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Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders., (© 2024. The Author(s).)

Quantifying proliferative virus particles is one of the most important experimental procedures in virology. Compared with classical overlay materials, newly developed cellulose derivatives enable a plaque-forming assay to produce countable clear plaques easily. HEp-2 cells are widely used in plaque assays for human respiratory syncytial virus (RSV). It is crucial to use an overlay material to keep HEp-2 cell proliferation and prevent RSV particles from spreading over the fluid. Among four cellulose derivatives, carboxymethyl cellulose sodium salt (CMC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), and hydroxyethyl cellulose (HEC), we found that HPMC was the optimal overlay material because HPMC maintained HEp-2 cell proliferation and RSV infectivity. Although MCC was unsuitable for RSV, it assisted the plaque-forming by human metapneumovirus in TMPRSS2-expressing cells. Therefore, depending on the cells and viruses, it is necessary to use different overlay materials at varying concentrations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

1.2C-4Cr-4Mo-10W-3.5V-10Co-Fe high-speed steel (JIS SKH57; ISO HS10-4-3-10) is often manufactured via casting and forging. By applying powder metallurgy, the properties of the abovementioned material can be improved. In this study, the effects of sintering conditions on the formation of precipitates and pores are evaluated. Additionally, strength with and without hydrostatic pressure during sintering is evaluated via static bending and impact tests. Sintering via hot isostatic pressing (HIP) at 1463 K can effectively eliminate pores and prevent the coarsening of precipitates. Toughness and strength improved by 50% by applying HIP.

The Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 439 is an in vitro test method of reconstructed human epidermis (RhE), which was developed for hazard identification of irritating chemicals in accordance with a primary skin irritation test using rabbits with 4-hr exposure. A regulation for quasi-drugs in Japan requires data from primary skin irritation tests using rabbits to undergo 24-hr exposure, and this is used as an evidence for 24-hr closed patch tests in humans. In this study with the same chemicals, primary skin irritation test data using rabbits undergoing 24-hr exposure and a 24-hr occlusive human patch test data were analyzed by comparing the results obtained with four test methods adopted in OECD TG 439. The performances of in vitro test methods showed a positive predictive value of 72.7-85.7% to predict the results of 24-hr primary rabbit skin irritation test knowing that its positive predictive value was 57.1% against humans only. The prediction factors of in vitro test methods were higher for the human patch test data with a sensitivity reaching 60 to 80%. Three surfactants gave false negatives in some of the RhE methods evaluated with the human patch test, but in each case, they were correctly classified as positive when evaluated at double concentration. Therefore, the approach of setting the margin to 2 was effective in eliminating false negatives. This suggests that in vitro test methods are useful for assessing skin irritation potential without animal testing for the application of quasi-drugs in Japan.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion., Objective: Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that ΔNp63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes., Method: Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis., Results: ΔNp73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-κB activation. Furthermore, the Toll-like receptor 3 signal enhanced ΔNp73 expression and thereby induced TSLP expression., Conclusion: Our results indicate that ΔNp73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of ΔNp73, can be a novel therapeutic target of AD., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient (Snx5 -/- ) mice. In comparison to wild-type (Snx5 +/+ ) mice, Snx5 -/- mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5 -/- thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5 -/- thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5 -/- thyrocytes were also confirmed by results showing that Snx5 -/- mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5 -/- mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Florid reactive follicular hyperplasia (FRFH), which is characterized by large germinal centers (GCs) within normal lymphoid follicles, is often observed in benign lesions of lymph nodes and other tissues. Because of the histologic similarity of FRFH to tumorous lesions such as follicular lymphoma, careful pathological examination is required to evaluate such lesions; however, little is known about the mechanism underlying the development of FRFH. In this study, we investigated T follicular helper (Tfh) cells in hyperplastic tonsils of patients with obstructive sleep apnea syndrome (OSA), which frequently exhibits typical FRFH. When we analyzed tonsils of OSA and recurrent tonsillitis (RT) as a control, tonsils of OSA were found to harbor Tfh cells with a nearly 3-fold higher ratio in total CD4 + T cells than that in tonsils of RT. Further analysis showed that, in comparison to Tfh cells of RT tonsils, Tfh cells of OSA tonsils were relatively tolerant to CD3-mediated activation-induced cell death (AICD) and also expressed lower levels of a Bob1 transcription coactivator and IL-4, which fosters the development of GC-B cells. Given that Bob1 controls the proliferative activity in response to CD3 stimulation and has been suggested to have a role in the production of IL-4 in Tfh cells, the unique structure of FRFH is possibly associated with the function of Bob1 lo Tfh cells., (Copyright © 2017 European Federation of Immunological Societies. All rights reserved.)

IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1 hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Lipid mediators such as leukotrienes and lipoxines broadly regulate innate and acquired immunity, and their dysfunction causes various immune-mediated disorders. We previously reported a salient feature of arachidonate 5-lipoxyganase (Alox5), which is responsible for the production of such lipid mediators, in the regulation of high affinity antibodies in vivo. The aim of this study was to determine the functional significance of Alox5-related lipid mediators during the processes of acquired humoral responses. The results of in vitro experiments using lymphocytes in tonsils and blood specimens showed that lipoxin A4 (LXA4) and leukotriene B4 (LTB4) have the capacity to differentiate naïve CD4 + T cells into T follicular helper (Tfh) cells, which activate naïve B cells to form germinal centers. Such a function of LXA4 was further supported by results of in vitro studies using BML-111 and BOC-2, which are an agonist and an antagonist, respectively, of FPR2 of an LXA4-specific cell-surface receptor. The results suggest that such lipid mediators have a potential role in the development of lymphoid follicles through the regulation of Tfh cell differentiation., (Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B-cell lymphoma-6 and Blimp-1 determine lineages of Tfh cells and other types of effector CD4(+) T cells, respectively, suggests that there are unique mechanisms to establish Tfh-cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B-cell lymphoma-6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1(-/-) mice were much higher than those in wild-type (WT) mice. In addition, expansion of Tfh cells within Bob1(-/-) CD4(+) T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T-cell-intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1(-/-) Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3-induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1-related mechanism to restrict numerical frequency against stimulation of TCRs., (© 2016 The Authors. European Journal of Immunology published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Seventy-three children who underwent plastic surgery for their external ear malformations between December 2010 and May 2013 at the Sapporo Medical University Hospital were evaluated. The predominance of right-sided malformation (62%) in males (71%) was similar to that reported previously, but the number of bilateral cases (9.3%) was lower than that in previous reports. We classified patients' ears using Marx's classification. The pure-tone average (average air conduction thresholds measured at 500, 1,000 and 2,000 Hz) was used as the representative value for the hearing level, which was compared with a patient's Marx classification. We evaluated the facial nerve position using high-resolution computed tomography scans. A thorough understanding of anatomical variations and complications, as well as performing appropriate treatments, is required for otolaryngologists to effectively manage congenital microtia., (© 2016 S. Karger AG, Basel.)

