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.

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.

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.

Overexpression of cysteine sulfinic acid decarboxylase stimulated by hepatocarcinogenesis results in autoantibody production in rats.

We developed a novel and efficient cDNA subtraction method to isolate rat hepatocellular carcinoma (HCC)-related genes. cDNAs from Solt-Farber procedure-driven HCCs were synthesized on Latex beads. The subtraction was accomplished by a simple centrifugation, PCR amplification, and dot blot screening. Among 2000 clones from the subtracted cDNA library, one clone with a full-length HCC-related cDNA was eventually obtained. Sequence analysis of this clone showed it to exhibit 90 and 60% similarity with the rat cysteine sulfinic acid decarboxylase (CSAD) and mammalian glutamic acid decarboxylases (GAD), respectively. Differences between our sequence data on CSAD and those reported previously were observed at two positions, which arose from a single amino acid substitution and frame shift mutation. The CSAD expression was restricted to the liver and kidney of rats. During hepatocarcinogenesis, expression of the CSAD mRNA and its protein was stimulated in the precancerous liver and maintained its high expression afterward. Interestingly, a high level of anti-CSAD autoantibody was detected in the HCC-bearing rats. The titer of anti-CSAD autoantibodies in these rats was 30-200 times higher than that in normal rats. The anti-CSAD autoantibody appeared in the precancerous state and was maintained afterward, and its pattern of appearance was similar to that of CSAD mRNAs and proteins. Thus, we propose that the high-titer CSAD autoantibody resulted from increased CSAD gene expression in the liver due to stimulation by the HCC. These results remind us of human autoimmune diseases including insulin-dependent diabetes mellitus and stiff-man syndrome, which are caused by autoantibodies against GAD.

Microangiographic assessment of collateral vessel formation following direct gene transfer of vascular endothelial growth factor in rats.

OBJECTIVE: The development of collateral microvessels following therapeutic angiogenesis with vascular endothelial growth factor (VEGF) was investigated using a new system of microangiography that employs monochromatic synchrotron radiation (SR) and a high definition video system to visualize arteries with a spatial resolution of 30 microns. METHODS: Ischemia was induced in the hindlimb of 20 rats by excision of the femoral artery, followed by transfection of the plasmid (400 micrograms) encoding VEGF or beta-galactosidase (control) into limb muscles. Microangiography was used to assess the development of collaterals in the ischemic limb four weeks after treatment. RESULTS: Gene transfer of VEGF produced morphologically similar, but significantly more extensive, collateral networks at the microvascular level as compared with the naturally occurring collateral arteries in the control animals (angiographic score: 0.88 +/- 0.08 versus 0.54 +/- 0.05, p < 0.01). No adverse vascular effects such as hemangiomas and/or arteriovenous (AV) fistulae were observed following VEGF treatment. The vasodilator effect of papaverine was evident in relatively large vessels in both groups. At the microvascular level (diameter < 100 microns), however, papaverine induced significant vasodilation in the VEGF-treated animals, and almost no vasodilation in the controls. CONCLUSIONS: SR microangiography allowed us to assess the development of small collateral arteries following VEGF-gene transfer. The information obtained may provide new insights regarding the collateral microcirculation and therapeutic angiogenesis.

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.

Amnesia following damage to the mammillary bodies.

It is not known whether lesions of the mammillary body per se can produce significant memory impairment in humans. The amnesia reported in patients with lesions in the mammillary bodies may have been produced by lesions coexisting in other memory-related areas, such as the medial thalamus, mammillothalamic tract, descending columns of the fornix, or amygdalofugal pathways. We describe a patient who developed anterograde amnesia following damage to the basal hypothalamus involving the mammillary bodies. The cause was a cystic craniopharyngioma. After surgical removal of the tumor, his memory function improved but remained considerably impaired, especially on delayed recall. Postsurgical MRI revealed small, atrophic mammillary bodies without residual tumor. There was no obvious evidence of damage to the hypothalamus. We therefore conclude that our patient's amnesia resulted from mammillary body lesions alone.

