method. CONCLUSIONS: The effectiveness of our newly combined procedure is equivalent to that of an ACh test to diagnose patients with coronary artery spasm.

Major complications during spasm provocation tests with an intracoronary injection of acetylcholine.

This study sought to clarify major complications associated with acetylcholine testing. Serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade were determined in 4 of 715 patients (0.56%), but no cases of death or irreversible complications occurred. The spasm provocation test using acetylcholine should be performed carefully, although it is considered a safe and reliable method.

New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine.

The incidence of provoked coronary spasm with the standard single spasm provocation test has been relatively low in patients with rest angina. The present study examined the clinical usefulness of a newly designed spasm provocation test, an intracoronary injection of acetylcholine (ACh) following an ergonovine (ER) test, in patients with rest angina who demonstrated low disease activity and atypical chest pain. Triple sequential spasm provocation tests were performed in 24 patients with atypical chest pain who had no ischemia and in 40 patients with rest angina who had distinct ischemia. Initially, an ACh test (20-100 microg) and then an ER test (40-64 microg) were performed and then, if no spasm was provoked, an intracoronary injection of ACh was given after the ER test to evaluate coronary spasm. Coronary spasm was defined as total or subtotal occlusion. In the 24 patients with atypical chest pain, no spasm was provoked by intracoronary injection of either ACh or ER, but coronary spasms were induced in 2 patients using the new method, with the remaining 22 not experiencing spasm (specificity of new method, 92%). In the 40 patients with rest angina, intracoronary injection of ACh induced coronary spasm in 22 patients (group I) and 6 (group II) demonstrated spasm with intracoronary injection of ER. Coronary spasm was not induced by either the ACh test or the ER test in 12 patients (group III). The intracoronary administration of ACh after the ER test provoked spasm in 11 of 12 patients. Diffuse spasms were provoked in 10 of 11 patients. In patients with rest angina, the frequency of chest pain attacks in 1 month experienced by patients in group III (0.8+/-0.8) was significantly lower than that of patients in group I (7.0+/-5.3, p<0.01) or II (3.5+/-2.3, p<0.05). No serious or irreversible complications related to this new combined method were observed. In conclusion, this method was safe and reliable for the induction of coronary spasm in patients with rest angina who may have low disease activity.

Clinical characteristics of female patients with coronary spastic angina: comparison with male patients.

There are many patients with vasospastic angina who have minor atherosclerosis, and in Japan the majority of them are male. No data exist concerning sex differences in patients with coronary spastic angina, so the present study sought to clarify the clinical characteristics between male and female patients with vasospastic angina. Between April 1991 and June 1998, 204 consecutive patients were diagnosed with vasospastic angina and of these, 26 (12.7%) were female. An acetylcholine test was performed with incremental doses of 20, 50, and 80 microg injected into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Ergonovine was injected in a total dose of 40 microg into the right coronary artery and 64 microg into the left coronary artery. Coronary spasm was defined as 99% or more luminal narrowing accompanied by ischemic changes on ECG. Compared with male patients, female patients had less organic stenosis (12 vs 33%, p<0.05), less history of smoking (15 vs 85%, p<0.01), and fewer focal spasms (31 vs 64%, p<0.01). There were no other differences between the 2 groups. In conclusion, Japanese female patients with vasospastic angina had the characteristics of diffuse provoked spasm, less organic stenosis, and less history of smoking, but only 1 in 10 of all patients with vasospastic angina are female.

Limited efficacy of magnesium for the treatment of variant angina.

Some patients with variant angina show both ST segment elevation at rest and exercise-induced ST segment elevation. Magnesium deficiency has also been observed in patients with variant angina. This study investigated the correlation between the degree of magnesium deficiency and the efficacy of intravenous administration of magnesium in patients with variant angina. Fifteen patients with angiographically confirmed variant angina were assessed for magnesium deficiency and whether intravenous administration of magnesium (19.2 mEq/l) suppressed exercise-induced ST segment elevation. All 15 patients were studied with a magnesium retention test (0.2 mEq/kg over 4 hr) to analyze magnesium deficiency. In our study, magnesium retention rate in patients with variant angina was not higher than that of controls (57 +/- 24% vs 45 +/- 10%, NS). All 15 patients had anginal attacks during accelerated exercise combined with hyperventilation after placebo infusion, whereas only 8 patients had anginal attacks after magnesium administration. ST segment elevation occurred in 14 patients after placebo infusion, but in only 4 patients after magnesium administration. There were no correlations between disease activity, degree of magnesium deficiency or failure of suppression of ST elevation by the intravenous administration of magnesium. Intravenous administration of magnesium can suppress exercise-induced coronary spasms in some patients with variant angina, but the degree of magnesium deficiency did not correlate with the suppressions of exercise-induced ST elevation after magnesium administration. Intravenous administration of magnesium had limited efficacy in patients with variant angina and exercise-induced ST segment elevation.

Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine.