In an aging society, the number of patients suffering from vertigo and dizziness is increasing. Vertigo is mostly thought to occur owing to otorhinolaryngologic disease. In contrast, it is difficult to diagnose dizziness, because of its varied causes, and we believe that the number of elderly patients suffering from dizziness is increasing. Here, we evaluated the relationship between canal paralysis and symptoms at the first medical examination and age-related changes in caloric response, and obtained the following 3 main findings: (a) 41.3% of the patients with canal paralysis complained of dizziness at the first medical examination, with an increased tendency in patients aged >70 years; (b) the slow-phase eye velocity (SPEV) of patients aged >70 years was lower than that of patients aged ≤69 years, and the SPEV of patients complaining of vertigo was higher than that of patients who complained of dizziness during a caloric test, and (c) the percentage of patients complaining of dizziness and those not complaining of symptoms during a caloric test increased with age. In conclusion, patients with canal paralysis tend to complain of dizziness at the first medical examination, and the percentage of patients without vertigo during a caloric test increased with age., (© 2016 S. Karger AG, Basel.)

Defensins are small antimicrobial peptides and effector components of innate immune responses. Recent studies have shed light on their beneficial functions for the prevention of infection and potential for development of new drugs. Here, we showed the expression profiles of human defensins in palatine tonsils with 3 different diseases: tonsillar hypertrophy, recurrent tonsillitis and focal infection of the tonsil. RT-PCR analysis and immunofluorescence revealed that the expression of human α-defensin 4 and β-defensin 3 (β3) in palatine tonsils with tonsillar hypertrophy was lower than that in recurrent tonsillitis and focal infection of the tonsil, suggesting that chronic inflammation induces defensin expression. Interestingly, β2 and β3 mRNAs were specifically expressed by palatine tonsil tissues but not in human peripheral blood mononuclear cells and mucosa of the small intestine. Additionally, we observed that exposure to a Toll-like receptor 4 ligand, lipopolysaccharide, which is used as a bacterial infection model, increases the production of β2 in culture supernatants from tonsillar epithelial cells in a dose-dependent manner. Taken together, these results indicate that β2 produced by tonsillar epithelial cells plays an important role in the innate immune response for bacterial infections., (© 2016 S. Karger AG, Basel.)

The tonsils are located at the entrance of the pharynx as a cardinal constituent of Waldeyer's ring, taking part not only in local immune responses, but also in systemic immunity. Functional deficits of tonsils primarily underlie the pathogenesis of various characteristic disorders, including tonsillar focal infections such as palmoplantar pustulosis and IgA nephropathy, in addition to the highly prevalent sleep disorder called obstructive sleep apnea syndrome. Although the mechanisms underlying these disorders remain unknown, the tonsils have long been postulated as a unique and enigmatic immune organ. Lymphoid cells and tissues from surgically resected tonsils are often employed to analyze the human immune response from a retrospective view. This approach has provided much new fundamental evidence for understanding innate and acquired immune responses, thereby facilitating further studies in the fields of mucosal immunity and specific humoral immunity originating in the germinal center. Future studies of the tonsils in basic and clinical research are expected to reveal the mechanisms of tonsil-related disorders as well as the nature of human immunity. In this review, which is primarily based on our original research over the past 3 decades, we summarize our findings and discuss the future prospects of studies focusing on the tonsils., (© 2016 S. Karger AG, Basel.)

Recently, the prevalence of allergic rhinitis has been dramatically increasing worldwide. As conventional therapies for allergic rhinitis, such as antihistamines, leukotriene receptor antagonists, nasal sprays and allergen immunotherapy, have limitations, the development of new drugs is required. Recent studies have revealed that epithelial cell-derived cytokines, including thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, are able to control immune cells, such as dendritic cells and T cells, thereby acting as 'master switches' in allergic disease. In addition, new roles have been identified for follicular helper T cells and regulatory B cells in allergic disease, and they are considered to be promising targets for new therapies. Thus, crosstalk between epithelial and immune cells, the epimmunome, underlies the pathogenesis of allergic rhinitis. Greater understanding of the epimmunome may lead to breakthroughs in the development of new treatments for allergic rhinitis and will help us cure many patients suffering from its severe symptoms in the future., (© 2016 S. Karger AG, Basel.)

Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease entity characterized by elevated serum IgG4 and extensive IgG4-positive plasma cell infiltration of various organs. Patients with IgG4-RD show nasal manifestations with chronic rhinosinusitis. The objective of this study was to evaluate the clinical characteristics of sinonasal lesions in patients with IgG4-RD., Methods: We evaluated radiological findings of sinonasal lesions in 79 patients with IgG4-RD who were divided into 3 groups according to severity. We also compared serological findings, including serum IgG4 and IgE levels, and eosinophil counts., Results: Rhinosinusitis was found in 41 patients (51.9%). Although there were no significant differences in the serum IgG4 and IgE levels of the groups, there was a significant increase in eosinophil counts (445 ± 311.9/mm³) in Group C. Furthermore, 14 of the 41 patients with rhinosinusitis (34.1%) showed improvement after prednisolone administration. Patients with IgG4-RD and serum eosinophilia tend to also have sinonasal lesions., Conclusions: Rhinosinusitis is common in patients with IgG4-RD, and its pathogenesis can be similar to eosinophilic chronic rhinosinusitis., (© The Author(s) 2015.)

