Unexpected anti-tumor effect of immune checkpoint inhibitors followed by transcatheter arterial chemoembolization for hepatocellular carcinoma.

The abscopal effect has recently attracted much attention because this effect is enhanced by immune checkpoint inhibitors (ICIs). However, little is known about the association between induction of the abscopal effect and local treatment against hepatocellular carcinoma (HCC). We describe a patient with advanced HCC who underwent selective transcatheter arterial chemoembolization (TACE) after treatment with an ICI that was found to remarkably regress in lesions in areas outside that targeted by selective TACE. An 82-year-old man had multiple recurrences in both lobes of the liver despite of repeated TACE and radiofrequency ablation, after resection of an HCC five years previously. After chemotherapy with atezolizumab and bevacizumab, his des-gamma-carboxy prothrombin (DCP) increased. CT during hepatic arteriography revealed multiple recurrent HCCs in both lobes of the liver. TACE with selective embolization at the level of the medial segmental arteries was performed against an approximately 50 mm-diameter tumor in the right lobe. Hepatic arterial phase imaging of contrast-enhanced CT performed 6 days after TACE showed hypo-enhancement of tumors in segment II and III in the left lobe. This case highlights that abscopal effects can be induced by local treatment against HCCs in combination with treatment with ICIs.

The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Giant Cell Tumor With Atypical Imaging Implying Osteosarcoma.

Giant cell tumor (GCT) of bone is benign and typically shows osteolytic changes on x-ray, whereas osteosarcoma is malignant and generally shows osteolytic and osteoblastic mixed images. We experienced a rare case of GCT with atypical radiological findings. The tumor found in the right knee of a 15-year-old girl comprised a wide range of osteoblastic and osteolytic lesion in medial femur. Technetium uptake, however, was detected only in osteoblastic part, and immunohistochemical staining of biopsy showed diffusely positive for antihistone G34W and almost negative for Ki-67. These results strongly suggest the tumor was GCT.

A novel pathogenic variant of ATP-binding cassette subfamily B member 4 causing gallstones in a young adult.

The low phospholipid-associated cholelithiasis (LPAC) syndrome was reported in European adults with cholelithiasis and a mutation of the ATP-binding cassette subfamily B member 4 (ABCB4). The ABCB4 encodes multidrug resistance 3, which is a phospholipid translocator. Reduced phospholipid transport can lead to the formation of biliary cholesterol stones. Here, we describe a 31-year-old Japanese man diagnosed with recurrent biliary colic. Although he recovered quickly after endoscopic treatment for the most recent presentation, he had a family history of similar problems. His mother had required endoscopic treatment for choledocholithiasis and his maternal aunt had died at age 29 years because of liver failure (etiology unknown). We, therefore, performed genetic analysis, which revealed a heterozygous ABCB4C717S. LPAC syndrome was diagnosed and the patient has received ursodeoxycholic acid for 2 years with no recurrence. The same variant was identified in the patient's mother, who was subsequently found to have a left intrahepatic calculus requiring left-sided lobectomy. She has received ursodeoxycholic acid for 1 year with no recurrence. ABCB4C717S is a novel pathogenic variant, and this is the first patient diagnosed with LPAC syndrome in Japan. We should consider LPAC syndrome in young adults with recurrent cholesterol gallstones to ensure early therapy.

[Hypopituitarism associated with autoimmune pancreatitis: a case report].

We herein report the case of a 64-year-old male patient with hypopituitarism associated with autoimmune pancreatitis (AIP). The patient was previously diagnosed with AIP based on the presence of a swollen pancreas, elevated serum immunoglobulin G4, and narrowing of the pancreatic duct by imaging. Magnetic resonance imaging revealed a pituitary stem tumor, and loading test showed a decrease in the function of the anterior lobe suggesting severe failure of growth hormone secretion. Treatment with steroids was effective in reducing the pituitary lesion and improving the function of the anterior lobe. The present case illustrates the importance of pituitary function evaluation before steroid treatment in patients with AIP.

Brain-Specific Ultrastructure of Capillary Endothelial Glycocalyx and Its Possible Contribution for Blood Brain Barrier.

Endothelial glycocalyx coats healthy vascular endothelium and plays an important role in vascular homeostasis. Although cerebral capillaries are categorized as continuous, as are those in the heart and lung, they likely have specific features related to their function in the blood brain barrier. To test that idea, brains, hearts and lungs from C57BL6 mice were processed with lanthanum-containing alkaline fixative, which preserves the structure of glycocalyx, and examined using scanning and transmission electron microscopy. We found that endothelial glycocalyx is present over the entire luminal surface of cerebral capillaries. The percent area physically covered by glycocalyx within the lumen of cerebral capillaries was 40.1 ± 4.5%, which is significantly more than in cardiac and pulmonary capillaries (15.1 ± 3.7% and 3.7 ± 0.3%, respectively). Upon lipopolysaccharide-induced vascular injury, the endothelial glycocalyx was reduced within cerebral capillaries, but substantial amounts remained. By contrast, cardiac and pulmonary capillaries became nearly devoid of glycocalyx. These findings suggest the denser structure of glycocalyx in the brain is associated with endothelial protection and may be an important component of the blood brain barrier.

