A multicenter phase II study of carboplatin and paclitaxel for advanced thymic carcinoma: WJOG4207L.

BACKGROUND: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC. PATIENTS AND METHODS: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. RESULTS: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death. CONCLUSIONS: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.

Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Overexpression of mitochondrial manganese superoxide dismutase protects against radiation-induced cell death in the human hepatocellular carcinoma cell line HLE.

We investigated the potential role of mitochondrial manganese superoxide dismutase (Mn-SOD) in protective activity against irradiation by analyzing cell viability by a colony formation assay and by detecting apoptosis in stably human Mn-SOD gene-transfected HLE, a hepatocellular carcinoma cell line. We found that overexpression of Mn-SOD reduced the levels of reactive oxygen species in the mitochondria and intracellular phospholipid peroxidation product (4-hydroxy-2-nonenal) and prevented cell death. The production of intracellular nitric oxide after irradiation was not changed by Mn-SOD overexpression. The results suggested that Mn-SOD might play an important role in protecting cells against radiation-induced cell death by controlling the generation of mitochondrial reactive oxygen species and intracellular lipid peroxidation.

Computer-based exercises in anemia diagnosis (PlanAlyzer).

PlanAlyzer is a microcomputer-based, event-driven system for instructional research in medical education. Aimed at the second year medical student, PlanAlyzer elicits and critiques a student's approach to the diagnosis of a common medical disorder. In this paper we discuss the concept, development, implementation and formative evaluation of the PlanAlyzer system for the evaluation of anemia.

[Long-term clinical course and prognosis of patients with Crohn's disease].

The aim of the present study is to clarify long-term clinical course, prognosis and factors influencing prognosis of patients with Crohn's disease suffering for more than 10 years. Sixty-eight patients (47 males, 21 females) with Crohn's disease in whom the clinical course could observed well at our hospital for more than 10 years were studied. We classified these patients into three groups (good, fair, bad) according to their changes of IOIBD assessment score. And we compaired some clinical factors in these groups to clarify factors influencing prognosis. The results were as follows: 1) Twelve patients (18%) were in good prognosis group, and 24 patients (35%) in fair one, and 32 patients (47%) in bad one. 2) IOIBD assessment score at the time of diagnosis, site of leision, and radiographic findings at the time of diagnosis showed significant difference between bad prognosis group and the other two groups. Although there have been many reports that Crohn's disease is generally progressive, our results indicated that more than half of the patients showed favorable prognosis during the follow-up period for more than ten years.

Significance of mitochondrial enhancement in hepatic energy metabolism in relation to alterations in hemodynamics in septic pigs with severe peritonitis.

Liver mitochondrial phosphorylative activity, hepatic adenine nucleotides, and hemodynamic parameters were studied in 23 pigs with peritonitis induced by cecal ligation and perforation. Between 2 and 7 days after treatment, the onset of an apparent hyperdynamic state, characterized by an increased cardiac index and decreased total peripheral resistance index, occurred. In this period, the energy charge level was barely maintained and the occurrence of liver mitochondrial enhancement was observed. However, 10-14 days after treatment, the onset of a hypodynamic state with its inverse patterns in hemodynamics took place. In this period, the energy charge level fell to 0.68, concomitant with a marked decrease in mitochondrial function. Further, a high positive correlation between the cardiac index and liver mitochondrial phosphorylative activity was noted (r = 0.85, p less than 0.01). These results suggest that liver mitochondria play a major role in the metabolic and hemodynamic adaptations occurring during sepsis.

Hepatic and systemic metabolic responses to aerobic and anaerobic intra-abdominal abscesses in a highly reproducible chronic rat model.

