Stage IV renal cell carcinoma achieves pathologic complete response after two ipilimumab plus nivolumab courses despite severe immune-related adverse events: a case report.

BACKGROUND: Ipilimumab (Ipi) plus nivolumab (Nivo) is the recommended first-line treatment for renal cell carcinoma (RCC). This report describes a case where pancreatic metastases disappeared after only two courses of Ipi + Nivo therapy. The primary tumor was cured by surgery, and a pathological Complete Response (pCR) was observed despite multiple serious immune-related Adverse Events (irAEs). CASE PRESENTATION: A 54-year-old woman with RCC and pancreatic metastasis at stage IV, diagnosed with intermediate risk according to the International Metastatic RCC Database Consortium classification, underwent initiation of Ipi + Nivo therapy. On day 26, she developed hyperthyroidism accompanied by tachycardia, leading to the commencement of metoprolol tartrate treatment. Following the resolution of tachycardia, a second course of Ipi + Nivo therapy was administered on day 50. By day 70, the patient exhibited Grade 3 hepatic dysfunction, followed by the onset of hypothyroidism on day 75, necessitating treatment with steroids and levothyroxine. After positive treatment, a Grade 3 skin disorder emerged on day 87 while tapering steroids, prompting treatment with methylprednisolone (mPSL) pulse therapy. The skin disorder responded to steroids, allowing for tapering. However, on day 113, a recurrence of Grade 3 skin disorder occurred, necessitating another mPSL pulse. The patient responded well to treatment, exhibiting improvement in her condition. On day 131, she presented at the hospital with complaints of respiratory distress, prompting a Computed Tomography (CT) scan that revealed interstitial pneumonia. By day 272, subsequent CT imaging showed the disappearance of pancreatic metastasis and shrinkage of the primary tumor. On day 294, she underwent a laparoscopic left nephrectomy. Pathological analysis confirmed a pCR in the primary tumor, indicating successful eradication of RCC through surgical intervention. CONCLUSIONS: This case report presents a scenario where multiple severe irAEs appeared in a patient, yet metastases disappeared after only two courses of Ipi + Nivo therapy. The patient was ultimately cured by surgery and achieved a pCR. This case highlights that despite the occurrence of severe irAEs during RCC treatment with Ipi + Nivo therapy, they can be managed appropriately to maximize the therapeutic effects of checkpoint inhibitors.

Risk factors for thromboembolism during first-line treatment of patients with unresectable advanced or recurrent colorectal cancer: a retrospective short study.

BACKGROUND: While cancer is a risk factor for developing thromboembolism, so is the use of molecularly targeted therapies. This study aimed to determine whether thromboembolism incidence differed between vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitor use in patients with unresectable advanced or recurrent colorectal cancer, and to compare the risk of thromboembolism caused by cancer and the use of molecular targeted therapy drugs. MAIN BODY: We retrospectively evaluated patients with unresectable advanced or recurrent colorectal cancer who were treated with a cytotoxic anticancer drug and a VEGF or EGFR inhibitor combination between April 2016 and October 2021. Patients were compared in terms of the regimen administered, thromboembolism occurrence during the first-line treatment period, patient background, and clinical laboratory values. Of the 179 included patients, 12 of 134 (8.9%) in the VEGF-inhibitor group and 8 of 45 (17.8%) in the EGFR-inhibitor group developed thromboembolism, with no significant difference between the groups (P = 0.11). There was no significant difference in time to thromboembolism between patients in the VEGF- inhibitor group and patients in the EGFR-inhibitor group (P = 0.206). The cutoff value determined by a receiver operating characteristic analysis for the occurrence of thromboembolism was one point. Multivariate analysis using the occurrence of thromboembolism as the response variable identified at least one risk factor for thromboembolism (odds ratio = 4.17, P = 0.006, 95% confidence interval = 1.51-11.50). Molecular targeted therapies were not identified as a risk factor. CONCLUSIONS: Although the small sample size, there was no difference in the incidence of thromboembolism between the two molecular-targeted therapies in first-line treatment of patients with unresectable advanced or recurrent colorectal cancer. Our results suggest that risk factors for thromboembolism may be more strongly influenced by cancer itself than by the use of molecularly targeted therapies.

Alleviation of Dyspnea and Changes in Physical Activity Level by Air Flow to the Face With a Fan.