Postencephalitic focal retrograde amnesia after bilateral anterior temporal lobe damage.

BACKGROUND: Marked retrograde amnesia with no or almost no anterograde amnesia is rare. Recently, a combination of ventrolateral prefrontal and temporopolar cortical lesions has been suggested as the cause of such isolated or focal retrograde amnesia. It is also assumed that when the right-sided cortical structures are damaged, autobiographical episodic memories are affected. OBJECTIVE: To search for new anatomic substrates for focal retrograde amnesia. METHODS: We performed extensive neuropsychological tests and obtained detailed neuroimages on a 43-year-old woman who showed a severe, persistent retrograde amnesia but only a limited anterograde amnesia after probable herpes simplex encephalitis. RESULTS: Tests of autobiographical memory revealed that she had a memory loss extending back to her childhood for both semantics and incidents; however, the ability to recall specific episodes appeared much more severely impaired than the ability to recall factual information about her past. The patient also showed profound impairments in recalling public memories; however, her scores improved nearly to a control level on forced-choice recognition memory tasks, although the recall of memories for a decade just before her illness remained mildly impaired. MRI revealed focal pathologies in the temporal poles and the anterior parts of the inferotemporal lobes on both sides, predominantly on the left, with some extension to the anterior parts of the medial temporal lobes. There was additional damage to the left insular cortex and its surrounding structures but no evidence of frontal lobe damage on MRIs or cognitive tests. CONCLUSIONS: A profound retrograde amnesia may be produced by damage to the bilateral temporal poles and anterior inferotemporal lobes in the absence of frontal lobe pathologies, and a dense and persistent episodic old memory loss can arise even with a relatively small lesion in the right anterior temporal lobe if it is combined with extensive damage to the left.

Penile verrucous carcinoma with anaplastic transformation following radiotherapy. A case report with human papillomavirus typing and flow cytometric DNA studies.

We report a case of penile verrucous carcinoma with anaplastic transformation after radiotherapy. A 49-year-old man with penile verrucous carcinoma initially underwent excision and chemotherapy followed by radiotherapy when the carcinoma recurred locally. Twenty-four months after the completion of radiotherapy, the verrucous cancer transformed to an anaplastic spindle-cell carcinoma, which resulted in his death 10 months after diagnosis. Autopsy confirmed a huge hemorrhagic recurrent lesion and lung metastases. In situ hybridization with biotinylated DNA probes did not detect any type of human papillomavirus (HPV) (types 6/11, 16/18, and 31/33/51) in either the primary or the anaplastic tumor. Immunohistochemical HPV capsid antigens were also negative in both lesions. A flow cytometric analysis, using paraffin-embedded materials, showed a diploid DNA content in the excised verrucous carcinoma and an aneuploid content in the anaplastic tumor. This patient most likely had radiation-induced transformation of an anaplastic carcinoma. Wide excision and, if necessary, amputation, are preferred to radiotherapy.

Results of surgery for portacaval shunt in a patient with situs inversus diagnosed and evaluated by per rectal portal scintigraphy.

A 70-yr-old man diagnosed with situs inversus was hospitalized because of hepatic encephalopathy. Per rectal portal scintigraphy showed portal hypertension and a region with high radionuclide activity in the right lateral region of the abdomen. In percutaneous transhepatic portograms, a giant portacaval shunt was seen in the region with high radionuclide activity. After the portacaval shunt was obstructed surgically, the hepatic encephalopathy disappeared. In per rectal portal scintigraphy done 2 wk after surgery, the pattern was normal and the region with high radionuclide activity had disappeared.

Hepatic distribution of blood flow from the superior or inferior mesenteric vein mapped by portal scintigraphy with iodine-123-iodoamphetamine.

