Analysis and evaluation of factors contributing to the occurrence of immune-related adverse events with immune checkpoint inhibitors.

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

Rogue and solitary waves in coupled phononic crystals.

In this work we present an analytical and numerical study of rogue and solitary waves in a coupled one-dimensional nonlinear lattice that involves both axial and rotational degrees of freedom. Using a multiple-scale analysis, we derive a system of coupled nonlinear Schrödinger-type equations in order to approximate solitary waves and rogue waves of the coupled lattice model. Numerical simulations are found to agree with the analytical approximations. We also consider generic initialization data in the form of a Gaussian profile and observe that they can result in the spontaneous formation of rogue-wave-like patterns in the lattice. The solitary and rogue waves in the lattice demonstrate both energy isolation and exchange between the axial and rotational degrees of freedom of the system. This suggests that the studied coupled lattice has the potential to be an efficient energy isolation, transfer, and focusing medium.

A Japanese single-hospital observational trial with a retrospective case-control analysis of varicella zoster virus reactivation after autologous peripheral blood stem cell transplantation.

BACKGROUND: Varicella zoster virus (VZV) reactivation following hematopoietic stem cell transplantation (SCT) is common. To help reduce its incidence and to identify predictive factors for VZV reactivation after autologous SCT (auto-SCT), we conducted a retrospective analysis in patients with hematologic malignancy at our hospital. METHODS: We conducted a single-hospital observational trial with a retrospective case-control analysis of post-auto-SCT VZV reactivation in patients with malignant lymphoma (ML) and multiple myeloma (MM) between January 2001 and December 2010, in the Department of Hematology at our hospital. First, we analyzed the cumulative incidence of VZV reactivation during the post-SCT period. Second, we conducted a case-control analysis to identify the risk factors for VZV reactivation within 1 year after SCT. Univariate analyses were performed using Fisher's exact test for categorical variables. A multivariable model and logistic regression were used to assess the risk factors for VZV reactivation. RESULTS: We included 97 patients in this study. The median duration of follow-up was 1027 days. Forty-two patients experienced VZV reactivation after SCT, while 29 (69.0%) experienced reactivation within 1 year after SCT. The cumulative incidence was 30.7% at 1 year and 51.2% for the total observation period. Multivariate analysis showed that engraftment after day 10 was an independent risk factor for VZV reactivation (P = 0.03). CONCLUSIONS: Our study showed a high incidence of VZV reactivation in the first year after auto-SCT in ML and MM patients. Patients with delayed engraftment are at high risk for VZV reactivation and should be considered for prolonged VZV prophylaxis.

Accurate and rapid novel genetic diagnosis for detection of sentinel lymph node metastasis in breast cancer patients.

BACKGROUND: The transcription-reverse transcription concerted reaction (TRC) test is a novel molecular-based procedure, which can assess nodal metastasis accurately and quickly. We examined the usefulness of the TRC test with a double marker, cytokeratin 19 (CK19) and carcinoembryonic antigen (CEA) mRNA, to detect sentinel lymph nodes (SLN) metastasis in breast cancer patients. METHODS: A total of 264 SLNs from 131 breast cancer patients were assigned to a training set (109 SLNs from 50 patients) and validation set (155 SLNs from 81 patients). Cytokeratin 19 and CEA mRNA were detected by TRC tests, and the sensitivity and specificity of the SLN metastasis between the TRC and histology cohorts were compared. RESULTS: Mean copy numbers of CK19 and CEA by TRC tests were increased according to the metastatic size. In the training set, TRC test showed 100% sensitivity, specificity and concordance rates against the permanent histopathology test. In the validation set, sensitivity was 97.1%, specificity was 99.2% and the concordance rate was 99.4%. CONCLUSION: Our results showed that the detection of CK19 and CEA mRNA using the TRC test is, an accurate and rapid method for detection of SLN metastasis and can be applied as an intraoperative molecular diagnosis in breast cancer patients.

Checkpoint and physiological apoptosis in germ cells proceeds normally in spaceflown Caenorhabditis elegans.

