Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial

Background Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. Methods This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. Results Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (−). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (−) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (−) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (−). No associations of HLA class I expression with the immune response or oncological outcomes were observed. Conclusions This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy (AU)

Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.

BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed. CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

Association between Sarcopenia and Overactive Bladder in Elderly Diabetic Patients.

OBJECTIVES: To determine the association between sarcopenia and overactive bladder (OAB) in elderly diabetic patients using the Japanese version of SARC-F called SARC-F-J. DESIGN: Cross-sectional study. SETTINGS AND PARTICIPANTS: The study included 329 elderly diabetic patients (aged ≥65 years) who regularly visited the outpatient clinic at Community hospital in Japan. MEASUREMENTS: The condition of OAB was evaluated using the OAM symptom score, which involves a self-administered questionnaire, and sarcopenia was evaluated using the self-administered SARC-F-J questionnaire comprising five items. The odds ratio for OAB due to sarcopenia was calculated using multiple logistic regression analysis, with OAB as the dependent variable and sarcopenia as the explanatory variable. RESULTS: A total of 329 patients (186 males, 143 females) were included for analysis in the present study. Of these patients, 22.9% had sarcopenia and 18.7% had OAB. After adjusting the variables, the odds ratio for OAB due to sarcopenia was 4.46 (95% confidence interval [CI], 1.14-17.36, P = 0.031) and 2.09 (95% CI, 0.52-8.26, P = 0.293) for males and females, respectively. CONCLUSION: This study found that sarcopenia was significantly associated with OAB in elderly diabetic male patients based on SARC-F-J. Moreover, the possibility of the development of OAB should be considered during the medical examinations of elderly diabetic male patients with sarcopenia.

Spectrophotometer is useful for assessing vitiligo and chemical leukoderma severity by quantifying color difference with surrounding normally pigmented skin.

BACKGROUND: Acquired skin hypopigmentation has many etiologies, including autoimmune melanocyte destruction, skin aging, inflammation, and chemical exposure. Distinguishing lesions from normally pigmented skin is clinically important to precisely assess disease severity. However, no gold standard assessment method has been reported. We aimed to investigate whether spectrophotometers are useful for assessing vitiligo and rhododendrol (4-(4-hydroxyphenol)-2-butanol) (Rhododenol® )-induced leukoderma disease severity by quantifying skin color. METHODS: Mexameter® MX18 and CM-700d spectrophotometer were used for assessing vitiligo/leukoderma by measuring melanin index, L*a*b* color space, and ΔE*ab value, which represents the color difference between two subjects and is calculated by the values of L*a*b*. RESULTS: MX18 and CM-700d can quantitatively distinguish vitiligo/leukoderma from normally pigmented skin based on melanin index. CM-700d consistently quantified the color of vitiligo/leukoderma lesions and surrounding normally pigmented skin in L*a*b* color spaces and ΔE*ab. ΔE*ab is well correlated with melanin index and clinical appearance. CONCLUSION: ΔE*ab has been frequently used in aesthetic dentistry; however, current study is the first to use it in the measurement of skin color. ΔE*ab seems to be a useful parameter to evaluate the color contrast between vitiligo/leukoderma and surrounding normally pigmented skin and can be used to evaluate disease severity and patient's quality of life.

The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis.

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02-16.75)), but low in pure class V (0.30 (0.00-0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

Quantitative Assay of Macroautophagy Using Pho8△60 Assay and GFP-Cleavage Assay in Yeast.

It is intrinsically difficult to directly measure a specific protein reduction that is mediated by nonselective autophagy, because the degradation proceeds at a relatively slow pace, and the residual nondegraded part becomes the background. Several methods for measuring nonselective autophagy have been reported in the past. One classical simple method is called bulk degradation assay, which measures the release of degraded amino acids after radioisotope labeling of the total cellular proteins. In 1995, we developed a quantitative Pho8△60 assay in the yeast, Saccharomyces cerevisiae, for studying autophagy, which is widely used for its advantages that are described in the following sections. Another method used in recent times is the GFP-based processing assay in yeast. We will describe these two methods in this chapter.

Stimulation of liver regeneration after hepatectomy in mice by injection of bone marrow mesenchymal stem cells via the portal vein.

AIM: To investigate whether mouse bone marrow mesenchymal stem cells (BMC) stimulate liver regeneration after partial hepatectomy. METHODS: Isolated BMCs were purified by density gradient centrifugation. We performed a 70% hepatectomy in male BALB/c mice followed by injection of BMCs into the portal vein (PV-BMC group), or the tail vein (IV-BMC group), or of saline into the portal vein (control group). RESULTS: The wet weight of the liver remnant increased significantly in the PV-BMC group at 3 and 5 days after hepatectomy compared with the IV-BMC and control groups. The Ki-67 labeling index revealed that the increase to result from stimulation of DNA synthesis. The constitutive interleukin-6 and hepatocyte growth factor mRNAs in the remnant liver tended to increase in the PV-BMC group at 3 days after hepatectomy. CONCLUSIONS: These results demonstrated that BMC injection into the portal vein enhanced liver growth after partial hepatectomy in mice.

