Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

A predictive factor of insufficient liver regeneration after preoperative portal vein embolization.

BACKGROUND: Preoperative portal vein embolization (PVE) is performed to enhance the future remnant liver function (FRLF) and volume (FRLV). However, the volume of the nonembolized liver does not increase enough in some patients, which results in an insufficient FRLF. The aim of this study was to evaluate the predictors of insufficient FRLF after PVE for extended hepatectomy. METHODS: This retrospective study included 172 patients (107 patients with cholangiocarcinoma, 40 patients with metastatic liver cancer and 25 patients with hepatocellular carcinoma) who underwent PVE before extended hepatectomy. The total liver function was evaluated by measuring the indocyanine green plasma clearance rate (KICG). Computed tomography volumetry was conducted to evaluate the total liver volume and FRLV. The KICG of the future remnant liver (remK) was calculated using the following formula: KICG × FRLV/total liver volume. The safety margin for hepatectomy was set at remK after PVE (post-PVE remK) ≥ 0.05. RESULTS: One hundred and twenty-three patients with a post-PVE remK level of >0.05 underwent hepatectomy without postoperative liver failure [sufficient liver regeneration (SLR) group], and 9 patients with a post-PVE remK level of <0.05 did not due to insufficient FRLF [insufficient liver regeneration (ILR) group]. In the SLR group, the KICG values did not change after PVE (median, 0.144-0.146, p = 0.523); however, the %FRLV and remK increased significantly (35.0-44.3%, p < 0.001 and 0.0488-0.0610, p < 0001, respectively). In contrast, in the ILR group, the KICG values decreased significantly (0.128-0.108, p = 0.021) and the %FRLV increased marginally (27.4-32.6%, p = 0.051). As a result, the remK did not increase significantly (0.0351-0.0365, p = 0.213). A receiver operating characteristic curve demonstrated an remK value of 0.04 obtained before PVE (pre-PVE remK) to be the optimal cutoff point for defective liver regeneration. The univariate and multivariate analyses revealed that a pre-PVE remK value of <0.04 was a factor for ILR. It was also correlated with postoperative liver failure in the analysis of the patients who underwent hepatectomy. CONCLUSIONS: The patients in the ILR group did not achieve SLR after PVE due to a significant decrease in the KICG and an insufficient increase in %FRLV. A pre-PVE remK value of <0.04 is a useful predictor of insufficient regeneration of the nonembolized liver, even after PVE.

Criteria for drain removal following liver resection.

BACKGROUND: Abdominal drains have been placed prophylactically and removed in liver resection without robust evidence. The present study was designed to establish the optimal time for removal of such drains. METHODS: Data on abdominal prophylactic drains were analysed in a consecutive series of patients who underwent liver resection for malignancy between 2006 and 2009. Bilirubin levels in drain fluid were measured and bacteriological cultures were taken on days 1, 3, 5 and 7 after surgery. Drains were removed on day 3 if the drain-fluid bilirubin level was less than 5 mg/dl and bacteriological cultures were negative. Drains remained in situ until these conditions were met. RESULTS: A total of 514 abdominal drains were placed in 316 patients operated on in the study period. Fifty-eight patients (18·4 per cent) had positive drain-fluid cultures and 14 (4·4 per cent) had bile leakage (drain-fluid bilirubin level 5 mg/dl or more). Only one patient required ultrasound-guided abdominal drainage. On multivariable analysis, drain-fluid bilirubin level on day 3 after surgery was the strongest predictor of infection (odds ratio 15·11, 95 per cent confidence interval 3·04 to 92·11; P < 0·001). The area under the receiver operating characteristic curve on day 3 had the highest predictive value: 83·6 per cent accuracy and 3·9 per cent false-positive rate for a drain-fluid bilirubin level of 3·01 mg/dl (51·5 µmol/l). CONCLUSION: The '3 × 3 rule' (drain-fluid bilirubin level below 3 mg/dl on day 3 after operation) is an accurate criterion for removal of prophylactically placed abdominal drains in liver resection.

Immune recovery after autologous PBSC transplantation without in vitro graft manipulation for refractory systemic lupus erythematosus.