It is important for human life in space to study the effects of environmental factors during spaceflight on a number of physiological phenomena. Apoptosis plays important roles in development and tissue homeostasis in metazoans. In this study, we have analyzed apoptotic activity in germ cells of the nematode C. elegans, following spaceflight. Comparison of the number of cell corpses in wild type or ced-1 mutants, grown under either ground or spaceflight conditions, showed that both pachytene-checkpoint apoptosis and physiological apoptosis in germ cells occurred normally under spaceflight conditions. In addition, the expression levels of the checkpoint and apoptosis related genes are comparable between spaceflight and ground conditions. This is the first report documenting the occurrence of checkpoint apoptosis in the space environment and suggests that metazoans, including humans, would be able to eliminate cells that have failed to repair DNA lesions introduced by cosmic radiation during spaceflight.

Development of less invasive surgical procedures for thoracic esophageal cancer.

In order to minimize the invasiveness of the operative procedure for thoracic esophageal cancer, several procedures have been introduced since January 1997. They included: (i) perioperative use of steroids; (ii) muscle-sparing thoracotomy without costectomy; (iii) preparation of the gastric tube with preservation of sufficient blood supply; (iv) reconstruction of the alimentary tract via posterior-mediastinal route; and (v) formation of anastomosis between the remaining esophagus and the gastric tube at a location between the gastroepiploic arteries of the gastric greater curvature. Twenty-one patients who did not receive preoperative chemoradiotherapy underwent the newly developed procedure, and were compared with those receiving the original procedure. Hospital mortality was zero, and postoperative systemic inflammatory response syndrome was suppressed. The mean postoperative hospital stay was 21.5 days, and the actuarial 3-year survival rate was 76.2%. From the comparison with those receiving the original procedure, it can be concluded that the newly developed procedures were effective in minimizing surgical invasiveness and were sufficiently curative in terms of cancer treatment.

Prognostic value of preoperative serum immunosuppressive acidic protein in patients with esophageal squamous cell carcinoma.

Immunosuppressive acidic protein (IAP) is a potent biological marker of immunological surveillance in patients with malignant tumors. The aim of this study was to analyze the clinicopathologic significance of IAP in patients with esophageal carcinoma. Preoperative serum IAP concentration was measured by enzyme-linked immunosorbent assay in 115 patients with primary esophageal squamous cell carcinomas. The associations between clinicopathologic factors, C-reactive protein (CRP) values and IAP concentration were determined. Prognostic values were determined by multivariate analysis using Cox's proportional hazards model. The IAP concentration is significantly higher in patients with stage II-IV cancers than in those with stage I cancer. Significant differences in IAP concentration were observed depending upon tumor size, tumor depth, lymph node status and CRP values. A high IAP concentration, more than 500 micro g/mL, was an independent prognostic factor. Thus, a high IAP concentration is associated with tumor progression and poor survival in patients with esophageal squamous cell carcinoma.

Effects of the concomitant administration of tamsulosin (0.8 mg/day) on the pharmacokinetic and safety profile of theophylline (5 mg/kg): a placebo-controlled evaluation.

We performed a single-blind, sequential-design study to investigate the effects of concomitant oral tamsulosin 0.8 mg/day on the pharmacokinetics and safety of intravenous theophylline 5 mg/kg in healthy subjects. Ten healthy volunteers aged 19-39 years received placebo on study days 0, 1, 2 and 10 and tamsulosin on days 3-9. Theophylline was administered intravenously on days 1 and 9. Theophylline and tamsulosin pharmacokinetic data were determined following administration of the drugs on days 1 and 9 and day 9, respectively. No differences were observed in theophylline pharmacokinetic parameters with and without concomitant tamsulosin, and there were no abnormalities in tamsulosin pharmacokinetic data. Some significant changes in vital signs and a number of mild adverse reactions were reported, but the overall safety profile of tamsulosin and theophylline was acceptable. The results of the study suggest that no dose adjustment in tamsulosin is necessary when it is administered concomitantly with theophylline.

Effects of the concomitant administration of tamsulosin (0.8 mg) on the pharmacokinetic and safety profile of intravenous digoxin (Lanoxin) in normal healthy subjects: a placebo-controlled evaluation.