MRI findings of mucoepidermoid carcinoma of the parotid gland: correlation with pathological features.

OBJECTIVE: The aim of this study was to correlate the MRI appearance and pathological findings in each grade of the mucoepidermoid carcinoma (MEC) of the parotid gland. METHODS: We reviewed surgically proven MECs of parotid glands in 20 patients. Pathologically, 5 tumours were high-grade, 3 were intermediate and 12 were low-grade. MR images were evaluated with emphasis on signal intensities on T(2) weighted images, margin characteristics and lymph node metastasis, correlating these with pathological features. RESULTS: Among the high-grade MECs, four out of five tumours showed inhomogeneous low to intermediate signal intensity on T(2) weighted images, reflecting high cellularity. All tumours had an ill-defined margin, reflecting invasive tumour growth. Among the intermediate-grade MECs, all three tumours showed intermediate signal intensity on T(2) weighted images and two tumours had an ill-defined margin. Among the low-grade MECs, 11 of the 12 tumours had a hyperintense area on T(2) weighted images because of the existence of abundant mucin secreting cells. Seven tumours had an ill-defined margin, reflecting peritumoural inflammatory changes rather than invasive tumour growth. Lymph node metastasis was seen in three high-grade MECs. CONCLUSION: MECs of the parotid gland show variable MRI findings reflecting their histological nature, which seems to have certain tendencies depending on the tumour grade.

[The strategy for aortic root reconstruction; Bentall operation or native valve preserving operation?].

Bentall operation has been a gold-standard procedure for the aortic root reconstruction in the patients with aortic root aneurysms and aortic valve insufficiency (AI). Recently, native aortic valve preserving operation has been widely spread. In this study, we described the results of aortic root reconstruction in our institution and evaluated our operative methods. We selected Bentall operation for severely damaged or cardiac redo cases, and David operation for simple annuloaortic ectasia and AI. Recently, we have utilized Valsalva graft which provides the advantage of capability of larger prosthetic valve implantation and better hemodynamic performance.

Choledochal cyst associated with duodenal atresia: case report and review of the literature.

We report a rare case of choledochal cyst (CC) associated with congenital duodenal atresia (DA) and annular pancreas (AP). A girl was born at 37 weeks of gestation weighing 2,974 g with a prenatal diagnosis of DA. She underwent a duodenoduodenostomy for type III DA with an AP 1 day after birth. At 4 years of age, she was admitted for evaluation of cholangitis and pancreatitis. Radiological studies demonstrated a fusiform-type CC with pancreaticobiliary maljunction (PBMJ). Excision of the CC and hepaticojejunostomy were performed. The patient was discharged without complications. Despite the fact that CC, DA, and AP are embryologically closely related entities, to the best of our knowledge, only eight such cases have been documented. We must be aware of the possible combination of CC in the follow-up of the patients with DA associated with AP.

Salivary duct carcinoma of the parotid gland: clinical and MR features in six patients.

This study reports the clinical and MR features of salivary duct carcinoma (SDC) of the parotid gland, which is a rare and highly malignant tumour. We assessed retrospectively the clinical and MR features of six patients with histologically proven SDC of the parotid gland. The five men and one woman, ranging in age from 65-71 years (mean, 67 years), had undergone MRI before surgery. All patients presented with parotid masses and four patients had facial paralysis. Two had been aware of the parotid mass for more than 10 years. On MRI, all of the tumours had an ill-defined margin along either the entire circumference or part of the circumference. Four tumours showed infiltration into the subcutaneous or parapharyngeal space. Two tumours showed a wholly solid internal content, and four tumours had varying proportions of cystic content. The signal intensity of the solid portion was low to intermediate on both T(1) weighted and T(2) weighted images. Three patients showed multiple cervical lymph node swellings. Although SDC can show non-specific MRI findings, the combined findings (e.g. low-to-intermediate signal intensities on T(2) weighted images, ill-defined boundaries, infiltration into the surrounding fat space, facial nerve paralysis and associated cervical lymphoadenopathy, seem to suggest a high-grade malignancy.

An animal model of intrinsic dental erosion caused by gastro-oesophageal reflux disease.

