Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Lorlatinib for the treatment of patients with non-small cell lung cancer.

Lorlatinib is a novel third-generation tyrosine kinase inhibitor (TKI) which targets anaplastic lymphoma kinase (ALK) as well as receptor tyrosine kinase c-ros oncogene 1 (ROS1). A critical limitation of conventional ALK/ROS TKIs is their association with acquired resistance mutations (particularly ALK G1202R and ROS1 G2032R) in the ALK or ROS1 gene, although these are not the only resistance mechanisms. Another limitation of this class of drugs is their inadequate efficacy against central nervous system metastasis, likely attributable to the blood-brain barrier (BBB). Therefore, lorlatinib was developed to overcome these limitations by being more potent, selective and permeable to the BBB than previous-generation ALK/ROS1 TKIs and subsequently received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) in April 2017. In September 2018, Japan became the first country where lorlatinib received approval for treating patients with ALK-rearranged non-small cell lung cancer. Eventually, the FDA approved lorlatinib (Lorbrena; Pfizer) in November 2018. Lorlatinib use is expected to increase in importance, owing to its promising efficacy in clinical trials.

Epstein-Barr virus maintains lymphomas via its miRNAs.

Epstein-Barr virus (EBV) has evolved exquisite controls over its host cells, human B lymphocytes, not only directing these cells during latency to proliferate and thereby expand the pool of infected cells, but also to survive and thereby persist for the lifetime of the infected individual. Although these activities ensure the virus is successful, they also make the virus oncogenic, particularly when infected people are immunosuppressed. Here we show, strikingly, that one set of EBV's microRNAs (miRNAs) both sustain Burkitt's lymphoma (BL) cells in the absence of other viral oncogenes and promote the transformation of primary B lymphocytes. BL cells were engineered to lose EBV and found to die by apoptosis and could be rescued by constitutively expressing viral miRNAs in them. Two of these EBV miRNAs were found to target caspase 3 to inhibit apoptosis at physiological concentrations.

Two case reports of successful withdrawal of mycofenolate mofetil after living donor lobar lung transplantation.

BACKGROUND: Lung transplantation cases have immunosuppression maintained using a calcineurin inhibitor, anti-metabolites, and steroid. CASE REPORT: We report 2 clinical cases in which anti-metabolites (mycophenolate mofetil) were successfully withdrawn after living donor lobar lung transplantation by monitoring immune function using the ImmuKnow® assay. In the first case, a 43-year-old woman underwent living donor lobar lung transplantation for pulmonary alveolar proteinosis. Two healthy relatives donated a lower lobe each. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. Six months posttransplantation, she developed invasive pulmonary aspergillosis. During anti-fungal treatment, we withdrew mycophenolate mofetil and tacrolimus trough levels were kept around 8 ng/mL. Despite the resulting low-level immunosuppression, the ImmuKnow assay showed immune function to be in the moderate range with tacrolimus and steroid alone, encouraging us to maintain this strategy to avoid recurrence of invasive pulmonary aspergillosis. In the second case, a 24-year-old man underwent living donor lobar lung transplantation for cystic fibrosis. Two healthy relatives donated a lower lobe each. Immunosuppression was maintained using tacrolimus, mycophenolate mofetil, and steroid. Five months posttransplantation, he developed persistent Pseudomonas aeruginosa pneumonia derived from the paranasal sinuses. Under ImmuKnow assay monitoring, mycophenolate mofetil was withdrawn, but immune function was maintained within the moderate range using tacrolimus and steroid alone. DISCUSSION: Respiratory function in both cases was maintained; no findings of bronchiolitis obliterans syndrome were noted during this period. To the best of our knowledge, no reports have described successful anti-metabolite withdrawal in lung transplantation with ImmuKnow monitoring. Immune evaluation by ImmuKnow could offer a useful method to monitor and control immune status, particularly among recipients susceptible to infection, revealing that moderate immune function could be maintained using tacrolimus and steroid in living donor lobar lung transplantation.

Synovial chondromatosis of the temporomandibular joint with calcium pyrophosphate dihydrate crystal deposition disease (pseudogout).