Autologous hematopoietic SCT (ASCT) has been investigated as salvage therapy for refractory systemic lupus erythematosus (SLE). Although immune recovery after ASCT with in vitro purging of lymphocytes has been extensively studied, little information is available about immune recovery after ASCT without in vitro purging. Therefore, we analyzed the immune recovery of a patient who successfully underwent ASCT without in vitro purging for refractory SLE. In addition to the numbers of PBL subsets, T-cell receptor rearrangement excision circles (TRECs) and the T-cell receptor repertoire diversity of both CD4+ and CD8+ T cells were sequentially analyzed. All SLE-related symptoms disappeared within 3 months after ASCT and the serum anti-dsDNA Ab became undetectable. The number of CD4+CD45RO+ memory T cells remained lower than that in healthy adult controls, but the number of CD4+CD45RA+ naïve T cells showed a rapid increase after ASCT. TRECs of both CD4+ and CD8+ T cells were strongly suppressed before ASCT, but consistently increased after ASCT. The T-cell receptor repertoire of CD8+ T cells was skewed before ASCT, but the diversity recovered after ASCT. ASCT with the reinfusion of a large number of autologous T cells did not impair the recovery of naive T cells or resetting of the immune system.

A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins.

BACKGROUND/AIMS: A major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), has previously been shown to induce cell-cycle arrest and apoptosis in various cancers. However, little is known about its effects on hepatocellular carcinomas (HCCs). METHODS: Four HCC cell lines, HLE, HepG2, HuH-7 and PLC/PRF/5, were treated with EGCG or vehicle. Cell viability was assessed by trypan blue staining and WST-8 assay. Cell-cycle, apoptosis and apoptosis-related proteins in HLE cells were evaluated by flow cytometry and Western blotting. The effect of EGCG was also studied in vivo using a xenograft model. The effect of co-treatment with EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was also assessed. RESULTS: EGCG inhibited the growth of all HCC cell lines at concentrations of 50-100 microg/ml. In HLE cells, EGCG induced apoptosis but not cell-cycle arrest and appears to have down-regulated Bcl-2alpha and Bcl-xl by inactivation of NF-kappaB. Oral administration of EGCG showed similar effects in HLE xenograft tumors. Co-treatment with EGCG and TRAIL synergistically induced apoptosis in HLE cells. CONCLUSIONS: EGCG induced apoptosis in HLE cells, both in vitro and in vivo. Moreover, it enhanced TRAIL-induced apoptosis. Therefore, EGCG treatment may be useful for improving the prognosis of HCCs.

A novel single-nucleotide polymorphism at the 5'-flanking region of SAA1 associated with risk of type AA amyloidosis secondary to rheumatoid arthritis.

OBJECTIVE: To address whether the gamma haplotype at exon 3 of the SAA1 gene is directly associated with type AA amyloidosis or is merely in linkage with an unknown polymorphism that is primarily associated with disease risk, we examined the SAA1 gene for new polymorphisms. METHODS: We analyzed DNA samples from 44 rheumatoid arthritis (RA) patients with AA amyloidosis (amyloid group), 55 RA patients without AA amyloidosis (RA group), and 58 non-RA healthy subjects (non-RA group). We also examined DNA samples from 50 Caucasians to compare linkage disequilibrium relationships involving SAA1 region polymorphisms between Japanese and Caucasoid populations. RESULTS: We observed 3 novel single-nucleotide polymorphisms (SNPs) in the 5'-flanking region of SAA1: -61C/G, -13T/C, and -2G/A. Comparison of allele frequencies and ratios of individuals with particular alleles between the study groups revealed statistically significant differences between the amyloid and RA groups and between the amyloid and non-RA groups. Statistical analysis revealed that the -13T/C SNP was strongly associated with AA amyloidosis. In addition, we found tight linkage between the -13T allele and the alpha haplotype, rather than the beta haplotype, at exon 3 in the Caucasoid population, while -13T was closely linked to the gamma and beta haplotypes, rather than the alpha haplotype, in the Japanese population. Since the linkage disequilibrium relationship was reversed between the Japanese and Caucasoid populations, different exon 3 haplotypes of SAA1 are found to be associated with the risk of AA amyloidosis in different ethnic groups. CONCLUSION: Our data suggest that the SAA1 -13T allele, rather than SAA1 exon 3 haplotypes, is primarily associated with AA amyloidosis risk.

Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA-amyloidosis in patients with rheumatoid arthritis.