Ultrastructural Alteration of Pulmonary Capillary Endothelial Glycocalyx During Endotoxemia.

BACKGROUND: The most recent diagnostic criteria for sepsis include organ failure. Microvascular endothelial injury is believed to lead to the multiple organ failure seen in sepsis, although the precise mechanism is still controversial. ARDS is the primary complication during the sequential development of multiple organ dysfunction in sepsis, and endothelial injury is deeply involved. Sugar-protein glycocalyx coats all healthy vascular endothelium, and its disruption is one factor believed to contribute to microvascular endothelial dysfunction during sepsis. The goal of this study was to observe the three-dimensional ultrastructural alterations in the pulmonary capillary endothelium, including the glycocalyx, during sepsis-induced pulmonary vasculitis. METHODS: This study investigated the three-dimensional ultrastructure of pulmonary vascular endothelial glycocalyx in a mouse lipopolysaccharide-induced endotoxemia model. Lungs were fixed with lanthanum-containing alkaline fixative to preserve the glycocalyx. RESULTS: On both scanning and transmission electron microscopic imaging, the capillary endothelial glycocalyx appeared as a moss-like structure entirely covering the endothelial cell surface in normal mice. In the septic lung following liposaccharide injection, however, this structure was severely disrupted; it appeared to be peeling away and coagulated. In addition, syndecan-1 levels were significantly reduced in the septic lung, and numerous spherical structures containing glycocalyx were observed on the endothelial surface. CONCLUSIONS: It appears that endothelial glycocalyx in the lung is markedly disrupted under experimental endotoxemia conditions. This finding supports the notion that disruption of the glycocalyx is causally related to the microvascular endothelial dysfunction that is characteristic of sepsis-induced ARDS.

Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event-reporting database.

OBJECTIVE: To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients. METHODS: Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008-10 April 2015) assuming the following: treated in Japan; TCZ RA treatment; ≥1 SI; unable to exclude causality between TCZ and SIs. RESULTS: The database included 7653 RA patients; 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date; 60.7% of patients had signs/symptoms ≤28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection. CONCLUSION: This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs.

Three-dimensional ultrastructure of capillary endothelial glycocalyx under normal and experimental endotoxemic conditions.

BACKGROUND: Sugar-protein glycocalyx coats healthy endothelium, but its ultrastructure is not well described. Our aim was to determine the three-dimensional ultrastructure of capillary endothelial glycocalyx in the heart, kidney, and liver, where capillaries are, respectively, continuous, fenestrated, and sinusoidal. METHODS: Tissue samples were processed with lanthanum-containing alkaline fixative, which preserves the structure of glycocalyx. RESULTS: Scanning and transmission electron microscopy revealed that the endothelial glycocalyx layer in continuous and fenestrated capillaries was substantially thicker than in sinusoids. In the heart, the endothelial glycocalyx presented as moss- or broccoli-like and covered the entire luminal endothelial cell surface. In the kidney, the glycocalyx appeared to nearly occlude the endothelial pores of the fenestrated capillaries and was also present on the surface of the renal podocytes. In sinusoids of the liver, glycocalyx covered not only the luminal side but also the opposite side, facing the space of Disse. In a mouse lipopolysaccharide-induced experimental endotoxemia model, the capillary endothelial glycocalyx was severely disrupted; that is, it appeared to be peeling off the cells and clumping. Serum concentrations of syndecan-1, a marker of glycocalyx damage, were significantly increased 24 h after administration of lipopolysaccharide. CONCLUSIONS: In the present study, we visualized the three-dimensional ultrastructure of endothelial glycocalyx in healthy continuous, fenestrated, and sinusoidal capillaries, and we also showed their disruption under experimental endotoxemic conditions. The latter may provide a morphological basis for the microvascular endothelial dysfunction associated with septic injury to organs.

[Three Poor Performance Status(PS)Cases of Metastatic Breast Cancer Controlled with Adjustment of Dosing Interval and Dosage of Bevacizumab and Paclitaxel].