This report describes a very rare case of synovial chondromatosis with deposition of calcium pyrophosphate dihydrate (CPPD) crystals (pseudogout) in the temporomandibular joint (TMJ) of a 46-year-old male patient. Synovial chondromatosis is a non-neoplastic disease characterized by metaplasia of the connective tissue leading to chondrogenesis in the synovial membrane. Pseudogout is an inflammatory disease of the joints caused by the deposition of CPPD, producing similar symptoms to those observed in gout but not hyperuricaemia. Both diseases commonly affect the knee, hip and elbow joints, but rarely affect the TMJ.

[Important factors surrounding chest surgery for the patients complicated with digestive disease].

OBJECTIVE: Important factors surrounding chest surgery for the patients complicated with digestive disease were discussed according to the experiences of clinical settings. METHODS: Check points regarding each context, preoperative, perioperative, postoperative, and outpatient care were considered independently. RESULTS: If digestive diseases are uncontrolled, the operation should be postponed until they are appropriately cared. Dental problems such as teeth caries or denture insufficiency should be cleared preoperatively. Dysphagia after the head and neck surgery must be evaluated and alternative feeding methods should be established. The patients with digestive tract disorder have malabsorption and are prone to malnutrition. According to the appropriate assessments of digestion and absorption, an enteral nutrition or a total parenteral nutrition should be considered before and after operation, to improve nutrition status. Immunonutrition is particularly beneficial to reduce the postoperative infection or various stresses of invasive operations in the chest surgery. Chronic pancreatitis is characterized by absorption impairment and pancreatic diabetes. They should also be controlled before the operation using digestive enzymes and an exogenous insulin. CONCLUSION: Teeth problems, dysphagia, malabsorption, malnutrition and pancreatic diabetes should be assessed and cared appropriately before and after the chest surgery using compensative therapy.

A case of tongue carcinoma associated with chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) can occur at various sites, including the oral mucosa, where it is associated with a high risk of head and neck cancer. We report the case of a 46-year-old woman with tongue cancer that developed following Hodgkin's lymphoma and chronic GVHD, and we discuss the possible causes of cancer development.

Comparability and reproducibility of the carotid-femoral pulse wave velocity measurements using a multi-element carotid tonometry sensor.

To evaluate the comparability and reproducibility of the carotid-femoral pulse wave velocity (PWV) measured by the newly developed device compared to that measured by the standard device and the validity of brachial-ankle PWV as a substitute of carotid-femoral PWV. We measured aortic PWV twice in 21 normotensive males by using the standard devices and the newly developed device. We also measured brachial-ankle PWV in the same subjects. There was a strong, significant correlation between aortic (carotid-femoral) PWV measured by using two different devices (r = 0.741, P = 0.00012). Interquartile range of the differences of carotid-femoral PWV measured by Form (0.75 m/s (-0.36, 0.39)) was smaller than that by Complior (1.67 m/s (-1.03, 0.63)). There was no correlation between carotid-femoral PWV, measured by either device, and brachial ankle PWV. Our present results suggest that carotid-femoral PWV measured by using Form was comparable to, and may be more reproducible than, that measured by Complior that has been widely used as a predictable marker for cardiovascular events. Our results also suggest brachial-ankle PWV may not be a substitute for carotid-femoral PWV.

Subcutaneous administration of lactone form of simvastatin stimulates ectopic osteoinduction by rhBMP-2.

OBJECTIVE: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. MATERIALS AND METHODS: Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. RESULTS: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group. CONCLUSION: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.

Pedunculated oncocytic carcinoma in buccal mucosa: immunohistochemical and ultrastructural studies.

PURPOSE: In this study we evaluated pedunculated oncocytic carcinoma (OC) in the buccal mucosa via immunohistochemical and ultrastructural studies. PATIENT AND METHODS: An 84-year-old man was referred to our clinic with a pedunculated mass about 4 cm in diameter in the right buccal mucosa. An incision biopsy revealed the diagnosis of oncocytic tumor, and enucleation was performed. The tumor was stained for immunohistochemical analysis using the ABC method and antibodies against cytokeratin (CK), epithelial membrane antigen (EMA), desmin, S-100 protein and muscle-specific actin, respectively. The tumor was stained with uranyl acetate and lead citrate for visualization by electron microscopy. RESULTS: Histopathology results revealed that the tumor consisted of oncocytic cells, characterized by eosinophilic and granular cytoplasm, and atypical nuclei. These cells had infiltrated local blood vessels, salivary glands and muscles. Immunohistochemical staining indicated that these cells were positive for CK and EMA, and negative for desmin, muscle-specific actin and S-100 protein. Electron microscopy revealed numerous dilated cytoplasmic mitochondria, and the cell contours and nucleic shapes of tumor cells were often irregular. CONCLUSIONS: Because the histopathologic features of OC are similar to those of benign oncocytoma, the diagnosis of OC must be confirmed by a combination of clinical and ultrastructural characteristics.