This study examines the incidence of spasm by intracoronary injection of acetylcholine in Japanese patients who underwent coronary angiography. The subjects were 685 consecutive patients (477 men, mean age 63.2 +/- 7.5 years) who were studied with an acetylcholine test. Acetylcholine was injected in incremental doses of 20, 50, and 80 microg into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Spasm was defined as total or subtotal occlusion. Coronary vasospasm was determined in 221 patients (32.3%). Spasm occurred often during effort and rest in patients with angina (25 of 51, 49.0%), exertional angina (25 of 74, 33.8%), recent myocardial infarction (30 of 80, 37.5%), healed myocardial infarction (14 of 37, 37.8%), and especially in patients with rest angina (83 of 124, 66.9%), whereas spasm was relatively uncommon in patients with nonischemic heart disease (23 of 252, 9.1%). Spasm was superimposed on significant atherosclerotic lesions in 35.9% of patients as well as on nonfixed atherosclerotic lesions in 30.8% of patients. We conclude that >9% of Japanese patients may have coronary vasospasm with intracoronary injection of acetylcholine and recommend the provocation test for evaluating coronary vasospasm if coronary angiography is undertaken.

Investigation of the most effective provocation test for patients with coronary spastic angina: usefulness of accelerated exercise following hyperventilation.

This study sought to compare the clinical usefulness of the hyperventilation plus cold stress test or the hyperventilation combined with accelerated exercise test with other single tests in patients with coronary spastic angina. The study examined 24 patients (23 men, mean age 66 years) with angiographically confirmed coronary spastic angina and less than 50% stenosis. Moreover, none had spontaneous ST segment elevation before the study. Under no medication for at least 24 h prior, 4 procedures were performed from 09.00 h to 11.00 h: (i) a hyperventilation test for 5 min (HV(5)); (ii) HV(5) combined with a cold stress test for the last 2 min (HV(5)+CS(2)); (iii) a treadmill exercise test based on Bruce's protocol (TM(3)); and (iv) a treadmill exercise test accelerated at 1 min intervals according to Bruce's protocol immediately after HV(5) (HV(5)+TM(1)). The rate of appearance of chest pain and ischemia-induced ECG changes due to HV(5)+TM(1) were significantly higher than the other 3 tests. HV(5)+CS(2) was not superior to HV(5) alone. The incidence of provoked ST segment elevation due to HV(5)+TM(1) was higher than with the other 3 procedures. Thus, in patients with coronary spastic angina, no spontaneous ST segment elevation and near normal coronary arteries, HV(5)+CS(2) was no more useful than HV(5) alone. It is recommended that the newly designed HV(5)+TM(1) combination test be used for documenting evidence of ischemia in patients with coronary spastic angina, low disease activity and near normal coronary arteries.

[Intravesical bacillus Calmette-Guerin instillation therapy for carcinoma in situ of the urinary bladder and prediction of effects by urinary cytologic examination].

PURPOSE: We investigated the effects of intravesical BCG instillations for carcinoma in situ (CIS) of the urinary bladder. And we have retrospectively analyzed the prediction of effects by fresh urinary cytologic examinations before instillation. MATERIAL AND METHODS: 33 patients were treated for bladder CIS (1991-1997) with a median follow-up of 30 months (range from 9 to 90 months). The patients (27 males and 6 females) ranged in age from 46 to 91 (average 71 years) and received 6 to 12 weekly BCG Tokyo 172 strain 80 mg instillations. They were divided into 3 groups based on tumor history: primary (9), secondary (15), concurrent (9). The prediction of effects were analyzed by scoring fresh urinary cytologic examinations before instillation. RESULTS: 22 cases (67%) were responded and they have remained free of disease for follow-up period. The statistic evaluation proved to show the significance between the effects of treatment and the sum of scoring (cellular appearance and existence of large nuclear cells). CONCLUSION: We confirmed the effects of this treatment. The prediction of effect of this treatment seemed to be indicative by fresh urinary cytologic examinations before instillation, especially cellular appearance and existence of large nuclear cells.

A case of variant angina pectoris with similar findings on both rest and matched exercise thallium-201 studies.

A patient with variant angina showed similar findings on both the rest and matched exercise 201Thallium (201Tl) myocardial perfusion scintigrams. The 65-year old man was admitted to hospital because of rest angina. His electrocardiogram during the attack disclosed ST segment elevation on inferior leads. However, emergency coronary arteriogram showed no fixed stenosis. Intracoronary injection of acetylcholine induced a spasm on the distal right coronary artery, but not in the left coronary artery. In the rest 201Tl study, septal perfusion was low on the early image, although partial redistribution of this site was observed on the delayed image without the appearance of chest pain or electrocardiographic ischemic change. Similary, in the 201Tl exercise study undergone 2 weeks later, septal redistribution was diagnosed because the early image had decreased septal perfusion. Both the exercise 123I-metaiodobenzylguanidine study and the rest 123I-betamethyl-p-iodophenyl-pentadecanoic acid study showed inferior abnormalities on the early and delayed images. Although a coronary spasm was not induced in the left anterior descending artery with the acetylcholine test, septal redistribution was observed on the delayed image of both the rest and exercise 201Tl studies. The mechanism of the redistribution on the rest 201Tl study was unclear.