BACKGROUND: Dyspnea is an unpleasant subjective symptom and is associated with decreased physical activity level (PAL). Effect of blowing air toward the face has received a great deal of attention as a symptomatic therapy for dyspnea. However, little is known about the duration of its effect and its impact on PAL. Therefore, this study aimed to measure dyspnea severity and changes in dyspnea and PALs with air blasts to the face. METHODS: The trial conducted was open-label, randomized, and controlled. This study included out-patients with dyspnea caused by chronic respiratory deficiency. Subjects were provided a small fan and instructed to blow air toward their faces either twice a day or when having trouble breathing. Subsequently, severity of dyspnea and PALs was measured using visual analog scale and physical activity scale for the elderly (PASE), respectively, before and after 3-week treatment. Amounts of changes in dyspnea and PALs before and after treatment were compared using analysis of covariance. RESULTS: Overall, 36 subjects were randomized, and 34 were analyzed. Mean age was 75.4 y (26 males [76.5%] and 8 females [23.5%]). Visual analog scale score for dyspnea (SD) before treatment was 33 (13.9) mm and 42 (17.5) mm in the control and intervention groups, respectively. PASE score before treatment was 78.0 (45.1) and 57.7 (38.0) in the control and intervention groups, respectively. No significant difference in changes in dyspnea severity and PAL was observed between the 2 groups. CONCLUSIONS: No significant difference was observed for dyspnea and PALs in subjects after blowing air toward their own faces with a small fan for 3 weeks at home. Disease variability and impact of protocol violations were high due to small number of cases. Further studies with a design focused on subject protocol adherence and measurement methods are required to understand impact of air flow on dyspnea and PAL.

Eicosapentaenoic acid (EPA)-induced inhibitory effects on porcine coronary and cerebral arteries involve inhibition of prostanoid TP receptors.

This study was performed to elucidate whether eicosapentaenoic acid (EPA) suppresses spasm-prone blood vessel contractions induced by a thromboxane mimetic (U46619) and prostaglandin F2α (PGF2α) and determine whether the primary target of EPA is the prostanoid TP receptor. Accordingly, we assessed: (1) the tension changes in porcine basilar and coronary arteries, and (2) changes in the Fura-2 (an intracellular Ca2+ indicator) fluorescence intensity ratio at 510 nm elicited by 340/380 nm excitation (F340/380) in 293T cells expressing the human TP receptor (TP-293T cells) and those expressing the human prostanoid FP receptor (FP-293T cells). EPA inhibited both porcine basilar and coronary artery contractions induced by U46619 and PGF2α in a concentration-dependent manner, but it did not affect the contractions induced by 80 mM KCl. EPA also inhibited the increase in F340/380 induced by U46619 and PGF2α in TP-293T cells. In contrast, EPA showed only a marginal effect on the increase in F340/380 induced by PGF2α in FP-293T cells. These findings indicate that EPA strongly suppresses the porcine basilar and coronary artery contractions mediated by TP receptor and that inhibition of TP receptors partly underlies the EPA-induced inhibitory effects on these arterial contractions.

Docosahexaenoic acid inhibits U46619- and prostaglandin F2α-induced pig coronary and basilar artery contractions by inhibiting prostanoid TP receptors.

Docosahexaenoic acid (DHA, an n-3 polyunsaturated fatty acid) inhibits U46619 (a TP receptor agonist)- and prostaglandin F2α-induced contractions in rat aorta and mesenteric arteries. However, whether these effects could be replicated in vasospasm-prone vessels, such as coronary and cerebral arteries, remains unknown. Here, we evaluated the changes in pig coronary and basilar artery tensions and intracellular Ca2+ concentrations in human prostanoid TP or FP receptor-expressing cells. We aimed to clarify whether DHA inhibits U46619- and prostaglandin F2α-induced contractions in spasm-prone blood vessels and determine if the TP receptor is the primary target for DHA. In both pig coronary and basilar arteries, DHA suppressed U46619- and prostaglandin F2α-induced sustained contractions in a concentration-dependent manner, but did not affect contractions induced by 80 mM KCl. SQ 29,548 (a TP receptor antagonist) suppressed U46619- and prostaglandin F2α-induced contractions by approximately 100% and 60%, respectively. DHA suppressed both U46619- and prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human TP receptor-expressing cells. However, DHA did not affect prostaglandin F2α-induced increases in intracellular Ca2+ concentrations in human FP receptor-expressing cells. These findings suggest that DHA potently inhibits TP receptor-mediated contractions in pig coronary and basilar arteries, and the primary mechanism underlying its inhibitory effects on arterial contractions involves inhibiting TP receptors.

Lowering effect of viable Pediococcus pentosaceus QU 19 on the rise in postprandial glucose.

In the present study, we investigated the glucose-decreasing action of lactic acid bacteria (LAB). The finding of this study could be helpful for people in controlling their blood sugar levels. The LAB candidate was isolated from a Japanese fermented food and identified as Pediococcus pentosaceus by an analysis of its genome sequence. Postprandial blood glucose elevation was investigated using oral starch tolerance tests in mice. Normal mice were fed starch and lyophilized cells of P. pentosaceus QU 19 at the same time. Even without pre-administration of P. pentosaceus QU 19, elevation of the blood glucose level was significantly suppressed by the intake of P. pentosaceus QU 19 at the same time as oral administration of starch. According to the results for its survival in simulated digestive juice and the reduction of blood glucose level in mice, P. pentosaceus QU 19 has potential hypoglycemic activity. In vitro measurements revealed that the glucose-decreasing action of P. pentosaceus QU 19 is probably caused by the glucose assimilation of the strain, not the inhibition of carbohydrate-splitting enzymes which has been reported for other LABs previously. These findings indicate that specific strains of LAB, especially P. pentosaceus QU 19, and foods fermented by LAB may be beneficial for people who must manage glucose ingestion.