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: One of the causes for poor vasculogenesis of diabetes mellitus (DM) is known to rise from the dysfunction of bone marrow-derived endothelial progenitor cells (BM EPCs). However, the origin of its cause is less understood. We aimed to investigate the effect of oxidative stress in early stage of diabetic BM-EPC and whether its vasculogenic dysfunction is caused by oxidative stress., Methods: Bone marrow c-Kit+Sca-1+Lin- (BM-KSL) cells were sorted from control and streptozotocin-induced diabetic C57BL6J mice by flow cytometry. BM-KSLs were then assessed for vasculogenic potential (colony forming assay; EPC-CFA), accumulation of intracellular ROS (CM-H2DCFDA), carbonylated protein (ELISA), anti-oxidative enzymes expression (RT-qPCR) and catalase activity (Amplex Red)., Results: Compared to control, DM BM-KSL had significantly lower EPC-CFUs in both definitive EPC-CFU and total EPC-CFU (p < 0.05). Interestingly, the oxidative stress level of DM BM-KSL was comparable and was not significantly different to control followed by increased in anti-oxidative enzymes expression and catalase activity., Conclusions: Primitive BM-EPCs showed vasculogenic dysfunction in early diabetes. However the oxidative stress is not denoted as the major initiating factor of its cause. Our results suggest that primitive BM-KSL cell has the ability to compensate oxidative stress levels in early diabetes by increasing the expression of anti-oxidative enzymes.

Objectives: Mikulicz's disease (MD) is an immunoglobulin (Ig) G4-related disease with systemic symptoms. Submandibular gland (SMG) biopsy is recommended for patients with possible IgG4-related MD for accurate differential diagnosis; however, it is difficult for certain patients to undergo this procedure. In contrast, labial salivary gland (LSG) biopsy is more convenient. Here we present an analysis of patients with IgG4-related MD whose LSG specimens were infiltrated with abundant IgG4-positive plasma cells., Methods: Sixteen patients diagnosed with IgG4-related MD underwent simultaneous SMG and LSG biopsies. We evaluated patients' serological and (18)F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) and grouped them as LSG+ (LSG specimens with > 40% IgG4-positive plasma cells/IgG-positive plasma cells, 11 patients) or LSG- (LSG specimens with < 40% IgG4-positive plasma cells/IgG-positive plasma cells, 6 patients)., Results: There were not significant differences in serum IgG and IgG4 levels between the two groups; however, serum concentrations of soluble interleuikin-2 receptor (sIL-2R) were significantly higher in the LSG+ group. All patients with increased (18)F-FDG uptake in their parotid glands were a part of the LSG+ group., Conclusions: When a SMG biopsy is not possible, the serum concentration of sIL-2R and (18)F-FDG-PET/CT findings may predict whether LSG biopsy will facilitate the diagnosis of IgG4-related MD.

UVA radiation is the most prevalent component of solar UV radiation; it deeply penetrates into the skin and induces profound alterations of the dermal connective tissue. In recent years, the detrimental effects of UVA radiation were more precisely demonstrated at cellular and molecular levels, using adequate methods to identify biological targets of UVA radiation and the resulting cascade impairment of cell functions and tissue degradation. In particular gene expression studies recently revealed that UVA radiation induces modulation of several genes confirming the high sensitivity of dermal fibroblasts to UVA radiation. The major visible damaging effects of UVA radiation only appear after years of exposure: it has been clearly evidenced that they are responsible for more or less early signs of photoageing and photocarcinogenesis. UVA radiation appears to play a key role in pigmented changes occurring with age, the major sign of skin photoaging in Asians. Skin susceptibility to photoaging alterations also depends on constitutive pigmentation. The skin sensitivity to UV light has been demonstrated to be linked to skin color type., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 73-year-old woman visited another hospital with complaints of occasional episodes of gross hematuria. A computed tomographic (CT) scan revealed extensive calcification in the left kidney, and she was referred to our hospital for further examinations. The physical examination was unremarkable other than mild back pain on her left side. Blood chemistry was normal. The CT scan revealed a mildly enhanced tumor of 6 cm in diameter accompanied by extensive calcification in the left kidney. Angiography revealed a hypovascular tumor in the left kidney. A left radical nephrectomy was carried out. Gross appearance of the specimen showed extensive calcification from the renal pelvic to the parenchyma of the lower pole of the left kidney. The histopathological diagnosis was renal cell carcinoma, alveolar type, mixed subtype, pT2pN0pM0.

Background: The present study was undertaken to investigate the value of gamma-seminoprotein (gamma-Sm) and the gamma-Sm/prostate specific antigen (PSA) ratio in combination with serum PSA in detecting prostate cancer., Methods: Prostate specific antigen, gamma-Sm and the gamma-Sm/PSA ratio were evaluated in 112 patients with untreated prostate cancer and 90 patients without prostate cancer who had serum PSA and gamma-Sm levels above their respective detection limits., Results: When data for all of the patients were analyzed, serum PSA and gamma-Sm levels were significantly higher and the gamma-Sm/PSA ratio was significantly lower in patients with prostate cancer than patients without prostate cancer. The serum PSA and gamma-Sm levels significantly increased and the gamma-Sm/PSA ratio significantly decreased with advancing clinical stage in patients with prostate cancer. Among the patients with serum PSA levels ranging from 1.8 to 6 ng/mL, the gamma-Sm/PSA ratio was significantly lower (P < 0.05) and gamma-Sm levels were lower (P = 0.054) in the patients with prostate cancer than in those without prostate cancer, but serum PSA levels were not significantly different (P = 0.53). A receiver operating characteristic (ROC) analysis demonstrated that the areas under the ROC curves were 0.54 for PSA, 0.65 for gamma-Sm and 0.69 for the gamma-Sm/PSA ratio for prediction of prostate cancer in the PSA range from 1.8 to 6 ng/mL, although the ROC analysis suggested that the gamma-Sm/PSA ratio does not provide significant advantage over PSA in detecting prostate cancer when all of the patients were analyzed., Conclusions: These results suggest that the gamma-Sm/PSA ratio and gamma-Sm may facilitate differentiation between patients with and without prostate cancer who have intermediate PSA levels.