A single, uniform abscess was formed in 100% of the animals inoculated with a fecal pellet made of sterile rat feces, agar, and a known number and strain of bacteria. The effects of monoclonal Escherichia coli abscess (83 rats) were compared to those of sterile abscess (34 rats) and sham operation (35 rats without abscess). Bacteroides fragilis was added to the sterile pellet to study the effect of an anaerobic monoclonal abscess (16 rats) or of a biclonal abscess containing both aerobes and anaerobes (32 rats). After inoculation, a peritonitis stage with leucopenia, hypoglycemia, body weight loss, and slight fever was followed by the abscess stage with leucocytosis and a slight hyperglycemia. Mild hepatic energy charge deficiency and hepatic lactic acidosis were observed in sterile abscess rats, and slightly enhanced energy charge was seen in monoclonal E. coli abscess rats. The addition of B. fragilis to the sterile pellet, alone or together with E. coli, produced hepatic energy charge deficiency and hepatic lactic acidosis, which were significantly enhanced compared with the monoclonal E. coli abscess rats. The greatest effect was seen in the biclonal E. coli plus B. fragilis abscess, suggesting that anaerobic or combined aerobe and anaerobe abscesses may produce a greater hepatic injury than an aerobic organism abscess alone. This may account for the apparent synergic interaction between aerobic and anaerobic organisms.

Beclomethasone dipropionate administration via cecostomy in ulcerative colitis.

Beclomethasone dipropionate was administered via a cecostomy to four patients with active ulcerative colitis that was refractory to conventional glucocorticosteroid therapy. From a tube cecostomy, beclomethasone dipropionate solution was administered continuously throughout the day. Clinical manifestations, laboratory examinations, and endoscopic and/or radiographic findings markedly improved within 1-2 wk. A serial decrease in the index of disease activity was observed from the time administration began (mean score, 226.0) to 2 wk later (137.4 points). An excellent clinical response was recognized without any significant side effects, and the urgent need for total colectomy was avoided in all four patients.

Findings from an evaluation of PlanAlyzer's double cross-over trials of computer-based, self-paced, case-based programs in anemia and chest pain diagnosis.

We report on three years of research trials of the PlanAlyzer I Project--a carefully controlled research study using a microcomputer-based, self-paced, case-based, event-driven system for medical education. PlanAlyzer presents cases, elicits and critiques a second year student's approach to the diagnosis of anemias and chest pain. PlanAlyzer uses text, hypertext, images and critiquing theory. Students were randomized, one half becoming the experimental group who received the interactive PlanAlyzer cases in anemia, the other half becoming the controls who received the exact same content material in a text format. Later in each year there was a crossover, the controls becoming the experimentals for a similar intervention with the cardiology PlanAlyzer cases. Results at the end of the first two years of trials show that the programs have achieved some significant efficiency and economy gains. 96 faculty hours of classroom time were saved by using PlanAlyzer in their place, with no loss in student achievement. In terms of student proficiency and efficiency, combining the anemia and cardiology trials, the 328 students in the two years of full scale trials were able to accomplish the project's instructional objectives. The experimentals accomplished this in 43% less time than the controls. On the average, for both the anemia and chest pain programs, this amounted to students spending 7.5 hours longer on the 30 text cases than on the same 30 computer cases to achieve the same level of mastery. There have been no significant proficiency differences (as measured by current post-tests) between the experimental and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Significant efficiency findings while controlling for the frequent confounders of CAI research in the PlanAlyzer project's computer-based, self-paced, case-based programs in anemia and chest pain diagnosis.

