Protocol improvement and multisite validation of a digital soft agar colony formation assay for tumorigenic transformed cells intermingled in cell therapy products.

BACKGROUND AIMS: The administration of human cell-processed therapeutic products (hCTPs) is associated with a risk of tumorigenesis due to the transformed cellular contaminants. To mitigate this risk, these impurities should be detected using sensitive and validated assays. The digital soft agar colony formation (D-SAC) assay is an ultrasensitive in vitro test for detecting tumorigenic transformed cells in hCTPs. METHODS: In this study, we first evaluated the colony formation efficiency (CFE) precision of tumorigenic reference cells in positive control samples according to a previously reported D-SAC assay protocol (Protocol I) from multiple laboratories. However, the CFE varied widely among laboratories. Thus, we improved and optimized the test protocol as Protocol II to reduce variability in the CFE of tumorigenic reference cells. Subsequently, the improved protocol was validated at multiple sites. Human mesenchymal stromal cells (hMSCs) were used as model cells, and positive control samples were prepared by spiking them with HeLa cells. RESULTS: Based on the previously reported protocol, the CFE was estimated using an ultra-low concentration (0.0001%) of positive control samples in multiple plates. Next, we improved the protocol to reduce the CFE variability. Based on the CFE results, we estimated the sample size as the number of wells (Protocol II) and assessed the detectability of 0.0001% HeLa cells in hMSCs to validate the protocol at multiple sites. Using Protocol I yielded low CFEs (mean: 30%) and high variability between laboratories (reproducibility coefficient of variance [CV]: 72%). In contrast, Protocol II, which incorporated a relatively high concentration (0.002%) of HeLa cells in the positive control samples, resulted in higher CFE values (mean: 63%) and lower variability (reproducibility CV: 18%). Moreover, the sample sizes for testing were estimated as the number of wells per laboratory (314-570 wells) based on the laboratory-specific CFE (42-76%). Under these conditions, all laboratories achieved a detection limit of 0.0001% HeLa cells in hMSCs in a predetermined number of wells. Moreover, colony formation was not observed in the wells seeded with hMSCs alone. CONCLUSIONS: The D-SAC assay is a highly sensitive and robust test for detecting malignant cells as impurities in hCTPs. In addition, optimal assay conditions were established to test tumorigenic impurities in hCTPs with high sensitivity and an arbitrary false negative rate.

Comparison of Oncological Outcomes of Pembrolizumab as Second-line Therapy and Maintenance Avelumab Therapy in Advanced Urothelial Carcinoma After Platinum-based Chemotherapy.

BACKGROUND/AIM: Sequential therapy using chemotherapy and subsequent immune checkpoint inhibitor (ICI) treatment prolongs the survival of patients with advanced urothelial carcinoma (UC). However, no comparison data for oncological outcome between pembrolizumab and avelumab has been reported. Thus, we compared oncological outcomes between pembrolizumab as second-line therapy and maintenance avelumab therapy in patients with advanced UC. PATIENTS AND METHODS: We retrospectively evaluated patients with advanced UC treated with pembrolizumab or avelumab between January 2018 and February 2023. We compared oncological outcomes after adjusting for patient characteristics. Immune-related adverse events (AEs) in each group were evaluated using the Common Terminology Criteria for Adverse Events. RESULTS: There were 186 and 44 patients in the pembrolizumab- and avelumab-treated cohorts, respectively. After propensity score matching, 43 patients from each group were selected and analyzed. Median progression-free survival from the initiation of pembrolizumab and avelumab treatments was 126 and 139 days, respectively (log-rank test, p=0.625). Median overall survival in the pembrolizumab and avelumab cohorts were 658 days and not reached, respectively (log-rank test, p=0.249). Thirty-eight (20.4%) and 14 (31.8%) all-grade immune-related AEs were observed in 186 pembrolizumab- and 44 avelumab-treated patients, respectively (chi-squared test, p=0.112). Regarding endocrine-related AEs, 12 (6.5%) and none (0%) were observed in pembrolizumab- and avelumab-treated patients, respectively (Fisher's exact probability test, p=0.129). CONCLUSION: Pembrolizumab and maintenance avelumab therapy provide equivalent oncological outcomes in patients with advanced UC. Although no significant difference was observed, there might be a potential risk of higher endocrine-related AEs due to pembrolizumab compared to avelumab maintenance therapy.