A 67-year-old man visited our hospital with complaints of scrotal swelling associated with occasional febrile episodes. Physical examination disclosed a huge scrotal mass, approximately the size of a child's head, with numerous papillomatous lesions on its surface. His past medical history was significant in that he was diagnosed with penile carcinoma at the age of 35 years old and was treated with partial penectomy followed by radiation and chemotherapy at other hospital. During this admission tumor marker squamous cell carcinoma (SCC) and microbiological tests for mcroflariae were both negative. Ultrasound (US), computed tomographic (CT) scan and magnetic resonance imaging (MRI) revealed markedly thickened scrotal skin and small hydrocele with no evidence of local recurrence of the previous penile carcinoma. A percutaneous cystostomy was created because of chronic urinary retention and possible urine extravasation into the scrotum. Histopathological examination of the biopsy specimen from the scrotal mass demonstrated lymphangiectasia consistent with elephantiasis of the scrotum. Surgical excision of this huge scrotal mass was performed in August 1997. The resected tissue weighed 1,400 g. Convalescene was uneventful. He subsequently underwent perineal urethrostomy in place of the suprapubic cystostomy.

A 68-year-old man visited our hospital with complaints of abdominal pain and fever. Physical examination disclosed findings consistent with acute abdomen. Computed tomographic (CT) scan revealed a 5 cm cystic mass contiguous with the dome of the bladder and fluid collection in the peritoneal cavity. Cystogram demonstrated deformity of the bladder and no communication between the mass and the bladder. A diagnosis of generalized peritonitis either due to the infected urachal cyst or ruptured bladder was made, and emergency exploratory laparotomy was carried out. Based upon findings consistent with an infected urachal cyst associated with its intraperitoneal perforation, resection of the entire urachal remnant including the dome of the bladder was performed. Pathologic examination showed an acutely inflammed urachal cyst and chronic inflammation of the bladder wall.

Purpose: Carboxyterminal propeptide of type 1 procollagen (P1CP) is believed to be a marker of new bone formation. We investigated the possible application of serum P1CP as a biochemical marker for bone metastases in patients with prostate cancer., Materials and Methods: Prostate specific antigen (PSA), prostatic acid phosphatase (PAP), P1CP and alkaline phosphatase were measured in 136 serum samples from 79 patients with untreated prostate cancer, 29 with stage D2 disease in remission and 28 with progressive stage D2 carcinoma., Results: Serum P1CP and alkaline phosphatase were significantly elevated in untreated patients with a positive bone scan (278.9 +/- 61.9 ng./ml. and 826.5 +/- 176.3 international units per 1., respectively) compared to those with a negative bone scan (104.2 +/- 4.2 and 200.8 +/- 9.1, respectively, p <0.05). The areas under receiver operating characteristics curves were 0.86 for P1CP, 0.87 for alkaline phosphatase, 0.88 for PSA and 0.85 for PAP. The best accuracy rates for P1CP, alkaline phosphatase, PSA and PAP to predict bone lesions were 84, 87, 86 and 84%, respectively. P1CP provided a greater specificity and positive predictive value. These serum markers correlated significantly with the extent of disease on bone scan (p <0.05). The incidence of positive serum P1CP and alkaline phosphatase decreased significantly in response to endocrine therapy in patients with bone metastasis, and increased progressively in association with progression of the tumor (p <0.05) parallel to PSA and PAP., Conclusions: These findings suggest that serum P1CP is a useful indicator for predicting bone metastases.

Procollagen 1 carboxyterminal peptide (P1CP) is thought to be an indicator of new bone formation. The present report demonstrates that effective endocrine therapy induced an initial increase followed by a delayed decrease in serum levels of P1CP and alkaline phosphatase in spite of an immediate decrease in serum PSA and PAP and improvement of clinical symptoms in prostate cancer patients with bone metastases. The transient increase in P1CP and alkaline phosphatase is a healing reaction and is followed by apparent improvement. Short-term effects of endocrine therapy on prostate cancer patients with bone metastases should be comprehensively evaluated based upon the entire spectrum of clinical and laboratory findings including serial changes of serum prostate markers and bone markers as well.

Background: The objective of this study is to evaluate the efficacy of ureteroscopic lithotripsy as the treatment of ureteral stones in the recent era by comparing the result using a semirigid ureteroscope with the result using a conventional ureteroscope., Methods: Between 1991 and 1994, 136 patients with ureteral calculi underwent transurethral ureteroscopic lithotripsy in our hospital. From July 1991 to March 1993, 14F rigid ureteroscope with the rod lens system was used for 82 patients (group 1), whereas from April 1993 to July 1994 either a 9.5F or 7F semirigid fiberoptic ureteroscope was used for 54 patients (group 2). Insertion of ureteroscopes was performed under continuous irrigation of saline without mechanical dilation of the ureteral orifice in both groups., Results: The rates of complete removal of stone at the first trial were 56.1% in group 1 and 72.2% in group 2 with the overall complete removal rate of 62.5%. The complete removal rates of stones in the upper, middle and lower ureters were 18.2%, 54.8% and 72.4% in group 1 and 14.3%, 72.7% and 88.0% in group 2, respectively. The major reasons for unsuccessful treatments was upward migration of stones during the procedure. As intraoperative complications, ureteral disruption occurred in 1 case in group 1, and ureteral perforation in 5 patients in group 1 (6.1%) and 2 in group 2 (3.8%). Acute bacterial infection with prolonged fever was observed in 3 patients in group 1 and in none in group 2., Conclusion: From these results, the new semirigid ureteroscope with fiberoptic imaging bundles made the transurethral lithotripsy a safer and more efficient procedure for the treatment of ureteral calculi especially those in the lower ureters.