UNLABELLED: We previously reported the clinical meaning of measurements of the relative contributions of the superior and inferior mesenteric veins with [123I]iodoamphetamine after oral (in an enteric capsule) and rectal administration. The same method was used to map blood flow in the liver from both of these veins in 82 subjects, 31 with chronic hepatitis and 51 with cirrhosis. METHODS: Three hours after administration of a capsule containing 22.8 MBq of [123I]iodoamphetamine, data showing hepatic blood flow from the superior mesenteric vein were collected for 10 min. Next, 111 MBq of [123I]iodoamphetamine was administered rectally and data showing hepatic blood flow from the inferior mesenteric vein were collected for 30 min. Shunt indices from the superior and inferior mesenteric veins were calculated from these data. RESULTS: In patients with chronic hepatitis, blood from the superior mesenteric vein flowed into the right lobe or both lobes, but, in some patients with cirrhosis, blood from this vein flowed into the left lobe. In some patients with chronic hepatitis, blood from the inferior mesenteric vein flowed into the left lobe, but, in most patients with cirrhosis, the liver was not visualized during this examination and evaluation was not possible. Of the 53 patients in whom blood flow from both veins could be evaluated, 47 had blood from the two veins mixed to some extent in the liver and 6 had portal streamlining, with blood from the superior mesenteric vein going to the right lobe and blood from the inferior mesenteric vein going to the left lobe. CONCLUSION: These results suggest that blood flow in the superior and inferior mesenteric veins can be found mixed in the liver in most subjects with liver disease.

Maternal antigenic stimulation actively produces suppressor activity in offspring.

Pregnant B10.A(3R) and B10.A(5R) mice were immunized with heterologous erythrocyte and protein antigens and the active immune responsiveness of their offspring was investigated by the plaque-forming cell (PFC) assay. In offspring derived from mothers which were stimulated with optimal amounts of antigens and which had fully developed antibody-forming cells, there was a clear-cut suppression in development of specific PFC over a significant period after delivery. In order to characterize the suppressor cell population, spleen cells were prepared from offspring whose mothers were immunized and thereafter treated by anti I-Jk or anti I-Jb monoclonal antibody and complement (C') followed by adoptive transfer to normal corresponding mouse strain. Only the group that received 3R spleen cells treated with anti I-Jb monoclonal antibody and C' had no suppressed PFC. To clarify the suppressor site in offspring, precursor B-cells of experimental offspring responded as hapten specific antibody forming cells by employing homologous hapten and heterologous carrier antigens. These results suggest mechanisms for suppression in offspring whose mothers were stimulated during pregnancy.

Dominant inheritance of Kabuki make-up syndrome.

We report on a total of 4 individuals in 2 families with Kabuki make-up syndrome. In family 1, the proposita, a 2 4/12-year-old girl and her mother had typical Kabuki make-up syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl and her mother had typical Kabuki make-up syndrome. The proposita died at age 6 months. Analysis of 2 families indicates that the condition is an autosomal dominant inheritance with variable expressivity.

Loss of tumorigenicity of human breast cancer cells engineered to produce IL-2, IL-4 or GM-CSF in nude mice.

Human breast cancer cells (OCUB-M), retrovirally transduced with granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-2 (IL-2) or IL-4 gene were examined for their antitumor activities in nude mice. Although cell proliferation rates in vitro of these cytokine-producing cells were not significantly different from that of wild-type cells, nude mice that were subcutaneously inoculated with cytokine-producing cells did not develop tumors in contrast to mice that were injected with wild-type cells. Injection of GM-CSF-producing cells into the vicinity of growing wild-type tumors retarded subsequent growth of wild-type tumors. Histological examination of tumors which received GM-CSF-producing cells revealed marked infiltration of mononuclear cells around the tumors. Irradiation of cytokine-producing cells diminished their proliferation capacity but production of cytokine(s) was retained. Therefore, inoculation of irradiated cytokine producer cells into growing tumors can be used as a therapeutic maneuver for breast cancer.

Magnesium cation induced conformational change of yeast tRNAPhe as studied by singlet-singlet energy transfer.