Richard E. Clark in his widely published comprehensive studies and meta-analyses of the literature on computer assisted instruction (CAI) has decried the lack of carefully controlled research, challenging almost every study which shows the computer-based intervention to result in significant post-test proficiency gains over a non-computer-based intervention. We report on a randomized study in a medical school setting where the usual confounders found by Clark to plague most research, were carefully controlled. PlanAlyzer is a microcomputer-based, self-paced, case-based, event-driven system for medical education which was developed and used in carefully controlled trials in a second year medical school curriculum to test the hypothesis that students with access to the interactive programs could integrate their didactic knowledge more effectively and/or efficiently than with access only to traditional textual "nonintelligent" materials. PlanAlyzer presents cases, elicits and critiques a student's approach to the diagnosis of two common medical disorders: anemias and chest pain. PlanAlyzer uses text, hypertext, images and critiquing theory. Students were randomized, one half becoming the experimental group who received the interactive PlanAlyzer cases in anemia, the other half becoming the controls who received the exact same content material in a text format. Later in each year there was a crossover, the controls becoming the experimentals for a similar intervention with the cardiology PlanAlyzer cases. Preliminary results at the end of the first two full trials shows that the programs have achieved most of the proposed instructional objectives, plus some significant efficiency and economy gains. 96 faculty hours of classroom time were saved by using PlanAlyzer in their place, while maintaining high student achievement. In terms of student proficiency and efficiency, the 328 students in the trials over two years were able to accomplish the project's instructional objectives, and the experimentals accomplished this in 43% less time than the controls, achieving the same level of mastery. However, in spite of these significant efficiency findings, there have been no significant proficiency differences (as measured by current factual and higher order multiple choice post-tests) between the experimental and control groups. Very careful controls were used to avoid what Clark has found to be the most common confounders of CAI research. Accordingly, this research proved Clark's rival hypothesis, that the computer, in itself, does not appear to contribute to proficiency gains, at least as measured by our limited post-testing. Clark's position is that the computer is primarily a vehicle--as is either a pill or a hypodermic needle for delivering a drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical experience of postoperative hepatic failure treatment with pig or baboon liver cross-hemodialysis with an interposed membrane.

The present study emphasizes the principle of using liver support to restore the blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), which reflects the redox potential of liver mitochondria and correlates with hepatic energy charge (ATP + 0.5ADP/ATP + ADP + AMP). Eleven surgical patients with grade IV hepatic coma were treated by an ex vivo pig or baboon liver cross-hemodialysis with an interposed Cuprophan membrane when their blood ketone body ratios had decreased to below 0.4 compared with the normal of above 0.7. Three patients were treated by cross-hemodialysis using a standard Cuprophan membrane dialyzer without increase of blood ketone body ratio and without marked beneficial effect. However, five of eight patients who had blood ketone body ratios of above 0.25 became fully alert after treatment by cross-hemodialysis using the larger pore size and greater surface area Cuprophan membrane, concurrent with a rise in the decreased blood ketone body ratio, and three of them were later discharged. By contrast, in the three patients with blood ketone body ratios below 0.25, there was no restoration of consciousness and no improvement in their blood ketone body ratios by this liver support. It is suggested that, as long as the blood ketone body ratio remained over 0.25, this metabolic liver support is effective in restoring grade IV hepatic coma.

The effects of heterologous liver cross-hemodialysis on adenylate energy charge of the remnant liver after major hepatic resection.

The effect of liver support on the adenylate energy charge (ATP + 0.5ADP)/(ATP + ADP + AMP) of the remnant liver after major hepatic resection was studied in rabbits. The present study emphasized the principle of restoring the decreased energy charge level of the remnant liver after major hepatic resection by use of an ex vivo heterologous liver cross-hemodialysis with an interposed Cuprophan membrane. The energy charge level provides the cell with a very sensitive intracellular control mechanism. Regulatory enzymes from biosynthetic sequences exhibit very little activity at low levels of energy charge, and their activities increase sharply at high-energy charge levels. The energy charge level of the remnant liver maximally decreased from the control level of 0.860 to 0.767 at 24 hours after 70% hepatectomy. The energy charge level increased from 0.767 to 0.857 after two hours of cross-hemodialysis with an interposed Cuprophan membrane between the 24-hour, 70% hepatectomized rabbit and an ex vivo pig liver with high energy charge. The above results suggest that this ex vivo pig cross-hemodialysis may be effective for biosynthesis in the regenerative processes of the remnant liver.