A 20-day, nonrandomized, open-label, placebo-controlled study was performed to investigate whether concomitant administration of tamsulosin (0.8 mg) affects the pharmacokinetic and safety profile of intravenous digoxin (0.5 mg) in healthy subjects. Ten healthy subjects aged 21-39 years received a single oral dose of placebo on study days 1-8 and tamsulosin on days 9-18. Tamsulosin was initiated at 0.4 mg/day and the dose was increased to 0.8 mg/day from day 11. On days 2 and 15, subjects received a single intravenous dose of digoxin (0.5 mg). Safety monitoring was carried out throughout the study. Following digoxin administration, blood was drawn and urine collected over a 96-h period for pharmacokinetic determinations. Plasma tamsulosin concentrations were measured at regular intervals after dosing on day 15. The digoxin pharmacokinetic parameters with and without concomitant tamsulosin were compared. No significant difference was observed, and no irregularity was found in the plasma tamsulosin concentration data. Six subjects experienced adverse events while receiving placebo and seven while on tamsulosin. The most frequent adverse event was mild dizziness reported by four subjects. Moderate chest pain was reported in two subjects, but this was not considered to be related to the administration of the study medications. Some significant changes in vital signs were observed; however, none was accompanied by symptoms of medical concern. These changes were not temporally related to the administration of study drugs. Thus, concurrent administration of digoxin with tamsulosin did not produce any change in the pharmacokinetics of digoxin and the safety profile was acceptable. As reflected in the prescribing information for tamsulosin, no adjustment in tamsulosin dosing is required when it is administered concomitantly with digoxin.

[Breast cancer].

Neoadjuvant chemotherapy (NAC) represents a new approach based on sound theoretical, pharmacokinetic, and experimental principles. The purpose of NAC is to improve control of the primary site by downstaging and to improve control of micrometastatic disease. NAC has been standard therapy in the management of locally advanced breast cancer. Patients with earlier stage breast cancer may also benefit from treatment with NAC. Recently some investigators have mentioned that NAC can be used instead of adjuvant chemotherapy and would be most appropriate for patients who wish to preserve their breast but who have tumors too large for breast conserving surgery. In this article, we reviewed the present status of NAC (indication, clinical response, pathologic response, survival, possibility of breast conservation, prognostic/predictive factors, neoadjuvant endocrine therapy) and discussed several unanswered questions on NAC (survival benefit, optimal number of treatment cycles, optimal regimens) and future direction. Combined modality therapy including NAC appears to provide excellent local control, the possibility of breast conservation, and, probably, an increased survival rate, at least for some subsets of patients. Furthermore, through sequential sampling, NAC provides indeed the opportunity to identify molecular mechanisms associated with pathologic response and to study the possibility to guide the choice for induction treatment and patient populations submitted to neoadjuvant chemotherapy.

Spontaneous reduction in Epstein-Barr virus (EBV) DNA copy number in EBV-infected epithelial cell lines.

We found that spontaneous and 12-0-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus (EBV) reactivation occurred in short-term (ST)-cultured EBV-infected epithelial cell lines GT38 and GT39 after their establishment; however, it diminished in the long-term (LT)-cultured cells passaged for more than 2 years from ST-cultured cells. We hypothesized that the EBV reactivation may be related to the EBV DNA copy number in the cells. A higher level of EBV DNA content was detected in ST-cultured cells than in LT-cultured cells by Southern hybridization using an EBV DNA XhoI probe. Fluorescence in situ hybridization using EBV DNA BamHI W fragments showed that ST-cultured cells contained a higher EBV DNA copy number than that of LT-cultured cells. EBV DNA-negative cells were detected in small proportions in LT-cultured cells, but were undetected in ST-cultured cells. These results demonstrate that EBV genomes are not maintained stably in the cell lines, and some of them are lost in continuous passages of the cells. We discuss the mechanisms of reduction of EBV reactivation and EBV DNA in the cell lines.

[Effect of different concentrations of tranilast on posterior capsule opacification].