[Surgical treatment for stage IV lung cancer].

OBJECTIVE: To find out the optimal surgical indication in stage IV lung cancer patients, we evaluated them retrospectively. METHODS & RESULTS: From 1975 to 2005, 62 patients without multiple metastases were operated at our hospital. The most common histological type was adenocarcinoma (67.7%). The metastatic lesions were lung (33.9%), brain (24.2%), liver, bone, adrenal gland and so on. The overall survival rate of stage IV lung cancer was 10.4% at 5-year. Five-year survival for patients with lung or brain metastasis who had no lymph node metastasis were significantly more superior than those with lymph node metastasis (p=0.0389, 0.0021). Four of 62 patients had 5-year survival. Two were lung and the others were brain and adrenal gland metastasis without lymph node metastasis. CONCLUSION: Stage IV lung cancer with lung or brain or adrenal gland metastasis without lymph node metastasis should be resected.

Toll-like receptors 2 and 4 are differentially involved in Fas dependent apoptosis in Peyer's patch and the liver at an early stage after bile duct ligation in mice.

BACKGROUND AND AIMS: Surgical management of extrahepatic cholestasis is frequently complicated by bacterial translocation and severe liver injury. The aim of this study was to clarify the involvement of Toll-like receptors (TLRs) in the pathogenesis of bacterial translocation and liver injury in obstructive cholestasis. METHODS: TLR2 deficient (TLR2(-/-)), MyD88(-/-), Jalpha281(-/-), gld/gld, and lpr/lpr mice, all of which have a C57BL/6 background, and C3H/HeN and TLR4 mutated C3H/HeJ mice were subjected to bile duct ligation (BDL). Faecal IgA and serum alanine aminotransferase levels were determined after BDL. Apoptosis was examined by histological and flow cytometric analyses of cells from Peyer's patches and the liver. RESULTS: The size and number of B cells in Peyer's patches markedly decreased on day 3 after BDL. Increased apoptosis in Peyer's patch B cells was evident on day 1 after BDL in control mice but not in lpr/lpr, MyD88(-/-), or C3H/HeJ mice. On the other hand, TLR2 and Fas ligand expression on intrahepatic NK1.1(+) T cells increased on day 1 after BDL in C57BL/6 mice. Liver injury and apoptosis were evident on day 1 after BDL in control and C3H/HeJ mice but were significantly reduced in TLR2(-/-), Jalpha281(-/-), gld/gld, and lpr/lpr mice. CONCLUSIONS: TLR4 and TLR2 may play important roles in Fas dependent apoptosis in Peyer's patch B cells and hepatocytes, respectively, at an early stage after BDL in mice.

Clinicostatistical study of carotid calcification on panoramic radiographs.

OBJECTIVE: The purpose was to evaluate carotid calcifications on panoramic radiographs, and relate to risk factors for vascular diseases. METHOD: Between 1997 and 2001, 2568 radiographs were retrospectively collected from new patients at Mie University Hospital whose ages ranged from 50 to 70 years. The mean age of the subjects was 62.2 years (men 61.9 years, women 62.3 years). Medical and social data were collected from case notes, and body weight, height, and age of menopause confirmed by telephone interviews. RESULT: About 106 carotid calcifications were found on the panoramic radiographs of 26 males and 80 females. The ratio of males to females was 1:3.07. The subjects with carotid calcifications had medical histories that included hypertension (27.6%), obesity (21.1%), hyperlipidemia (14.5%), and cardiovascular diseases (13.2%), all with recognized risk factors for atheromas. Of 76 patients who responded to follow up interviews, two (2.63%) died from cardiovascular stroke during an average follow up of 2.43 years. CONCLUSIONS: The results show carotid calcifications detected on panoramic radiographs can be used to help predict vascular strokes in patients. In cases where calcified carotid artery atheromas are detected, the dentist or oral and maxillofacial surgeon should refer the patient to a specialized physician.