To examine whether polymorphism at the SAA loci is associated with the development of amyloid protein A (AA)-amyloidosis, we determined the genotypes at the SAA1 and SAA2 loci in 43 AA-amyloidosis patients (amyloidosis population) and 77 patients with rheumatoid arthritis (RA) who had been ill for less than 5 years (early RA population). We also compared the frequencies of the genotypes at the SAA1 locus among 90 Korean, 95 Taiwanese, and 103 Japanese healthy subjects. The frequencies of the gamma/gamma genotype and gamma alleles at the SAA1 locus were significantly higher in the amyloidosis population than in the early RA population (34.9% versus 7.8%, and 58.1% versus 33.8%, chi2 test P=0.0001). The frequencies of the gamma allele at the SAA1 locus in Koreans, Taiwanese, and Japanese were 41.6%, 35.6%, and 37.4%, respectively. The length of the latent period of AA-amyloidosis was significantly longer in the patients with smaller numbers of the gamma allele at the SAA1 locus (Spearman's correlation coefficient: -0.42, P<0.05). On the other hand, the mean C-reactive protein (CRP) level during 2 years prior to the diagnosis of AA-amyloidosis was significantly higher in the patients with larger numbers of the gamma allele at the SAA1 locus (Spearman's correlation coefficient: 0.34, P<0.05). No significant association was found between amyloidosis and polymorphism at the SAA2 locus. We postulate that the allele SAA1gamma renders an RA patient susceptible to amyloidosis, possibly by affecting the severity of inflammation in RA.

Therapeutic effects of LK 423, a phthalimido-desmuramyl-dipeptide compound, on dextran sulfate sodium-induced colitis in rodents through restoring their interleukin-10 producing capacity.

A new phthalimido compound, N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-glutamic acid (CAS 142489-47-2, LK 423), was examined for its possible activity to modulate levels and species of cytokines in mice carrying a specific inflamed organ. Colonic inflammation was induced in mice by giving 5% dextran sulfate sodium (DSS) solution as drinking water. The capacity of spleen cells obtained from the DSS-inflamed mice to produce interleukin-10 (IL-10) in response to mitogen was significantly reduced when compared with the capacity of spleen cells from intact mice. Treatment of the mice administered DSS by subcutaneous multiple injections with a low dose of LK423 resulted in delaying the progression to full-blown inflammation in the colon. The mitogen-stimulated spleen cells obtained from the LK423-treated mice yielded significantly greater amounts of IL-10 and IL-6 than the untreated DSS group, and the peritoneal cells from the LK423-treated mice produced significantly lower levels of tumor necrosis factor alpha (TNF alpha). Based on this prophylactic effect of LK423 in the murine colitis model, its therapeutic effect was examined in rats in which colitis had been induced by feeding 3% DSS for 12 days. Intracolonic administration of LK423 to these rats for 7 days resulted in diminishing the ulcerative area in the colon. The immunological characteristics of this new compound are discussed from the point of view of its possible application as a therapeutic agent for inflammatory bowel diseases (IBD) and other inflammatory diseases.

Eosinophilic fasciitis complicated with peripheral polyneuropathy.

Peripheral polyneuropathy and the complication of eosinophilic fasciitis (EF) is rare; only 2 such cases have been described previously. A 40-year-old woman suffered from swelling of the extremities after strenuous exercise and complained of bilateral paresthesia on the soles of her feet. The diagnosis was EF according to clinical symptoms, peripheral eosinophilia, and histological examination of the fascia. Nerve conduction tests also revealed sensory disturbance as mononeuritis multiplex. After administration of prednisolone, the swelling and tenderness of the extremities improved immediately but the neuropathy lasted for 6 months.

[Cyclophosphamide pulse therapy for refractory rheumatic diseases].