Development of multiplex PCR for rapid identification of four Salmonella serovars most commonly isolated in Japan.

More than 2,500 serovars of Salmonella species have been reported to date. A multiplex-PCR method was developed and evaluated for discriminating the four Salmonella enterica subsp enterica serovars, namely, S. Enteritidis, S. Typhimurium, S. Thompson and S. Infantis, most commonly isolated in Japan. Twenty-two serovars of 84 Salmonella strains and 7 species of non-Salmonella strains were evaluated using primer pairs specific for the detection of Salmonella spp. Multiplex PCR generated, with 100% specificity, the expected amplicon of 333, 413, 551 and 658 bp of S. Enteritidis, S. Infantis, S. Typhimurium, and S. Thompson, respectively, while an additional non-specific amplicon (about 1,000 bp) was observed for S. Infantis, but it had no practical impact in the bacterial detection. This multiplex PCR assay can be applied to identify and discriminate clinically significant strains of Salmonella serovars rapidly and accurately without the need for serological examination.

Antimicrobial resistance in Salmonella strains clinically isolated in Hyogo, Japan (2009-2012).

The purpose of this study was to examine the in vitro susceptibilities to antimicrobial agents and genetic diversity of 195 clinical strains of Salmonella spp., which were isolated and examined for the extended-spectrum ß-lactamase (ESBL) blaCTX-M gene and the presence of gyrA, gyrB, parC, and parE genes mutations in Hyogo, Japan, from 2009 to 2012. Forty-three of the 195 strains were antimicrobial resistant. Two Salmonella enterica subsp. enterica strains, 1 serovar Schwarzengrund, and 1 serovar Enteritidis were identified as ESBL-producing strains possessing blaCTX-M-15 and blaCTX-M-2, respectively. Among 8 nalidixic acid-resistant strains, 7 had mutations in gyrA alone or in gyrA and parC. In conclusion, we identified CTX-M ESBL-producing Salmonella clinical strains with multidrug resistance. Further studies are needed to monitor these serious drug-resistant Salmonella strains in Japan.

Ingestion of low dose pyroglutamyl leucine improves dextran sulfate sodium-induced colitis and intestinal microbiota in mice.

Inflammatory bowel diseases (IBD) are based on chronic inflammation in the gastrointestinal tract. We previously found anti-inflammatory peptide pyroGlu-Leu in the enzymatic hydrolysate of wheat gluten. The objective of present study is to elucidate improvement of colitis by oral administration of pyroGlu-Leu in an animal model. Acute colitis was induced by dextran sulfate sodium (DSS), and various concentrations of pyroGlu-Leu were administrated by oral gavage for 7 days. A dose of 0.1 mg/kg body weight/day showed the most significant improvement. The pyroGlu-Leu concentration was significantly increased 24 h after oral administration both in the small intestine and the colon compared with the baseline. It was 20-fold higher in the small intestine than the colon. Administration of pyroGlu-Leu normalized population of Bacteroidetes and Firmicutes in the colon. These results indicate that pyroGlu-Leu has a potential therapeutic effect against IBD at a practical dose.

[Comparison of detection sensitivity in rapid-diagnosis influenza virus kits].

Rapid-diagnosis kits able to detect influenza A and B virus by immunochromatography developed by different manufacturers, while useful in early diagnosis, may vary widely in detection sensitivity. We compared sensitivity results for eight virus-detection kits in current use--Quick Chaser FluA, B (Mizuho Medy), Espline Influenza A & B-N (Fujirebio), Capilia Flu A + B (Nippon Beckton Dickinson & Alfesa Pharma), Poctem Influenza A/B (Otsuka Pharma & Sysmex), BD Flu Examan (Nippon Beckton Dickinson), Quick Ex-Flu "Seiken" (Denka Seiken), Quick Vue Rapid SP Influ (DP Pharma Biomedical), and Rapid Testa FLU stick (Daiichi Pure Chemicals)--against influenza virus stocks, contained five vaccination strains (one A/H1N1, two A/H3N2, and two B) and six clinical strains (two A/H1N1, two A/H3N2, and two B). Minimum detection concentrations giving immunologically positive signals in serial dilution and RNA copies in positive dilution in real-time reverse transcriptase-polymerase chain reaction (RT-PCR) were assayed for all kits and virus stock combinations. RNA log10 copy numbers/mL in dilutions within detection limits yielded 5.68-7.02, 6.37-7,17, and 6.5-8.13 for A/H1N1, A/H3N2, and B. Statistically significant differences in sensitivity were observed between some kit combinations. Detection sensitivity tended to be relatively higher for influenza A than B virus. This is assumed due to different principles in kit methods, such as monoclonal antibodies, specimen-extraction conditions, and other unknown factors.