The A76 or A73 nucleotide at the 3'end of tRNAPhe was modified with the fluorescent reagent of proflavine (PF). The distance between the fluorophore of the 3'end and the Y base was measured by singlet-singlet energy transfer under the conditions of 10 mM and 0.01 mM Mg2+. The distance obtained at 10 mM Mg2+ is very close to that obtained by the X-ray diffraction method, while the distance at 0.01 mM Mg2+ is significantly smaller. The difference in the distance is explained as a result of destabilization of the tertiary structure with reduction of the Mg2+ concentration. The calculated distance between A73 and A76 shows the stacked conformation of the CCA strand. Fluorescent quenching experiments showed that the degree of stabilization of 3'end A76 by stacking is lower than that of A73. The removal of the CCA segment causes a difference not only in the thermal melting curves but also in the fluorescent wavelength of the Y base at 0.01 mM Mg2+. The results suggest that the 3'end CCA strand has a helical structure and contributes to the stabilization of the whole structure of tRNAPhe.

Conformational changes and reassociation properties of small subunits of Escherichia coli ribosomes.

Studies on the reassociation of ribosomal subunits from Escherichia coli were carried out using an ultracentrifuge equipped with a UV absorption scanner, and the conformational changes of ribosomal subunits were followed by circular dichroism measurements. Reassociation between the fractionated 30S and 50 S subunits was promoted by the addition of uncharged tRNA at 4 degrees. Furthermore, a sharp increase in the amount of reassociated products was observed on treatment of the sample solution at temperatures above 25 degrees. Treatment at higher temperature only affected 30 S ribosomal slbunits. From CD measurements of Mg2+ concentration dependence for both ribosomal subunits, a significant decrease in molar ellipticity [theta] at the 264 nm positive peak and a slight change of [theta] at the 222 nm band were observed for both subunits in dissociation buffer. Samples of 30 S subunits pretreated at 37 degrees for 40 min showed a small CD change at the 222 nm band. The same samples showed a slight increase in S value and enhanced ability to form 70 S particles with 50 S subunits. On the other hand, we detected no significant changes in CD spectra, S value or the ability to form 70 S particles with 50 S ribosomal samples subjected to same heat treatments.

Small cell neuroendocrine carcinoma of the ovary.

A 64-year-old woman (gravida 0, para 0) had a unilateral ovarian mass measuring 14 cm in its greatest diameter, which was mostly solid. Microscopically, the tumour was characterized by two predominant proliferating patterns: a carcinoid-like pattern with trabecular, tubular, glandular, or insular arrangements and a closely packed nesting pattern with central coagulation necrosis and occasional glandular arrangements. These two patterns were intermingled, and numerous mitotic figures were present. Electron microscopy showed neurosecretory granules in the cells, which were argyrophilic and positive for neuroendocrine markers (chromogranin, leu 7, neuron-specific enolase, and synaptophysin). The tumour was aneuploid by flow cytometry. The patient received chemotherapy postoperatively, developed brain and multiple bone metastases and died of disease 10 months after surgery. This tumour must be distinguished from other small cell neoplasms, especially ovarian small cell carcinoma of the hypercalcaemic type.

Superiority of a new UICC-TNM staging system for gastric carcinoma.

BACKGROUND: The definition of the degree of lymph node metastasis (n-classification) for gastric cancer differs greatly in the new Union Internationale Contre le Cancer--TNM classification (5th edition) and the Japanese gastric cancer classification (JGC). The feasibility of the new TNM classification is evaluated in comparison with the JGC. METHODS: At Chiba University, 940 patients who underwent a gastrectomy were retrospectively classified into appropriate stages with both the TNM and JGC systems, and the survival curves of the respective stages were also compared. RESULTS: Patients with 1 to 6 metastatic nodes (TNM-pN1) showed similar survival rates whether the metastases were limited to the perigastric area (JGC-n1) or reached distant areas (JGC-n2). The patients with node metastasis that was limited to the perigastric area (JGC-n1) had significantly different survival rates, depending on the number of metastatic nodes (TNM-pN1 or pN2, P = .022). A similar phenomenon was also observed in patients with TNM-N2 and JGC-n2. A multivariate analysis indicated the TNM N-classification, rather than the JGC n-classification, as an independent prognostic factor. CONCLUSIONS: The new TNM classification appears to be a better prognostic indicator than the JGC system for patients with gastric carcinoma.

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.