OBJECTIVES: To explore the association between dental erosion and gastro-oesophageal reflux disease (GORD), we used an animal model of GORD. MATERIALS AND METHODS: We performed an operation to force gastro-duodenal contents reflux in male Wistar rats, and examined the teeth in the reflux rats at 15 or 30 weeks postoperatively. Dental erosion was evaluated based on a slightly modified index from a previous report. Estimation of pH was employed in the oesophageal and gastric contents. RESULTS: Macroscopically, dental erosion was only detected in the reflux rats. Histopathologically, dentin exposure was detected in three of the seven cases after 30 weeks. Alveolar bone destruction and osteomyelitis were also noted in severe cases. The pH of the oesophageal and stomach contents was 6.93 +/- 0.15 and 3.7 +/- 0.39, respectively. CONCLUSIONS: We confirmed the relationship between dental erosion and GORD. First step of dental erosion caused by GORD is the loss of surface enamel induced by regurgitation of an acidic liquid and acidic gas. Subsequently, further destruction of dental hard tissues and tooth supporting structure is accelerated by mixed juice with gastric and duodenal contents. The reflux animal model is a useful tool to examine the mechanism of dental erosion in GORD.

Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a "phase changing material" mattress in a newborn piglet model.

BACKGROUND: Therapeutic hypothermia, a safe and effective treatment for neonatal encephalopathy in an intensive care setting, is not available in low-resource settings. Aims/ METHODS: To assess two low-tech, low-cost cooling devices for use in low-resource settings: (i) commercially available water bottles filled with tepid water (25 degrees C); (ii) a mattress made of phase changing material (PCM) with a melting point of 32 degrees C (PCM works as a heat buffer at this temperature). Eleven anaesthetised newborn piglets were studied following transient hypoxia-ischaemia. The cooling device was applied 2-26 h after hypoxia-ischaemia with a target rectal temperature (T(rectal)) of 33-34 degrees C. T(rectal) undershoot was adjusted using cotton blankets; the cooling device was renewed when T(rectal) rose above 35 degrees C. T(rectal) data during cooling were dichotomised (within or without target) to assess: (a) the total period within the target T(rectal) range; (b) the stability and fluctuation of T(rectal) during cooling. RESULTS: Therapeutic hypothermia was achieved with both water bottles (n = 5) and the PCM mattress (n = 6). The mean (SD) time to reach target T(rectal) was 1.8 (0.5) h with water bottles and 1.9 (0.3) h with PCM. PCM cooling led to a longer period within the target T(rectal) range (p<0.01) and more stable cooling (p<0.05). Water bottle cooling required device renewal (in four out of five piglets). CONCLUSION: Simple, low-tech cooling devices can induce and maintain therapeutic hypothermia effectively in a porcine model of neonatal encephalopathy, although frequent fine tuning by adjusting the number of blankets insulating the piglet was required to maintain a stable temperature. PCM may induce more stable cooling compared with water bottles.

Aldo-keto reductase family 1, member B10 in uterine carcinomas: a potential risk factor of recurrence after surgical therapy in cervical cancer.

Aldo-keto reductase family 1, member B10 (AKR1B10), an enzyme that converts retinals into retinols is known to detect in non-small cell lung carcinoma (squamous cell- and adeno-carcinomas), but is barely expressed in normal tissues. Since these types of carcinoma occur frequently in the uterus (like in the lung), AKR1B10 may also be overexpressed in two major types of uterine cancer, cervical cancer (CC), and endometrial cancer (EMC). The objective of this study is to investigate AKR1B10 expression in uterine cancer and to analyze its clinical significance. In samples from uterine cancer patients, AKR1B10 was detected in 6 out of 30 (20.0%) CC cases and 6 out of 38 (15.8%) EMC cases. Statistical analysis indicated that AKR1B10 expression was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma only in CC. Although retinol (a metabolic product by AKR1B10) was observed in the normal epithelium, the molecule was not observed in cancer cells of AKR1B10-positive CC samples suggesting that the recurrence in CC may not depend on the convert of retinals into retinols via AKR1B10, a potential indicator in the management of patients with CC.

Functional outcome after sphincter excision for ultralow rectal cancer.

This article shows a prospective study investigating bowel function after transanal rectal resection with internal and external sphincterectomy for low rectal cancer. Eight patients underwent standard low anterior resection with colonic J-pouch anal anastomosis (LARJ), and eight patients underwent transanal rectal resection with internal and external sphincter resection (IESR). Manometry, manovolumetry, transit time study, and a questionnaire were performed before and after the operation. Six and 12 months after the operation, maximum resting pressure and squeezing pressure were significantly lower in IESR group than in LARJ group, whereas there was no significant difference between the two groups in terms of constant sensation, maximum tolerable volume, or neorectal compliance. Although the functional score of the IESR group remained low at 6 months after the operation in comparison with the LARJ group, it improved at 12 months after the operation. Transanal rectal resection with internal and external sphincterectomy showed usefulness in preserving bowel function and avoiding permanent colostomy.