Self-organization, quality control, and preclinical studies of human iPSC-derived retinal sheets for tissue-transplantation therapy.

Three-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation. Self-organizing hPSCs differentiated into both retinal and off-target tissues. Gene expression analyses identified the major off-target tissues as eye-related, cortex-like, and spinal cord-like tissues. For quality control, we developed a qPCR-based test in which each hPSC-derived neuroepithelium was dissected into two tissue-sheets: inner-central sheet for transplantation and outer-peripheral sheet for qPCR to ensure retinal tissue selection. During qPCR, tissue-sheets were stored for 3-4 days using a newly developed preservation method. In a rat tumorigenicity study, no transplant-related adverse events were observed. In retinal degeneration model rats, retinal transplants differentiated into mature photoreceptors and exhibited light responses in electrophysiology assays. These results demonstrate our rationale toward self-organizing retinal sheet transplantation therapy.

[Fever after Gemcitabine Administration is a Poor Prognostic Factor in Patients with Metastatic Urothelial Carcinoma : Multicenter Retrospective Study].

Gemcitabine (GEM) is currently a standard chemotherapeutic agent for metastatic urothelial carcinoma (mUC). Fever isknown to be an adverse effect of GEM ; however, itsincidence, etiology and clinical significance have not been evaluated. The objective of this study was to elucidate the characteristics and clinical significance of fever associated with GEM in patients with mUC receiving GEM plus cisplatin (GC) chemotherapy. Between 2005 and 2014, 184 patientswith mUC who received first-line GC therapy at 10 institutions were enrolled. GEM-associated fever (GEMAF) was defined as a body temperature ≥37.5ºC within 96 hours after administration of GEM with no evidence of specific conditions causing fever including infection. Clinical parametersbefore GC therapy were evaluated to determine predictorsof GEMAF. Furthermore, the impact of GEMAF on clinical outcomeswasals o evaluated. The median age was70 years and median follow-up was14.2 months. GEMAF wasobs erved in 44 patients (23.9%). In multivariate analysis, elevated C-reactive protein (CRP) before chemotherapy was an independent predictive factor for GEMAF (oddsratio 2.450, p＝0.041). There was a significant difference in progression-free survival (median 6.7 vs 8.0 months, p＝0.031) and cancer-specific survival (median 12.0 vs 15.8 months, p＝0.045) between patients with and without GEMAF. Results of this study suggest that GEMAF is a common adverse event of GC therapy for mUC and can be a poor prognostic factor. GEMAF may be associated with systemic inflammatory response induced by the tumor in patients with mUC.

The discrepancy between serum creatinine and cystatin C can predict renal function after treatment for postrenal acute kidney injury: multicenter study and pooled data analysis.

BACKGROUND: Although serum cystatin C and creatinine are used as practical markers of renal function, the discrepancy between them in postrenal acute kidney injury (AKI) cases was reported. The aim of this study was to determine whether the preoperative serum cystatin C (pre-CysC) level could predict clinical outcomes after treatment in patients with postrenal AKI. METHODS: Patients who underwent urological interventions with postrenal AKI were enrolled in this prospective observational study. Associations among preoperative serum creatinine (pre-sCr), pre-CysC, and nadir postoperative serum creatinine (post-sCr) were evaluated. In addition, based on our results in combination with detailed data from the literature, a predictive equation for postoperative serum creatinine (post-sCr) was developed by simple regression analysis and validated using Bland-Altman plots. RESULTS: Finally, 19 patients were eligible for analysis in this study. The value calculated by subtracting pre-CysC (mg/L) from pre-sCr (mg/dl) had a strong correlation to the decrement of serum creatinine (r = 0.9508, p < 0.0001). We added the data of 16 patients obtained from the literature to our series, which were totally randomized into 2 groups, training set and validation set in a 2:1 ratio (n = 23 and 12, respectively) to develop and validate a predictive equation for post-sCr. The mean difference between the predictive and actual post-sCr, -0.68 mg/dl (95% CI -1.62 to 0.26) in the validation set was within the limits of agreement. CONCLUSION: We showed that the discrepancy between pre-sCr and pre-CysC could predict improvement of renal function after intervention in patients with postrenal AKI.