A 24-year-old man presented with right scrotal swelling and was diagnosed as having a testicular cancer. A high inguinal orchiectomy was carried out. Histological examination revealed immature teratoma and yolk sac tumor of the testis. Eight months later, 2 separate metastatic lesions appeared in the lungs, both of which were removed by operation after a course of combination chemotherapy with Etoposide and Cisplatin. The histology showed one to be composed of immature teratoma, and the another of yolk sac tumor.

We studied whether flow cytometric determination of proliferative cell activity estimated by the bromodeoxyuridine in vitro labeling technique provides significant prognosticators beyond the classical histological evaluation in the patient with bladder cancer. We evaluated 81 patients with transitional cell carcinoma of the bladder using fresh bladder specimens. Clinical followup of at least more than 24 months was requested, with the mean followup being 37.9 +/- 10.5 months. Tumor grade and stage were the histological prognostic parameters. Flow cytometric bivariate measurements of deoxyribonucleic acid (DNA) ploidy and bromodeoxyuridine labeled cell index were evaluated. Tumors with a bromodeoxyuridine labeled cell index of more than 10.7%, which was the value of the mean plus 2 times the standard deviation obtained in grade 1 bladder tumors, were designated as high bromodeoxyuridine labeled cell index tumors. A total of 51 patients with low bromodeoxyuridine labeled cell index tumors demonstrated a 98.0% 3-year actuarial survival rate estimated by the Kaplan-Meier method, compared to 42.9% for those with high index tumors. Multivariate survival analysis was performed with Cox's proportional regression model to study statistical individual prognostic values of histological and flow cytometric parameters. Histological tumor grade was the single most important prognostic factor (risk ratio 13.2, p < 0.05), with tumor stage being the second most important (risk ratio 9.2, p < 0.05), followed by bromodeoxyuridine labeled cell index status (risk ratio 6.9, p < 0.05). DNA ploidy status did not influence the clinical outcome. When grade 3 tumors were classified as low and/or high bromodeoxyuridine labeled cell index tumors, 3-year actuarial survival rates were 85.7% and 27.3%, respectively. These results indicate that DNA/bromodeoxyuridine bivariate analysis can be used as an effective adjunct to histological examination for prognostication and decision-making in treatment of bladder cancer patients.

An evaluation was made of the long-term results and risk factors of tumor recurrence in patients with superficial bladder cancer who were treated with intravesical bacillus Calmette-Guerin (BCG) and who had a mean follow-up period of 57 months. Eligible for the study were a total of 102 patients who were treated by transurethral resection of tumors and were considered to be free from tumor from 1984 to 1989. A suspension containing 80 mg Tokyo 172 strain BCG in 50 ml normal saline was given intravesically to 50 patients once a week for six weeks without further maintenance instillation. To the other 52 patients was additionally given monthly intravesical BCG instillation for 12 months. The actuarial nonrecurrent rates according to sex, different BCG treatment protocol, tumor grade, tumor status including primary or recurrent tumors, and solitary or multiple tumors were estimated by Kaplan-Meier method. The estimated three-, five- and seven-year actuarial nonrecurrent rates in all 102 cases were 77.3%, 68.5% and 60.6%, respectively. When nonrecurrent rates were compared to tumor characteristics, no statistically significant differences were observed between primary and recurrent tumors or between solitary and multiple tumors estimated by generalized Wilcoxon method. On the other hand, when nonrecurrent rates were compared with tumor grades, grade 3 tumor showed a 40.0% three-year nonrecurrent rate. The differences between grade 3 and grade 1 and between grade 3 and grade 2 were statistically significant (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a 41-year-old Japanese man with metastases of the lung, bone, lymph nodes and the base of the tongue 34 months after right radical nephrectomy. One month after systemic administration of human lymphoblastoid interferon (IFN), the metastasis to the base of the tongue completely disappeared, while other metastases increased both in size and number. Though the true effect of IFN-alpha on the metastatic renal cell carcinoma to the base of the tongue is still unknown, our case indicates that the tongue is a possible sensitive site to IFN-alpha therapy.

Kock and associates have made a major contribution to the ideal continent urinary diversion by developing a method for creating a continent internal reservoir for urine using the ileum. However, substantial problems have unfortunately resulted due to early and late postoperative complications. In an effort to further elucidate this problem, we herein summarize the incidence of early and late postoperative complications following a series of technical modifications made in patients who underwent Kock continent ileal reservoir construction from our ongoing experience to develop more suitable modifications of this procedure. From January 1985 through December 1991, 47 patients have undergone Kock pouch construction for continent urinary diversion. Our basic technique utilized in this study was slightly modified from that described by Skinner et al. Based on our earlier experience, several changes in the technique were made. One major change is that one row of surgical staples fixes the created nipple to the back wall of the reservoir for the efferent limb, and a further 3-cm longitudinal mucosal incision is made through the outer layer of the intussuscepted ileal nipple and the opposite wall of the reservoir which are sewn to the reservoir edge. A total of eleven patients (11/47) suffered one or more early surgical complications. A 31.8% (7/22) morbidity with an operative mortality rate of 4.3% (2/47) and a 16.0 (4/25) morbidity were observed in the early phase and late phase, respectively. Prolonged urinary leakage from the ileal reservoir and/or through a pin hole in the afferent limb made by surgical staples was observed in six patients (27.3%) in the early phase.(ABSTRACT TRUNCATED AT 250 WORDS)