A standard symptomatic therapy regimen of bevacizumab(BV)plus paclitaxel(PTX)was planned for use in 3 cases of metastatic breast cancer. Due to poor patient performance status(PS)because of malignant pleural effusion and ascites, the initial standard regimen was determined to be unsuitable. However, adjustment and fine-tuning of the BV plus PTX interval and dosage were found to be effective in improving symptoms, and consequently obtained good efficacy. Adverse effects were managed with drug withdrawal and symptomatic therapy. The 3 clinical cases all included females aged 62-76 years old, with a median age of 67.6. One case was classified as PS 3, and 2 were classified as PS 4. The main deciding factors for initiating the regimen of BV plus PTX were 2 cases of malignant pleural effusion and 1 case of malignant ascites, which contributed to worsening of the overall PS. With adjustment and fine-tuning of the BV plus PTX interval and dosage, we were able to safely achieve symptomatic improvement in 3 metastatic breast cancer cases, in which the overall PS grade was unsuitable for standard chemotherapy.

A case of pancreatic intraepithelial neoplasia-3 with autoimmune pancreatitis.

We report a case of pancreatic intraepithelial neoplasia-3 (PanIN-3) with autoimmune pancreatitis (AIP). The patient, a 75-year-old man, had been diagnosed to have AIP with stenosis of the main pancreatic duct. After six years, computed tomography demonstrated dilatation of the main pancreatic duct in the mid-pancreas. Although we could not confirm the presence of any pancreatic tumor on the basis of imaging modalities alone, cytological examination of the pancreatic juice obtained by endoscopic retrograde pancreatography revealed atypical cells. Therefore, we performed pancreatoduodenectomy and obtained a pathologic diagnosis of PanIN-3 with AIP. The present case is informative in the context of pancreatic carcinogenesis in AIP.

Rapid G0/1 transition and cell cycle progression in CD8+ T cells compared to CD4+ T cells following in vitro stimulation.

T-cell population consists of two major subsets, CD4+ T cells and CD8+ T cells, which can be distinguished by the expression of CD4 or CD8 molecules, respectively. Although they play quite different roles in the immune system, many of their basic cellular processes such as proliferation following stimulation are presumably common. In this study, we have carefully analyzed time-course of G0/1 transition as well as cell cycle progression in the two subsets of quiescent T-cell population following in vitro growth stimulation. We found that CD8+ T cells promote G0/1 transition more rapidly and drive their cell cycle progression faster compared to CD4+ T cells. In addition, expression of CD25 and effects of its blockade revealed that IL-2 is implicated in the rapid progression, but not the earlier G0/1 transition, of CD8+ T cells.

Pancreatic hyperechogenicity associated with hypoadiponectinemia and insulin resistance: A Japanese population study.

AIM: To examine the relationship between pancreatic hyperechogenicity and risk factors for metabolic syndrome. METHODS: A general population-based survey of lifestyle-related diseases was conducted from 2005 to 2006 in Japan. The study involved 551 participants older than 40 year of age. Data for 472 non-diabetic adults were included in the analysis. The measures included the demographic factors, blood parameters, results of a 75 g oral glucose tolerance test, and abdominal ultrasonography. The echogenicity of the pancreas and liver was compared, and then the subjects were separated into two groups: cases with pancreatic hyperechogenicity (n = 208) and cases without (controls, n = 264). The differences between both groups were compared using an unpaired t-test or Fisher's exact test. Multiple logistic regression analysis was used to determine the relationship between the pancreatic hyperechogenicity and clinical and biochemical parameters. RESULTS: Subjects with pancreatic hyperechogenicity had decreased serum adiponectin concentration compared to control subjects [8.9 (6.5, 12.8) vs 11.1 (7.8, 15.9), P < 0.001] and more frequently exhibited features of metabolic syndrome. Logistic regression analysis showed that the following variables were significantly and independently associated with pancreatic hyperechogenicity: Presence of hypoadiponectinemia, increased body mass index (BMI), higher homeostasis model assessment of insulin resistance (HOMA-IR) score, and presence of fatty liver. Similar associations were also observed in subjects with pancreatic hyperechogenicity without fatty liver. Multivariate association analysis of data from participants without fatty liver showed that hypoadiponectinemia was significantly associated with pancreatic hyperechogenicity (OR = 0.93, 95%CI: 0.90 - 0.97, P < 0.001). This association was independent of other confounding variables. Additionally, an increased BMI and higher HOMA-IR score were significantly associated with pancreatic hyperechogenicity. CONCLUSION: Pancreatic hyperechogenicity is independently associated with increased BMI, insulin resistance, and hypoadiponectinemia in the general population.

Rapid proliferation of activated lymph node CD4(+) T cells is achieved by greatly curtailing the duration of gap phases in cell cycle progression.