Efficacy and safety of docetaxel and prednisolone for castration-resistant prostate cancer: a multi-institutional retrospective study in Japan.

OBJECTIVE: Although some new drugs for castration-resistant prostate cancer are available, docetaxel still plays an important role in castration-resistant prostate cancer treatment. In this study, we evaluated the efficacy and safety of docetaxel and prednisolone in patients with castration-resistant prostate cancer. METHODS: We conducted a retrospective chart review of castration-resistant prostate cancer patients who received docetaxel and prednisolone at 14 hospitals in the Sapporo Medical University Urologic Oncology Consortium from August 2004 to December 2011. RESULTS: A total of 140 patients with castration-resistant prostate cancer received docetaxel and prednisolone (median age, 73.8 years; median prostate specific antigen, 54.7 ng/ml). A median of six cycles (range: 1-43) of docetaxel and prednisolone was administered per patient. Median follow-up was 13.7 months. Median overall survival was 22.0 months. The log-rank test revealed that prostate specific antigen before docetaxel and prednisolone (<50 ng/ml) and the prostate specific antigen reduction rate (≥30%) were associated with overall survival (P < 0.001 and P < 0.001, respectively). Eighty patients (57.1%) achieved a prostate specific antigen reduction rate of over 30%. All except two (97.5%) reached 30% prostate specific antigen reduction within five cycles of docetaxel and prednisolone. There were two (1.4%) treatment-related deaths due to adverse events, which were interstitial lung disease, and febrile neutropenia and bacterial pneumonia. Interstitial lung disease occurred in 14 (10.0%) patients within a median of 2.5 cycles of docetaxel and prednisolone. Grade 5 interstitial lung disease was seen after three cycles of docetaxel and prednisolone. CONCLUSIONS: If a prostate specific antigen reduction rate of over 30% is not obtained within five cycles of docetaxel and prednisolone, other treatment options should be considered. Although most patients safely received docetaxel and prednisolone, we must always keep interstitial lung disease in mind as a possible lethal adverse event.

Serum cystatin C can be used as a marker of renal function even in patients with intestinal urinary diversion.

OBJECTIVE: Recently, serum cystatin C (CysC) has been used as a novel marker of renal function. However, there is a lack of data on CysC levels in patients with intestinal urinary diversion (UD). Here we report CysC levels in such patients. METHODS: We prospectively observed 38 patients who were diagnosed with bladder cancer and subsequently treated with radical cystectomy and UD at our institution in 2012 and 2013. Serum creatinine (sCr) and CysC were obtained optionally at the same time at least 1 month after radical cystectomy and UD. RESULTS: The median CysC and sCr concentrations were 1.12 mg/L (range 0.75-2.47 mg/L) and 0.99 mg/dL (range 0.61-2.22 mg/dL), respectively. The median estimated concentrations of glomerular filtration rate (GFR) based on CysC (eGFRcys) and GFR based on creatinine (eGFRcreat) were 61.08 mL/min/1.73 m2 (range 22.64-99.89 mL/min/1.73 m2) and 58.01 mL/min/1.73 m2 (range 23.48-91.82 mL/min/1.73 m2), respectively. CysC had a significant correlation with sCr (r = 0.8607, p < 0.0001) and eGFRcreat (r = -0.8993, p < 0.0001). eGFRcys also had a significant correlation with eGFRcreat (r = 0.8104, p < 0.0001). CONCLUSION: The correlation between CysC and sCr was strong and the correlation coefficient was equivalent to that in patients without UD. The results suggest that CysC is not affected by UD and can be used as a marker of renal function similarly to sCr in patients with UD.

Isolated pineal region metastasis from lung adenocarcinoma with obstructive hydrocephalus: a case report.