The lymphocyte activation gene 3 (LAG-3), expressed in human activated T and natural killer (NK) cells, is closely related to CD4 at the gene and protein levels. We report here the initial characterization of the LAG-3-encoded protein. We have generated two monoclonal antibodies after immunization of mice with a 30-amino acid peptide that corresponds to an exposed extra loop region present in the LAG-3 immunoglobulin-like first domain. The reactivity of these reagents is directed against LAG-3 since they recognize both membrane-expressed and soluble recombinant LAG-3 molecules produced in a baculovirus expression system. The two antibodies are likely to react with the same or closely related epitope (termed LAG-3.1) exposed on the LAG-3 first domain extra loop, as assessed in competition experiments on LAG-3-expressing activated lymphocytes. Cellular distribution analysis indicated that the LAG-3.1 epitope is expressed on activated T (both CD4+ and CD8+ subsets) and NK cells, and not on activated B cells or monocytes. In immunoprecipitation experiments performed on activated T and NK cell lysates, a 70-kD protein was detected after SDS-PAGE analysis. 45-kD protein species were also immunoprecipitated. Both the 70- and 45-kD proteins were shown to be N-glycosylated. In Western blot analysis, only the former molecule was recognized by the anti-LAG-3 antibodies, demonstrating that it is LAG-3 encoded. These anti-LAG-3 antibodies were used to investigate whether the LAG-3 protein interacts with the CD4 ligands. By using a high-level expression cellular system based on COS-7 cell transfection with recombinant CDM8 vectors and a quantitative cellular adhesion assay, we demonstrate that rosette formation between LAG-3-transfected COS-7 cells and human leukocyte antigen (HLA) class II-bearing B lymphocytes is specifically dependent on LAG-3/HLA class II interaction. In contrast to CD4, LAG-3 does not bind the human immunodeficiency virus gp120. This initial characterization will guide further studies on the functions of this molecule, which may play an important role in immune responses mediated by T and NK lymphocytes.

This study was undertaken to determine the production of tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) by biological response modifier (BRM) in patients with renal cell carcinoma (RCC). Peripheral blood mononuclear cells (PBMC), which were donated from thirteen patients with RCC and five healthy controls, were cultured with streptococcal preparation, OK432, and/or macrophage-colony stimulating factor (M-CSF), and the TNF levels and IFN-gamma levels in the supernatant were evaluated. TNF activities were assayed by cytotoxicity to L929 cells and IFN-gamma activities were measured by inhibition of the cytopathic effects of sindbis virus on FL cells. The highest levels of TNF in the supernatant were 235.4 +/- 96.0 U/ml/1 x 10(4) cells in patients with renal cell carcinoma and 251.6 +/- 71.8 U/ml/1 x 10(4) cells in healthy controls, which were noted at 12 hours of incubation with the concentration of OK432 adjusted to 0.05 KE/ml. There was no statistically significant difference between the TNF activities induced by in vitro culture of PBMC obtained from patients with renal cell carcinoma and those from healthy controls. The production of TNF by in vitro culture of PBMC with OK432 of 0.05 KE/ml was augmented by adding 100 U/ml M-CSF especially at 48 and 72 hours of incubation, whereas M-CSF alone did not stimulated TNF production. The medium levels of IFN-gamma in six different cultures of PBMC with 0.05 KE/ml OK432 at 12, 24 and 48 hours of incubation were 1.15 +/- 0.34 U/ml/l x 10(4) cells, 2.23 +/- 0.93 U/ml/l x 10(4) cells, and 7.83 +/- 4.00 U/ml/l x 10(4) cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Sixty-one renal cell carcinomas were analyzed by simultaneous flow cytometric bivariate measurements of deoxyribonucleic acid (DNA) and bromodeoxyuridine. Bromodeoxyuridine in vitro labeling was performed by sample incubation with bromodeoxyuridine under hyperbaric oxygen. DNA ploidy status statistically correlated only with the presence or absence of distant metastasis. When the mean bromodeoxyuridine labeling index (LI) was accordingly compared with each histologic feature, architecturally solid, grade 3, high-stage (beyond pT3a) tumor, and the presence of distant metastasis showed significantly higher LI. When LI were compared with DNA ploidy, diploid tumors showed a 6.3% +/- 4.9% LI, whereas aneuploid tumors exhibited a 7.6% +/- 5.4% LI. The difference was not statistically significant. Five patients with a mean survival time of 10.2 +/- 4.1 months who had a mean LI of 11.5% +/- 7.7% died, whereas 56 patients with a mean LI of 6.7% +/- 4.8% survived. The difference was significant (P less than 0.05). However, the results did not necessarily correlate with the histologic features of the malignant potential or with the prognosis in individual patients. These data indicate that flow cytometric DNA/bromodeoxyuridine bivariate analysis remains inconsistent for predicting the malignant potential or prognosis of renal cell carcinoma.

T lymphocytes express either the alpha/beta or the gamma/delta receptor (TCR) in a mutually exclusive fashion. Both structures are associated on the cell membrane with the CD3 proteins which are thought to transduce signals resulting from antigen recognition. The CD3 complex is present in both alpha/beta and gamma/delta cells and includes at least five proteins (designated gamma, delta, epsilon, zeta and eta). We have developed here a novel mAb, anti-CD3.TCR1, which immunoprecipitates the CD3 molecules from both alpha/beta and gamma/delta cells lysates following solubilization with Triton X-100. While the SDS-PAGE migration profile of the material recognized by either anti-CD3.TCR1 or anti-OKT3 are superimposable in both cell types, this mAb recognizes viable untreated gamma/delta T lymphocytes exclusively. These findings further support the view that molecular interactions within the TCR/CD3 protein complex are distinct in the two T lymphocyte populations.

We studied whether flow cytometry provides significant prognosticators beyond the classical histological evaluation in the patient with bladder cancer. A total of 203 patients with untreated bladder cancer was evaluated using fresh bladder tumor specimens. Tumor grading and stage were the histological prognostic parameters. Deoxyribonucleic acid (DNA) index, percentage S-phase cells, percentage G2/M-phase cells and hypertetraploid cell presence were assessed as flow cytometric prognostic parameters. Multivariate survival analysis was performed using Cox's proportional regression model to study statistical individual prognostic values of histological and flow cytometric parameters. Hypertetraploid cell presence was the single most important prognostic factor (p less than 0.01), with tumor grade being nearly as important (p less than 0.01), followed by tetraploidy (p less than 0.01) and tumor stage (p less than 0.05). No other parameters, including the DNA index or cell phase fractions, contributed to the model. These results indicated that combined use of histological and flow cytometric parameters may provide additional information regarding the clinical outcome for bladder cancer patients.