PURPOSE: To evaluate the effect of different concentrations(0.5, 1.0, 2.0%) of tranilast eyedrops in preventing fibrous posterior capsule opacification (PCO) in rabbits. METHODS: Experimental phacoemulsification procedures and in-the-bag placement of intraocular lens(IOL) implant were performed. An anterior eye segment analysis system(EAS-1000, Nidek Co, Ltd) was used to evaluate the degree of PCO during 5 weeks after surgery. RESULTS: The development of PCO was significantly suppressed in the eyes treated with tranilast eyedrops from 1 week after surgery. The mean PCO density after treatment with 0.5% tranilast was 59.1 +/- 9.3 (mean deviation +/- standard error) and 57.1 +/- 8.2, while for 1.0% tranilast it was 40.1 +/- 6.8 and 46.6 +/- 8.4, and for 2.0% tranilast it was 38.5 +/- 6.0 and 37.5 +/- 5.6 (computer compatible tape, CCT) at 1 week and 5 weeks, respectively. In the control group, the mean PCO density was 89.3 +/- 10.4 and 137.4 +/- 32.8 at 1 week and 5 weeks, respectively(p < 0.05). However, no significant statistical difference was observed in any of the findings for the 3 different tranilast concentrations. CONCLUSION: These results suggest that the 0.5% tranilast eyedrops, which are already available on the market, are sufficiently effective for inhibiting PCO.

[Indications for surgery for morbid obesity and effectiveness of bariatric surgery].

In this paper we describe a history and technical aspects of bariatric surgery. And surgical techniques of Divided Vertical Banded Gastroplasty and perioperative management are presented. Our indications for surgery for morbid obesity are almost equal to the guidelines for obesity surgery adopted by the American Society for Bariatric Surgery October 1986. From 1982 to 2000, 64 bariatric surgical procedures were performed at the author's institution. Vertical banded gastroplasty was performed in 45 patients, Horizontal gastric partitioning in 8 patients, Gastric bypass in 10 patients, and Divided vertical banded gastroplasty in 1 patient. The average weight loss one year after Vertical banded gastroplasty is 1/3 of the patient weight. Most of the preexisting comorbid conditions related to the obesity showed improvement or were completely resolved after surgery. No major complications were observed postoperatively. We concluded that surgical procedures for morbid obesity are very effective therapy.

The complete DNA sequence of the mitochondrial genome of Physarum polycephalum.

The complete sequence of the mitochondrial DNA (mtDNA) of the true slime mold Physarun polycephalum has been determined. The mtDNA is a circular 62,862-bp molecule with an A+T content of 74.1%. A search with the program BLAST X identified the protein-coding regions. The mitochondrial genome of P. polycephalum was predicted to contain genes coding for 12 known proteins [for three cytochrome c oxidase subunits, apocytochrome b, two F1Fo-ATPase subunits, five NADH dehydrogenase (nad) subunits, and one ribosomal protein], two rRNA genes, and five tRNA genes. However, the predicted ORFs are not all in the same frame, because mitochondrial RNA in P. polycephalum undergoes RNA editing to produce functional RNAs. The nucleotide sequence of an nad7 cDNA showed that 51 nucleotides were inserted at 46 sites in the mRNA. No guide RNA-like sequences were observed in the mtDNA of P. polycephalum. Comparison with reported Physarum mtDNA sequences suggested that sites of RNA editing vary among strains. In the Physarum mtDNA, 20 ORFs of over 300 nucleotides were found and ORFs 14 19 are transcribed.

[Pure sensory stroke due to a pontine lesion: a study of clinical symptomatology and somatosensory evoked potential findings].

We studied clinical symptomatology and somatosensory evoked potentials(SEP) of 7 pure sensory stroke patients due to pontine lesions. Clinical symptoms were examined by modality(pinprick, touch, vibration and joint position sense), intensity and distribution of the sensory disturbance. SEP were recorded by the median nerve stimulation in the upper extremities, and the posterior tibial nerve stimulation in the lower extremities. Patients 1-4 were characterized by decreased contra-lesional fingers or fingers, toes joint position sense, normal pinprick and vibration sense. We think that these patients' lesions were localized in the lemniscus medialis. Patients 5-7 were characterized by decreased contra-lesional upper extremity or upper and lower extremity vibration sense, decreased pinprick sense and normal joint position sense. We think that these patients' lesions involved spinothalamic tract. There was no abnormal finding of SEP with upper extremity stimulation, but disappearance or very low amplitude of P38 with lower extremity stimulation in 4 of the 7 patients. We conclude that 1) the vibration sense may be conducted also through the spinothalamic tract, 2) SEP findings are abnormal only with lower extremity stimulation in pontine pure sensory infarction.