INTRODUCTION: Although the brain is a common site of metastasis from lung cancer, pineal region metastasis from lung adenocarcinoma is rare. Most cases of pineal metastases are asymptomatic, and are diagnosed by autopsy. Therefore, the management of pineal region tumors remains controversial. Here, we present a rare case of lung carcinoma presenting with pineal region metastasis and obstructive hydrocephalus as the first manifestation of the lung adenocarcinoma. CASE PRESENTATION: A 63-year-old Japanese woman was referred to our hospital for treatment of a tumor of the pineal region associated with hydrocephalus. On admission, she was found to have a mass in her right lung on a chest radiograph. During the preoperative investigation, the patient began to show a progressively worsening level of altered consciousness. Therefore, neuroendoscopic surgery was performed as an emergency procedure, which resulted in improvement of the hydrocephalus and diagnosis of adenocarcinoma. A systematic investigation revealed adenocarcinoma of her right lung as the primary lesion. She was treated by a platinum-based chemotherapy regime. Stereotactic radiation to the pineal region was undertaken concurrently. After completion of the chemotherapy, the primary lesion and pineal region metastasis showed good partial response. CONCLUSION: The prognosis of pineal region metastasis is extremely poor, and only three patients with metastatic pineal region metastasis from lung cancer who were treated by chemotherapy have been reported. We performed neuroendoscopic surgery to obtain resolution of the obstructive hydrocephalus and the definite histological diagnosis. This resulted in improvement of the general condition of the patient, and the patient could be treated by chemotherapy and radiotherapy. We strongly believe that neuroendoscopic surgery was a good option in this case. This case report suggests that in the presence of an isolated pineal region tumor, metastasis should be considered a possible diagnosis, and careful examination for systemic malignant disease will be needed.

A case of diffuse alveolar hemorrhage associated with tegafur plus uracil and warfarin therapy.

A 72-year-old man who received warfarin for myocardial infarction (prothrombin time-international normalized ratio [PT-INR] controlled between 2.2 and 2.5) for 2 years. He developed lung cancer, underwent surgery, and received tegafur plus uracil (UFT) after 1 month. After 2 months, he was admitted for hemoptysis and dyspnea. Chest radiography and computed tomography showed bilateral alveolar infiltration (PT-INR, 8.9). Bronchoalveolar lavage fluid (BALF) disclosed hemorrhagic features in sequential samples. And he was diagnosed with diffuse alveolar hemorrhage (DAH). A known interaction exists between fluoropyrimidines and warfarin. So, they were discontinued, and vitamin K was intravenously administered. One day later, the PT-INR returned to 1.14. The symptoms improved and, alveolar infiltration resolved after 2 weeks. Alveolar hemorrhage may be due to an interaction between UFT and warfarin. When fluoropyrimidines and warfarin are prescribed simultaneously, we recommend that PT-INR should be closely monitored.

T cell activation by heat shock protein 70 vaccine requires TLR signaling and scavenger receptor expressed by endothelial cells-1.

Heat shock protein (HSP) 70 isolated from tumor-dendritic cell (DC) fusions (HSP70.PC-F) induces potent antitumor immunity and prevents growth of such tumors. In the present study, we have examined mechanisms underlying such antitumor activity of the HSP70.PC-F vaccine. The degree of antitumor immunity induced by HSP70.PC-F depended on intact TLR signaling in immunized animals, and mice in which the tlr2 and tlr4 genes were both inactivated did not respond to the vaccine. The reduced responses to HSP70.PC-F vaccine in such tlr knockout mice were restored by immunization of animals with HSP70.PC-F-pulsed wild-type DC, indicating a key role for this cell type in HSP70.PC-F-mediated immunity. Our studies also indicate a role for the scavenger receptor expressed by endothelial cells-1 (SREC-1) in antitumor immunity induced by HSP70.PC-F. These two receptor types appeared functionally interdependent, as indicated by the finding that tlr2 and tlr4 knockout decreases HSP70 binding in double-knockout DC and reduces SREC-1 expression. In addition, TLR-dependent, tumor cell killing was suppressed by SREC-1 knockdown in DC, suggesting a significant role for this receptor in HSP70.PC-F-mediated tumor immunity.