Uniform mixing of high-Tc superconductivity and antiferromagnetism on a single CuO2 plane of a Hg-based five-layered cuprate.

We report a site selective Cu-NMR study on underdoped Hg-based five-layered high-Tc cuprate HgBa2Ca4CU5O(12+delta) with a Tc = 72 K. Antiferromagnetism (AFM) has been found to take place at T(N) = 290 K, exhibiting a large antiferromagnetic moment of 0.67-0.69 microB at three inner planes (IP). This value is comparable to the values reported for nondoped cuprates, suggesting that the IP may be in a nearly nondoped regime. Most surprisingly, the AFM order is also detected with M(AFM)(OP) = 0.1 microB even at two outer planes (OP) that are responsible for the onset of superconductivity (SC). The high-Tc SC at Tc = 72 K can uniformly coexist on a microscopic level with the AFM at OP's. This is the first microscopic evidence for the uniform mixed phase of AFM and SC on a single CuO2 plane in a simple environment without any vortex lattice and/or stripe order.

Renal dysplasia with unilateral renal agenesis in a dog.

This report describes a renal dysplastic lesion associated with renal agenesis in a 3-year-old dog with chronic renal failure. Haematological examination revealed non-regenerative anaemia, azotaemia, increased creatinine and hyperphosphataemia. At necropsy, the right kidney and right ureter could not be identified. The left kidney was slightly enlarged, with a reduced cortico-medullary ratio. Histologically, the medulla of the left kidney had persistent mesenchyme and primitive tubules (tall pseudostratified columnar epithelium), dilated collecting ducts lined by flattened epithelium, and adenomatoid proliferation of cuboidal epithelium; fetal or immature glomeruli could not be identified. To our knowledge, this is the first report of a renal dysplastic lesion with unilateral agenesis in animals.

Bio-sorption of acidic gelatine hydro-gels implanted in the back tissues of Fisher's rats.

Recent advance in tissue engineering therapy requires new scaffold materials. Acidic gelatine powders (10 wt%) were, thus, dissolved in water, were or were not cross-linked, and freeze-dried. After sterilization, prepared small sponges were implanted in 7-week-old Fisher's rats' subcutaneous tissues for up to 2 weeks. Sponges absorbed body fluid and changed into hydro-gels in vivo. Non-cross-linked hydro-gels were absorbed within 3 days, while cross-linked hydro-gels were eliminated after 7 days' implantation. Histological observations revealed that the common captivation process was mild while granulocytes and macrophages were encountered. Because acidic gelatine sponges can accommodate various basic growth factors, it can be speculated that prepared sponges might be used as short-time hydro-gel scaffolds and growth-factor carriers.

Occlusal force and condylar motion in patients with anterior open bite.

Patients with open bite often show a weak occlusal force and temporomandibular disorders (TMDs). If these are the main cause of open bite, it may be hypothesized that both pre-pubertal and adult open-bite patients would show a weak occlusal force and abnormal condylar motion. The purpose of this study was to test this hypothesis. Test group subjects consisted of 13 consecutive pre-pubertal and 13 adult patients with anterior open bite. They were compared with age-matched normal subjects. The adult open-bite group showed a weaker occlusal force and a shorter range of condylar motion compared with the control subjects. In the pre-pubertal subjects, however, there were no significant differences in the occlusal force and range of condylar motion between the open-bite and control groups. Therefore, these results suggest that a weak occlusal force or TMDs may not be the main cause of open bite.

Characterization of apatite formed on alkaline-heat-treated Ti.

Alkaline-heat-treated titanium self-forms an apatite surface layer in vivo. The aim of the present study was to materialistically characterize the surface of alkaline-heat-treated titanium immersed in simulated body fluid (AHS-TI) and to examine the differentiation behavior of osteoblasts on AHS-TI. SEM, thin-film XRD, FTIR, and XPS analyses revealed that AHS-TI contained a 1.0- micro m-thick, low-crystalline, and [002] direction-oriented carbonate apatite surface. Human osteoblast-like SaOS-2 cells were cultured on polystyrene, titanium, and AHS-TI, and RT-PCR analyses of osteogenic differentiation-related mRNAs were conducted. On AHS-TI, the expression of bone sialoprotein mRNA was up-regulated as compared with that on polystyrene and titanium (p < 0.05). On AHS-TI, the expression of osteopontin and osteocalcin mRNAs was up-regulated as compared with that on polystyrene (p<0.05). The results indicate that the apatite was bone-like and accelerated the osteogenic differentiation of SaOS-2, suggesting that alkaline-heat treatment might facilitate better integration of titanium implants with bone.