A case of double cancer involving oral malignant melanoma and gastrointestinal stromal tumor (GIST).

We report a very rare case of double cancer involving palatal malignant melanoma and gastrointestinal stromal tumor (GIST), a rare tumor of the gastrointestinal tract originating from a primitive mesenchymal cell. After chemotherapy, radiation therapy, and treatment with interferon and OK-432, the GIST was resected and the melanoma disappeared. The patient has had no evidence of recurrent tumor, and the patient's clinical course has been uneventful for 1 year. This is probably the first report of synchronous double cancer involving oral malignant melanoma and GIST.

A case of thrombosis mimicking a buccal tumour: usefulness of MRI.

A rare case of thrombosis mimicking a tumour in the buccal region is reported. Since the entire round mass was located deeply, it was difficult to diagnose. Contrast computed tomography, magnetic resonance imaging (MRI) and ultrasound examinations may be useful, but MRI was most useful in this case because it allowed prediction of different kinds of histological structures in the soft tissue. The findings of T1 weighted imaging, T2 weighted imaging and examination with Gd-DTPA on T1 weighted imaging are useful for predicting the character of deeper soft tissue masses, and can differentiate thrombosis from lymphadenopathy, lipoma and other lesions.

A single dose of nateglinide improves post-challenge glucose metabolism and endothelial dysfunction in Type 2 diabetic patients.

AIMS: This randomized crossover placebo-controlled study aimed to assess the efficacy of nateglinide, a phenylalanine-derived insulin secretagogue, on forearm endothelial function in diabetic subjects before and after an oral glucose load. METHODS: Forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperaemia before and after an oral glucose load (75 g) with a prior use of placebo or nateglinide (90 mg) in 15 diet-treated Type 2 diabetic patients or age-matched controls with normal glucose tolerance. RESULTS: The peak FBF response and total reactive hyperaemic flow (flow debt repayment: FDR), indices of resistance artery endothelial function, were decreased after an oral glucose load in diabetic patients, but unchanged in controls. Nateglinide administered to diabetic patients accelerated insulin secretion and reduced post-challenge plasma glucose, and also abolished the post-challenge impairment of endothelial function. The peak FBF and FDR were well correlated with 120-min glucose levels and 30-min insulinogenic index. CONCLUSIONS: A single challenge of glucose was shown to impair endothelial function in diabetic patients, and the post-challenge endothelial dysfunction was improved by a prior use of nateglinide. Long-term effects of nateglinide on endothelial function in Type 2 diabetic patients need to be clarified in future studies.

Effects of near-infrared irradiation to stellate ganglion in glossodynia.

OBJECTIVE: This study was designed to assess the effect of stellate ganglion near-infrared irradiation (SGR) on glossodynia and the mechanism of action. STUDY DESIGN: Thirty-seven patients with glossodynia received SGR once weekly for 4 weeks. The response to treatment was evaluated on the basis of the change in pain intensity, assessed with a visual analogue scale (VAS) before and after 4 weeks of treatment. The temperature and blood flow of the tongue were also measured before and after first SGR. As control, eight healthy subjects were studied. RESULTS: Tongue pain as assessed by the VAS decreased in 28 of the 37 patients (75.7%). Mean pain intensity decreased significantly from 5.1 +/- 2.2 to 1.9 +/- 2.1 (P < 0.05). Tongue blood flow at rest in the patients with glossodynia [7.2 +/- 1.6 ml min(-1) (100 g)(-1)] was significantly lower than that in the healthy subjects [7.8 +/- 0.23 ml min(-1) (100 g)(-1)]. Five minutes after SGR, the temperature of the tongue rose 1.5 +/- 0.21 degrees C, and blood flow increased to 8.5 +/- 1.2 ml min(-1) (100 g)(-1). Tongue blood flow (at rest) after 4 weeks of SGR had increased to 7.7 +/- 1.1 ml min(-1) (100 g)(-1). CONCLUSION: SGR is an effective treatment for glossodynia. The mechanism by which SGR improves symptoms associated with glossodynia is thought to be as follows: SGR inhibits abnormally increased sympathetic activity associated with glossodynia. This is followed by normalization of decreased tongue blood flow, thereby alleviating pain.