Transurethral microwave thermotherapy using Prostatron was performed in 31 patients with benign prostatic hypertrophy, and the clinical effectiveness was evaluated by analyzing the subjective and objective responses following the treatment. The 22F balloon catheter to be placed in the prostatic urethra incorporates the microwave antenna, a cooling system and a fiberoptic thermosensor which allow an effective delivery of microwave energy to the center of the prostate, while preserving the mucosa and periurethral tissue. The maximum urethral temperature during the treatment ranged from 43.3 to 45.5 degrees C (44.7 +/- 0.96 degrees C: mean +/- S.D.) and the average power output was 27.4 Watt. The treatment was performed in a single session of an hour on the outpatient basis. In one patient who could not be relieved of the indwelling catheter underwent a transurethral resection, and the histological effect of thermotherapy on the resected specimen was examined. In the prostatic tissue, heat-induced necrotic change of the interstitial tissue as well as degenerative change of the acinar epithelium were remarkable, whereas the urethral mucosa was well preserved. In the remaining 30 patients, the clinical effects were evaluated 8 weeks after the treatment by a score scale for subjective symptoms, residual urine and maximum urinary flow rate, which was compared with the pretreatment score. Improvement of both subjective symptoms and objective findings was observed in 13 subjects (43.3%), that of subjective symptoms only in 14 cases, and that of objective findings only in 2 cases, resulting in a notable improvement in total 29 cases (97.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo studies on human malignant tumors are limited because of a lack of suitable animal models. In this study, the usefulness of SCID (severe combined immunodeficiency) mice, deficient in functions of both T- and B-lymphocytes, was evaluated. Inbred SCID mice were kept in isolated cages and 2 x 10(7) cells of KU-7, an established bladder carcinoma cell line, were inoculated in the subcutaneous tissue of the flank region of six SCID mice. Athymic nude mice were inoculated by the same method and served as the controls. The KU-7 cells were taken within 14 days in the injected region in all six SCID mice, while in only five out of eight nude mice. Tumors subsequently formed at the site of inoculation in these mice were confirmed to be transitional cell carcinomas histologically and intra-abdominal metastases were noted in two SCID mice. We conclude that SCID mice provide an ideal in vivo model for experimental studies of human urologic malignant tumors.

We have recently generated a series of gamma/delta T cell clones able to kill, after in vitro immunization, an Epstein-Barr Virus-transformed B cell line (designated E418) in a non-major histocompatibility complex-requiring fashion. A monoclonal antibody, termed anti-10H3, produced against E418 was selected by its ability to block these cytotoxic interactions. Further analysis indicated that the inhibitory effects of anti-10H3 were highly selective (i.e., no blocking activity with multiple control clones used as effector cells; no alteration of the natural killer-like function mediated by the relevant gamma/delta clones against 10H3+ tumor cells such as Rex). The molecule immunoprecipitated by anti-10H3, termed TCT.1, was characterized as a 43-kD protein broadly distributed in the hematopoietic system. The TCT.1 molecule has been further studied here by protein microsequencing. Results show that the TCT.1-derived peptide sequences are virtually identical to corresponding regions of Blast-1, a previously described surface protein with unknown function. The likely identity of the two molecules has been strengthened by analyzing the susceptibility of TCT.1 to phosphatidylinositol-specific phospholipase C digestion in light of the known anchorage of Blast-1 to the cell membrane through a glycosyl-phosphatidylinositol-containing lipid. The TCT.1/Blast-1-encoding gene is well characterized; it belongs to the immunoglobulin gene superfamily and it is located in the same band of chromosome 1 as the CD1 gene cluster. Together, these data further support the view that proteins distinct from the conventional class I/II histocompatibility molecules are involved in specific T cell recognition.

Gadolinium-labeled diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) was evaluated in an effort to clarify whether MRI could replace or be proved to be superior to computerized tomography (CT) and/or transurethral ultrasonography. A total of 57 bladder cancer patients was evaluated. MRI was performed with a superconducting magnet operating at 1.5 Tesla. The images acquired were multisections, having a fast spin-echo pulse sequence of less than a 14-second breath holding. Serial scans were performed before and immediately after Gd-DTPA venous injection. The findings on different imaging techniques were compared with the histological stagings. A proper diagnosis was made in 42 of 57 cases (73.7%) by Gd-DTPA-enhanced MRI, in 27 of 57 (47.4%) by CT and in 31 of 57 (54.4%) by transurethral ultrasonography when comparing the histological findings. The sensitivity and specificity for differentiating superficial and muscle-invasive tumor of each imaging method were, respectively, 96.2 and 83.3% in Gd-DTPA-enhanced MRI, 96.0 and 58.3% in CT, and 88.0 and 66.7% in transurethral ultrasonography. These data suggest that the staging of bladder cancer by Gd-DTPA-enhanced MRI appears to be superior and more accurate than the staging obtained by CT and transurethral ultrasonography.

A total of 56 human bladder tumors that were histologically proved to be transitional cell carcinoma was analyzed by simultaneous flow cytometric 2-color measurements of deoxyribonucleic acid (DNA) and bromodeoxyuridine. Bromodeoxyuridine in vitro labeling was performed by sample incubation with bromodeoxyuridine under high atmospheric pressure oxygen. Grade 1 tumors showed 33.3% aneuploidy with a mean bromodeoxyuridine positive stained ratio (labeling index) of 5.1 +/- 3.4%. Grade 2 tumors featured 51.7% aneuploidy with a mean labeling index of 8.9 +/- 7.7%. On the other hand, a markedly increased labeling index of 15.2 +/- 8.2% with aneuploidy was observed in all but 1 grade 3 tumors. When DNA ploidy and labeling indexes were compared according to the presence or absence of muscular invasion of tumors, all 16 muscle invasive tumors showed aneuploidy (mean labeling index 18.7 +/- 8.0%), while 17 of 40 nonmuscle invasive tumors showed aneuploidy (mean labeling index 8.6 +/- 5.4%). This labeling index difference was statistically significant (p less than 0.01). These results indicate that bromodeoxyuridine/DNA 2-color flow cytometry may provide an objective parameter for quantification of the malignant potential of bladder cancers.