We studied the efficacy of cyclophosphamide pulse therapy (CYP) for refractory rheumatic diseases except for lupus nephritis. Thirty-five patients were included in all, that is 9 patients with systemic lupus erythematosus (SLE), 10 with rheumatoid arthritis (RA), 7 with polymyositis/dermatomyositis (PM/DM), 2 with progressive systemic sclerosis (PSS), 2 with anti-phospholipid antibody syndrome (APS), 1 with mixed connective tissue disease (MCTD), 1 with juvenile rheumatoid arthritis (JRA), 1 with Behcet's disease (BD), 1 with Wegener's granulomatosis (WG) and 1 with allergic granulomatous angiitis (AGA). Moderate to marked improvement was noted in 4 patients with SLE (2 with CNS-lupus and 2 with vasculitis), 7 with RA (2 with interstitial pneumonia:IP, 2 with vasculitis and 2 with refractory arthritis), 4 with PM/DM (2 with IP and 2 with refractory myositis), 1 PSS with IP, 2 APS with thrombocytopenia, 1 JRA with vasculitis and BD with CNS disturbance. On the other hand, adverse reactions were observed in 9 out of 35 patients (25.8%). CYP should apply in the treatment for such refractory rheumatic diseases as CNS disturbance, vasculitis, IP and autoimmune thrombocytopenia.

Intracranial epidermoid carcinoma: CT and MRI.

We report a patient with an epidermoid carcinoma an extremely rare brain tumour, in the right cerebellopontine angle cistern. Contrast enhancement is the most important feature for differential diagnosis of epidermoid carcinomas from atypical benign epidermoid cysts.

Effect of beta-carotene, sodium ascorbate and cellulose on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats.

Male Sprague-Dawley rats were fed a diet containing either 0.005% beta-carotene, 0.02% sodium ascorbate or 1.5% cellulose for 14 weeks. Beginning on day 3, all animals were also given weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt.) throughout a 12-week period. The experimental diet was continued for an additional 14 weeks. At the end of the 26th week, surviving animals were sacrificed and the incidence of intestinal carcinomas was examined. A significantly lower incidence of carcinomas was observed in the beta-carotene-fed group (55.0%), compared with that in the control group given DMH (82.1%).

[The significance of portal infusion chemotherapy for prevention of recurrence in residual liver after hepatectomy for metastases from colorectal cancer].

We performed portal infusion chemotherapy using a reservoir for prevention of recurrence in residual liver after hepatectomy for metastases from colo-rectal cancer. To study the usefulness of portal infusion chemotherapy, the period from hepatectomy to recurrence in residual liver was investigated by three treatment groups for H2 cases; (a) a group of systemic chemotherapy, (b) a group of arterial infusion chemotherapy and (c) a portal infusion chemotherapy group. Treatment in (a) group was for 204 +/- 98.2 days (n = 6), in (b) group for 343.0 +/- 238.3 days (n = 8) and in (c) group for 961.0 +/- 1,172.4 days (n = 5). There was no statistically significant difference in the three groups, but (c) group had a better result in recurrence in residual liver. As for prevention of recurrence in residual liver after re-hepatectomy, there was no significant difference in the three groups, but (c) group had the longest survival.

Purification and characterization of thermostable beta-N-acetylhexosaminidase of Bacillus stearothermophilus CH-4 isolated from chitin-containing compost.

Thermostable exochitinase was purified to homogeneity from the culture fluid of Bacillus stearothermophilus CH-4, which was isolated from agricultural compost containing shrimp and crabs. The enzyme was a single polypeptide with a molecular mass of 74 kDa, and the N-terminal amino acid sequence was WDKVGVTDLI ISLNIPEADAVVVGMTLQLQALHLY. The enzyme specifically hydrolyzed C-4 beta-anomeric bonding of N-acetylchitooligosaccharides, as well as their p-nitrophenyl (pNP) derivatives. The enzyme also hydrolyzed pNP-beta-N-acetyl-D-galactosaminide (26% of the activity of pNP-beta-N-acetyl-D-glucosaminide). These results indicated that the enzyme is a beta-N-acetylhexosaminidase (EC 3.2.1.52). Kms for acetylchitooligosaccharides were 1 x 10(-4) to 6 x 10(-4) M, while those for the pNP derivatives were 4 x 10(-3) to 8 x 10(-3) M. The optimum temperature of the enzyme was 75 degrees C, and it retained 100 and 28% reactivity after heating at 60 and 80 degrees C, respectively. The enzyme exhibited 15 to 20% activity in a reaction mixture containing 80% organic solvents and maintained 91% of its original activity after exposure to 8 M urea. The optimum and stable pH was around 6.5. Fe2+, Zn2+, and Ca2+ activated the enzyme, but Hg2+ was inhibitory. N-Acetyl-D-glucosamine inhibited the enzyme competitively (Ki = 4.3 x 10(-4) M), whereas N-acetyl-D-galactosamine did not; in contrast, D-glucosamine and D-galactosamine activated it.