[A case of MPO-ANCA positive vasculitis associated with multiple pulmonary nodules following propylthiouracil treatment].

A 34-year-old woman who had been treated with propylthiouracil (PTU) for hyperthyroidism, was admitted because of bloody sputum and pyrexia. The chest CT scan showed some nodules in both lung fields. The serum level of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was high, but proteinase-3 antineutrophil cytoplasmic antibody (PR-3 ANCA) was negative. A limited form of Wegener's granulomatosis without PR-3 ANCA was ruled out, because of the absence of abnormalities in the upper airway and kidney. No lesions other than the multiple pulmonary nodules of the lung were detected. We diagnosed MPO-ANCA associated vasculitis induced by PTU. After the termination of PTU, bloody sputum, pyrexia, and pulmonary nodules improved spontaneously and the serum level of MPO-ANCA returned to normal gradually. The case of MPO-ANCA positive vasculitis associated with multiple pulmonary nodules following propylthiouracil treatment is very rare.

[A case of lung cancer mimicking rupture of a thoracic aortic aneurysm].

A 56-year-old man visited another hospital complaining of hemoptysis. A chest radiograph showed expansion of the left upper mediastinum which seemed to be a mass-like lesion. He was referred to our hospital for further investigations. Before further examination, however, he presented to the emergency room with sudden onset of severe back pain. Rupture of a thoracic aortic aneurysm was suspected because of the clinical symptoms and the findings of emergency enhanced CT scanning. Emergency surgery was performed at the other hospital, and frozen section results indicated that the lesion was a non-small cell lung cancer. The pathology report of the surgical specimens revealed poorly differentiated adenocarcinoma of the lung with infiltration of the aortic wall. Postoperative chemotherapy was added, and the patient is doing well 10 months after operation. Some cases of tumor mimicking aortic aneurysm have been reported. We reported this case of lung cancer mimicking the rupture of a thoracic aortic aneurysm.

[A case of posterior mediastinal mature teratoma].

The chest radiograph of a 57-year-old man, complaining of paroxysmal dyspnea, suggested the probably of a tumor. Chest CT showed a tumor containing calcification, behind the left crus of the diaphragm. Chest MRI suggested lipid components and a cystic lesion within the tumor. Their findings were clinically compatible with posterior mediastinal teratoma. The pathological diagnosis of the surgically resected tumor was mature teratoma with neither malignant components nor thymic tissue. Study of past case reports suggests that posterior mediastinal teratomas should have less malignant characteristics than anterior mediastainal teratomas. Our case is the fifteenth case report in the Japanese literature, and accumulation of more cases is required.

[A case of occult thyroid cancer detected as a solitary nodular lung metastasis].

An 82-year-old woman was admitted to our hospital with cough and back pain. A chest radiograph showed a solitary nodular lesion in the right lower lung field. It was diagnosed by a transbronchial biopsy as lung metastasis of a papillary adenocarcinoma of the thyroid. However, her cervical CT and ultrasonography showed only a cyst in a right lobe of the thyroid, and its biopsy did not show evidence of malignancy. In addition, multiple bone metastasis and pituitary metastasis were revealed. We therefore diagnosed this case as systemic metastasis of papillary adenocarcinoma of the thyroid. She was given best supportive care and she died seven months later. Autopsy revealed two tiny lesions (3mm and 6mm) in the thyroid right lobe to be papillary adenocarcinoma. We report this case because occult thyroid cancer caused systemic metastasis and the chest X-ray showed lung metastasis from the thyroid cancer as a solitary nodular lesion.

Role of scavenger receptors in the binding and internalization of heat shock protein 70.