We performed kidney preserving surgery for renal cell carcinoma in 10 patients with a solitary kidney or bilateral tumors. Two had cancer in a solitary kidney (contralateral kidney was nephrectomized for benign disease) and 8 had bilateral renal tumors, 3 and 5 of the latter 8 patients being asynchronous and synchronous, respectively. The kidney preserving surgery included partial nephrectomy in 3 patients and enucleation in 7 patients and was performed in situ and ex vivo followed by renal autotransplantation in 4 and 6 patients, respectively. Of the 10 patients, 4 are still alive after 2 years and 11 months-5 years and 6 months. Death occurred in 6 patients. Excluding one non-resectable patient and 2 patients of non-cancer death, 3 patients survived for 3 years-8 years and 8 months. The 10 patients, excluding one non-resectable, showed actuarial survival rates of 89, 89 and 63.3% for 1, 3 and 5 years, respectively, and excluding patients of non-cancer death, the above rates were 100, 100 and 85.7%, respectively. Postoperative local recurrence was found in 1 of 3 patients of partial resection and 2 of 7 patients of enucleation, and the latter 2 patients were those who had synchronous bilateral tumors and underwent renal autotransplantation following enucleation of a number of tumor nodules from seemingly less involved kidneys and contralateral radical nephrectomy; recurrence in the grafted kidney was already observable in the early postoperative period, which indicated re-growth of the residual tumor rather than recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Of 173 patients with renal cell carcinoma treated at the Keio University Hospital between 1979 and 1989, 48 cases were found to have their tumors incidentally (group 1), and the remaining patients presented with signs and/or symptoms related to their tumors (group 2). In this study we attempted to define the clinicopathological and ploidy characteristics of the tumors in the patients of the two groups. The number of patients having tumor stages not exceeding pT2NOMOV- was significantly higher in group 1 (81.3%) than in group 2 (36.0%) (p less than 0.001), and the median tumor size was significantly smaller in group 1 (4.32 +/- 2.38 cm) than in group 2 (7.86 +/- 4.07 cm) (p less than 0.001). The survival rate in group 1 was significantly favorable when compared with group 2 (p less than 0.005). And even in the same stage (pT1-2NOMOV-) there were statistical significance in the survival and relapse rate between the two groups (p less than 0.05), which indicate that renal cell carcinomas detected incidentally are associated with biologically low malignant potential. From 1985, flow cytometric DNA analysis was performed in 32 tumors from the group 1 and in 50 from the group 2. The frequency of occurrence of aneuploid pattern was significantly lower in tumors from the group 1 (25.0% in the overall patients and 16.0% in those with stage pT1-2NOMOV- tumors of group 1) than in those from the group 2 (52.0% in the overall patients and 42.9% in those with stage pT1-2NOMOV- tumors) (p less than 0.05). These results also suggest that renal cell carcinomas detected incidentally are associated with low malignant potential biologically.

In order to determine an optimum mode for systemic administration of recombinant interleukin 2 (rIL2), the effects of rIL2 on lymphocyte-mediated cytotoxicity against renal carcinoma cells were studied in vitro. Augmentation of the cytotoxicity by rIL2 was dose- and time-dependent. The optimum dose of rIL2 was 100-500 units (Jurkat units)/ml, and cytotoxicity increased significantly even at a low concentration such as 4 units/ml. We thus chose daily administration of multiple repeated dose for inpatients. To prevent withdrawal from the therapy as a result of untolerable adverse effects, the daily dose was set at 1 X 10(6) units, and rIL2 was given to 12 patients with metastatic renal cell carcinoma. Two-hour intravenous drip infusions containing 5 X 10(5) units of rIL2 was given daily 2 times to inpatients and after at least 28 days of this mode of administration, subcutaneous injection at a dose of 1 X 10(6) units was given 6 days a week to outpatients. Three patients showed complete response, 7 patients no change, and 2 patients progressive disease. Serious adverse effects due to capillary leak syndrome were not observed. We conclude that low-dose rIL2 is safe and has potential antitumor effects.

Using subtractive hybridization of a cDNA library we have identified a human gene, termed LAG-1 (for "Lymphocyte Activation Gene-1"). This cDNA codes for a 69 amino-acid polypeptide which belongs to a new class of recently described proteins secreted by activated lymphocytes and/or monocytes. The LAG-1 gene was cloned, sequenced and its chromosomal location assigned to chromosome 17 (q21 band). The promoter region of the LAG-1 gene was shown to include a GM-CSF-like decanucleotide sequence. Using a baculovirus vector expression system, we found that a 10 kDa recombinant LAG-1 protein is secreted by AcNPV infected SF9 cells, as determined in Western blot experiments by the reactivity of specific anti-peptidic heteroantibodies. Finally the natural LAG-1 protein was precipitated from the supernatant of internally labeled activated Nk cells and shown to migrate as a single entity of 14 kDa in SDS-PAGE analysis.

We report the results and complications of 103 consecutive patients who underwent percutaneous removal of renal and ureteral stones. The overall clinical success rate was 80.6%. For the recent 33 cases in which UL-arm fluoroscopy was used, however, the success rate was as high as 87.9%, which was considered to be due to easier establishment of percutaneous direct access. The most common complications were bleeding (18.5%), extravasation (15.5%) and fever (9.7%). Four cases with significant bleeding required arteriography, but there were no sign of arteriovenous fistula nor pseudoaneurysms in any cases. To study renal parenchymal damage in the percutaneous procedures, plasma renin activities (PRA) were compared in 54 cases after six months. However, significant elevation of PRA did not occur in any case.