Characterization of the development of ectopic chondroid/bone matrix and chondrogenic/osteogenic cells during osteoinduction by rhBMP-2: a histochemical and ultrastructural study.

OBJECTIVE: To investigate the characteristics of ectopic chondroid/bone matrix and chondrogenic/osteogenic cells induced by recombinant human bone morphogenetic protein-2 (rhBMP-2). MATERIALS AND METHODS: rhBMP-2 (5 microg) combined with atelocollagen was implanted into calf muscles of rats and removed on days 7, 10, 14, 21, or 28. Tissue sections were examined using: (i) hematoxylin/Alcian blue/Sirius red stain, (ii) enzyme histochemistry for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase activity, (iii) immunohistochemistry for types I, II, and X collagen, and (iv) electron microscopy. RESULTS: On day 7, numerous fibroblast-like cells with ALP activity were present on the pellet rim. On day 10, chondroid matrix (CM) had formed, contained both type I collagen and proteoglycans, and often continued into the BMP pellet. On day 14, bone-like matrix formed around hypertrophic chondrocytes simultaneously with endochondral ossification. Coexpression of types I and II collagen within chondrocytes and osteocytes was observed throughout the time course of the experiment. CONCLUSION: These results suggest that fibroblast-like cells invading the pellet differentiate into chondrocytes and form CM under the scaffold of the carrier component. It appears that some chondrocytes change their phenotype to produce the bone-like matrix and remain within the endochondral bone. This process enables rapid osteogenesis to occur.

Efficacy of immunoliposomes on cancer models in a cell-surface-antigen-density-dependent manner.

We have recently established a cancer-reactive human monoclonal antibody, GAH, with a positive ratio of over 90% against stomach cancer. GAH was formulated as polyethyleneglycol (PEG)-modified immunoliposomal doxorubicin (DXR) (ILD) and its efficacy was examined against gastrointestinal human cancers. In in vitro studies, a comparison of ILD with PEG-modified liposomal DXR (LD) demonstrated that ILD had dose-dependent cytotoxicity for GAH-reactive B37 cancer cells, but not LD. In concordance with this result, microscopic observations showed that ILD was bound to and GAH-dependently internalised by B37 cells. In in vivo studies, ILD exhibited significantly greater antitumour activity on cancer xenograft models than LD or free DXR. The relation between efficacy and antigen density was examined on 10 xenograft models bearing cancer cells with varying GAH reactivity. Immunoliposomal doxorubicin therapeutic activity correlated with the antigen density, with a minimum number being required. Also, ILD revealed strong antitumour activity on cancers with low sensitivity to DXR or LD, suggesting that ILD overcame the DXR resistance of antigen-positive cancer cells. Thus, these results show that GAH endows liposomes with targeting activity, resulting in strong efficacy against gastrointestinal cancers.

Trends in hospitalization after injury: older women are displacing young men.

OBJECTIVE: To evaluate trends in hospitalization after injuries in the USA. DESIGN: National Hospital Discharge Survey data from 1979 to 2000 were evaluated annually by age group, sex, injury severity score (ISS), length of stay, and discharge destination. SETTING AND SUBJECTS: National probability sample of hospitalized patients. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Incidence, duration, outcome, and population based rates of hospital admission after injuries. RESULTS: The number of young males admitted to hospitals after injuries has decreased dramatically; older females are now the group most frequently admitted. Total days in the hospital have decreased in all age groups, but have declined less in the older population than in the younger population; furthermore, most patients aged 65 and over were formerly discharged home, but now most are discharged to long term care facilities. Overall hospitalization rates after injury have decreased in all age groups, but have declined less in the older population; furthermore, male and female hospitalization rates for serious injury (ISS at least 9, excluding isolated hip fracture) are decreasing in younger age groups while increasing in older age groups. CONCLUSIONS: Older patients comprise a growing proportion of injuries requiring hospitalization. Trauma systems must address this change, and preventing injuries in older people is increasingly important.