Effects of theophylline on the selective increases in intratumoral blood flow induced by intracarotid infusion of adenosine and adenosine triphosphate in C6 glioma-transplanted rat brains.

We have previously reported that the intracarotid administration of adenosine or adenosine triphosphate (ATP) selectively increased blood flow in intracerebrally transplanted C6 glioma cells in rats, using the hydrogen clearance method. In the present paper, we studied the difference between the effects of adenosine and ATP, using theophylline, a P1 purinoceptor blocker. The selective enhancement of the tumor blood flow by intracarotid administration of adenosine was almost totally inhibited by theophylline. In contrast, the selective enhancement by ATP was shown definitely not to be inhibited by theophylline. Therefore, it is supposed that the selective increase of intratumoral blood flow by the intracarotid infusion of adenosine is closely related to the P1 purinoceptor, and the effect of the intracarotid infusion of ATP is composed not only of the effect as degraded into adenosine but also of the effect of ATP itself.

Effects of L-NMMA and L-NNA on the selective ATP-induced enhancement of intratumoral blood flow.

We studied the effects of NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine (L-NNA) on the selective ATP and adenosine-induced enhancement of intratumoral blood flow in rats measured by the hydrogen clearance method. Both adenosine and ATP produced a selective enhancement of the intratumoral blood flow. Neither L-NMMA nor L-NNA had a significant effect on either the CBF or the intratumoral blood flow. Adenosine-induced enhancement was not inhibited by L-NMMA or L-NNA. On the other hand, the ATP-induced enhancement was totally inhibited by both L-NMMA and L-NNA. The inhibitory action of L-NMMA against ATP was blocked by L-arginine, but not by D-arginine. It is suggested that the ATP-induced increase of intratumoral blood flow is evoked by nitric oxide synthesized from the endothelium of the intratumoral blood vessels.

Magnetic resonance imaging of experimental rat brain tumors: histopathological evaluation.

Using RG-C6 glioma-transplanted rats, we studied precontrast and postcontrast magnetic resonance imaging, extravasation of Evans blue, and histology. In all rats, tumor was enhanced with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). The necrotic portion in the tumor, however, was not enhanced. Hemorrhage and hydrocephalus were clearly visualized on both the precontrast and postcontrast images. Blood-brain barrier-disrupted areas stained with Evans blue and areas enhanced with Gd-DTPA on magnetic resonance imaging were nearly consistent. It is suggested that the mechanism of brain tumor enhancement with Gd-DTPA on magnetic resonance imaging is simply related to the degree of alteration of the blood-brain barrier. The Gd-DTPA-enhanced magnetic resonance imaging, even with low magnetic field, is useful for the evaluation of size, shape, and location of experimental rat brain tumors.

[Experience in the use of Kyosera Injection Port as a kind of implantable reservoir (the second report)].

A total of 30 pieces of Kyosera Injection Port, as a kind of implantable reservoir, was used in 29 cases of liver tumor for an intermittent repeated chemotherapy. Of these 27 cases were actually used between Aug. 1st, 1986 and Aug. 31st, 1989. In this paper we studied the safety of the reservoir. The observation period averaged 259.4 days, with the highest of 760 days and the lowest of 29 days. The injection times averaged 12.7 times, with the maximum of 40 times and the minimum of one. The reservoir was placed under the laparotomy, and the cases which underwent cholecystectomy were 93.1%. 16 cases were treated with intraarterial infusion, and 14 with intraportal infusion. We investigated the complication of Kyosera Injection Port in 27 cases. As a result, there were no complication such as catheter occlusion and infection via catheter. But of 27 cases, 8 cases were recognized a complication, and the rate was 29.6%. Lumbago was noted during infusion chemotherapy in three cases, and on the other hand, there were steatolysis and necrosis of the tissue surrounding the implantation site, a movement of port, a catheter out of vessel, a leakage of the drug, and intraabdominal bleeding after taking off the catheter. But of 8 complication cases, only two cases were not able to inject drug. As a result, the rate of complication was 70.4% in over all. On the other hand, of 27 cases, there were 5 cases which recognized the complication caused by reservoir in itself. The safety rate was 81.5%. In such a circumstance this reservoir was very safe and seemed suitable to the implantable reservoir.