Peripheral T cells are in G0 phase and do not proliferate. When they encounter an antigen, they enter the cell cycle and proliferate in order to initiate an active immune response. Here, we have determined the first two cell cycle times of a leading population of CD4(+) T cells stimulated by PMA plus ionomycin in vitro. The first cell cycle began around 10 h after stimulation and took approximately 16 h. Surprisingly, the second cell cycle was extremely rapid and required only 6 h. T cells might have a unique regulatory mechanism to compensate for the shortage of the gap phases in cell cycle progression. This unique feature might be a basis for a quick immune response against pathogens, as it maximizes the rate of proliferation.

[A case of hepatocellular carcinoma complicated by pleural effusion mixed with bile after radiofrequency ablation].

An 84-year-old Japanese man was admitted with hepatocellular carcinoma (HCC). He underwent transcatheter arterial chemoembolization and percutaneous radiofrequency ablation (RFA). Three weeks later, he developed sudden-onset right pleural effusion mixed with bile. Drip infusion cholangiography-computed tomography revealed leakage of the contrast agent, which passed from the HCC to the pleural cavity through a perforation in the diaphragm. The patient's condition improved after thoracic and endoscopic nasobiliary drainage. The occurrence of pleural effusion mixed with bile is a rare complication of RFA. This case provides important information about the morbidity, prevention, and treatment of this complication.

Effects of TiO2 nanoparticles on cytotoxic action of chemotherapeutic drugs against a human oral squamous cell carcinoma cell line.

BACKGROUND: Despite the rapid development of nanotechnology, the biological significance of TiO2 nanoparticles (NPs), possibly released from dental materials, is not well-understood. We investigated the effect of TiO2 NPs on the sensitivity of human oral squamous cell carcinoma (OSCC) cell line (HSC-2) to five popular chemotherapeutic agents. MATERIALS AND METHODS: Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The aggregation and cellular uptake of TiO2 NPs were assessed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. Adsorption of TiO2 NPs to anticancer drugs was assessed by the antitumor activity recovered from the TiO2 NP-free supernatant. RESULTS: When mixed with culture medium, TiO2 NPs instantly aggregated, and some particles were incorporated into the cells, exclusively in the vacuoles. TiO2 NPs showed no cytotoxicity nor hormetic growth stimulation at lower concentrations. Doxorubicin, melphalan, 5-fluorouracil and gefitinib were cytotoxic, whereas docetaxel was cytostatic with or without TiO2 NPs. TiO2 NPs, at wide concentration ranges (0.2-3.2 mM), did not significantly affect the adsorption of NPs to any of these anticancer drugs, nor affected their cytotoxic or cytostatic activity. CONCLUSION: This experimental study demonstrated for the first time that TiO2 NP do not affect the antitumor potential of chemotherapeutic agents against the HSC-2 OSCC cell line.

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule.

T cell activation is regulated by two distinct signals, signals one and two. Concanavalin A (ConA) is an antigen-independent mitogen and functions as signal one inducer, leading T cells to polyclonal proliferation. CD28 is known to be one of major costimulatory receptors and to provide signal two in the ConA-induced T cell proliferation. Here, we have studied the implication of other costimulatory pathways in the ConA-mediated T cell proliferation by using soluble recombinant proteins consisting of an extracellular domain of costimulatory receptors and Fc portion of human IgG. We found that T cell proliferation induced by ConA, but not PMA plus ionomycin or anti-CD3 mAb, is significantly inhibited by herpes virus entry mediator (HVEM)-Ig, even in the presence of CD28 signaling. Moreover, the high concentration of HVEM-Ig molecules almost completely suppressed ConA-mediated T cell proliferation. These results suggest that HVEM might play more important roles than CD28 in ConA-mediated T cell proliferation.

Detection of parasternal metastatic lymph nodes by sentinel lymph node methods in a patient with recurrence in the conserved breast.

We herein report a case of second sentinel lymph node biopsy (SLNB). A 57-year-old woman underwent breast-conserving surgery including axillary clearance at Aichi Cancer Center on October 20, 2003. Recurrent tumor in the conserved breast was diagnosed in March 2006. She received SLNB using radioactive tracer. Preoperative lymphoscintigraphy detected 2 parasternal lymph nodes as hot spots. No abnormal lymph nodes were revealed on preoperative computed tomography. Salvage mastectomy was performed along with dissection of the Rotter and infraclavicular lymph nodes and biopsy of the detected parasternal lymph nodes. Micrometastases were discovered in both parasternal lymph nodes detected as sentinel lymph nodes. No more metastases were seen in the other lymph nodes. Reoperative SLNB offers the possibility of detecting metastasis in residual lymph nodes and determining whether chemotherapy should be used.