Clinical benefits of steroid therapy on surgical stress in patients with esophageal cancer.

BACKGROUND: Despite improvements in surgical techniques and perioperative care, severe complications lead to long hospital stays for some esophageal cancer patients. The purpose of this study was to evaluate the safety and effectiveness of perioperative steroid therapy on the postoperative clinical course. METHODS: Fifty-seven patients operated for esophageal cancer in 1997 and 1998 were treated with perioperative steroid therapy. Fifty consecutive patients operated in 1995 and 1996 served as a control group. In the steroid group, each patient was given 250 mg of methylprednisolone intravenously before operation followed by 125 mg on postoperative days 1 and 2. Serum interleukin-6, polymorphonuclear cell elastase, and C-reactive protein levels, and the postoperative clinical course were compared between the groups. RESULTS: Morbidity rates including hyperbilirubinemia, anastomotic leakage, and liver dysfunction were significantly lower in the steroid group than in the control group. Days until extubation and hospital stay were significantly shorter for the steroid group. Inflammatory mediators, body temperature, heart rate, and respiratory index after the surgical procedure were significantly lower in the steroid group. Adverse effects possibly caused by steroid therapy were not observed. CONCLUSIONS: Perioperative steroid therapy was safe and effective for the inhibition of inflammatory mediators and the improvement of the postoperative clinical course of patients with esophageal cancer.

Tumorigenesis of Epstein-Barr virus-positive epithelial cell lines derived from gastric tissues in the SCID mouse.

To study the tumorigenesis of Epstein-Barr virus (EBV)-positive epithelial cell lines GT38 and GT39 derived from human gastric tissues, we inoculated these cells under the skin of severe combined immunodeficient (SCID) mice. The development of tumors was observed in each of the mice about 2 months after the inoculation. The tumors were diagnosed with undifferentiated carcinoma by hematoxylin/eosin staining. EBV-encoded small RNA1 was detected in the paraffin-embedded tumor sections. The tumor cells had human chromosome. The circular, but not linear, EBV DNA was detected in the tumors. The molecular sizes of EBV DNA termini were the same as that of the inoculated GT38 or GT39 cells. The expressions of EBV nuclear antigen 2 and latent membrane protein 1 reduced in the tumors. Transcripts of BamHI C and W promoters in latency III were detected in the tumors and the cultured cells in vitro. The tumor cells were passaged from one SCID mouse to other SCID mice and to cultures in vitro. This is the first evidence that the EBV-positive epithelial cell lines produced tumors in the SCID mouse.

Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers.

Zolpidem (ZOL) and zopiclone (ZPC) are non-benzodiazepine hypnotics, with unique effects on sleep architecture compared with conventional benzodiazepines. The two compounds have different profiles in action to two major subtypes of the GABA-A receptors, therefore different effects on sleep structure may be expected. In the present study, the effects of ZOL (10mg) and ZPC (7.5mg) were compared in nine healthy young male subjects during nine-night sessions, employing a crossover design. Time courses during the sessions were significantly different between the compounds in the ratio (%) of S2 and S1. Compared to the baseline, an increase of S2 and a decrease of S1 and SR were caused by ZPC, not by ZOL. SWS was increased by both ZPC and ZOL. Significant changes by ZOL were found during the first 150-min, while changes by ZPC were mostly observed during the second 150-min. This might be related to their half-lives. ZOL did not affect sleep latency in the morning, while ZPC caused a significant decrease. Subjective sleepiness, however, was not increased in the ZPC or ZOL mornings. It was speculated that difference in the action to the GABA-A receptor subtypes might be related to the differences in the effects on the sleep architecture between the compounds.

[Measures for the disposal of non-regulated alternative medical wastes--effects of disinfectants on activated sludges].

Effects on activated sludges of several disinfectants with strong and wide antimicrobial ability, were investigated using an oxygen up-take method. As a results, at the maximal non-reactive concentration of disinfectants, hexachlorophene has estimated value of 6 mg/l and shows the highest toxicity against activated sludges. At the lethal concentration of 50%, the toxicity of triclosan is the strongest disinfectant.