Extracellular heat shock protein 70 (Hsp70) exerts profound effects both in mediating tumor rejection by Hsp70-based vaccines and in autoimmunity. Further progress in this area, however, awaits the identification of the cell surface receptors for extracellular Hsp70 that mediate its immune functions. We have examined a wide range of candidate Hsp70 receptors and find significant binding through two main families of cell surface proteins, including 1) the scavenger receptor (SR) family and 2) C-type lectins of the NK family. In addition, given that the anticancer effects of Hsp70 vaccines have been shown to involve uptake of Ags by APC exposed to Hsp70-tumor Ag complexes, we have examined the ability of the receptors identified here to internalize Hsp70-peptide complexes. Our findings indicate that three members of the SR family (lectin-like oxidized low density lipoprotein receptor 1; fasciclin, epidermal growth factor-like, laminin-type epidermal growth factor-like, and link domain-containing scavenger receptor-1; and SR expressed by endothelial cells-1) are able to bind Hsp70-peptide complexes and mediate its efficient internalization. Indeed, each of the SR was able to mediate efficient uptake of Hsp70 when transfected into Chinese hamster ovary cells previously null for uptake. Curiously, Hsp70 internalization occurs independently of the intracellular domains of the SR, and Hsp70 uptake could be detected when the entire intracellular domain of lectin-like oxidized low density lipoprotein receptor 1 or SR expressed by endothelial cells-1 was truncated. The existence of a wide repertoire of cell surface Hsp70-binding structures may permit intracellular responses to extracellular Hsp70 that are cell specific and discriminate between Hsp70 family members.

Type F scavenger receptor SREC-I interacts with advillin, a member of the gelsolin/villin family, and induces neurite-like outgrowth.

The scavenger receptor expressed by endothelial cells (SREC) was isolated from a human endothelial cell line and consists of two isoforms named SREC-I and -II. Both isoforms have no significant homology to other types of scavenger receptors. They contain 10 repeats of epidermal growth factor-like cysteine-rich motifs in the extracellular domains and have unusually long C-terminal cytoplasmic domains with Ser/Pro-rich regions. The extracellular domain of SREC-I binds modified low density lipoprotein and mediates a homophilic SREC-I/SREC-I or heterophilic SREC-I/SREC-II trans-interaction. However, the significance of large Ser/Pro-rich cytoplasmic domains of SRECs is not clear. Here, we found that when SREC-I was overexpressed in murine fibroblastic L cells, neurite-like outgrowth was induced, indicating that the receptor can lead to changes in cell morphology. The SREC-I-mediated morphological change required the cytoplasmic domain of the protein, and we identified advillin, a member of the gelsolin/villin family of actin regulatory proteins, as a protein binding to this domain. Reduction of advillin expression in L cells by RNAi led to the absence of the described SREC-I-induced morphological changes, indicating that advillin is a prerequisite for the change. Finally, we demonstrated that SREC-I and advillin were co-expressed and interacted with each other in dorsal root ganglion neurons during embryonic development and that overexpression of both SREC-I and advillin in cultured Neuro-2a cells induced long process formation. These results suggest that the interaction of SREC-I and advillin are involved in the development of dorsal root ganglion neurons by inducing the described morphological changes.

Subacute cor pulmonale due to tumor embolism.

We describe a patient wih subacute cor pulmonale caused by tumor emboli in the lungs. A 64-year-old female suffering from a subacute progressive cough and shortness of breathing died of severe pulmonary hypertension seven days after admission. Neither chest CT scans nor lung perfusion scintigraphy showed any abnormal findings. Microscopic examination after an autopsy revealed diffuse intravascular tumor emboli occluding not only the small pulmonary arteries and arterioles, but also the lymphatic vessels, which were suggested to be metastases of a breast carcinoma resected five years previously. Thus, pulmonary tumor embolism should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with a past history of cancers.

Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins by macrophages stimulated with lipopolysaccharide.

Scavenger receptor expressed by endothelial cells I (SREC-I) is a novel endocytic receptor for acetylated low density lipoprotein (LDL). Here we show that SREC-I is expressed in a wide variety of tissues, including macrophages and aortas. Lipopolysaccharide (LPS) robustly stimulated the expression of SREC-I in macrophages. In an initial attempt to clarify the role of SREC-I in the uptake of modified lipoproteins as well as in the development of atherosclerosis, we generated mice with a targeted disruption of the SREC-I gene by homologous recombination in embryonic stem cells. To exclude the overwhelming effect of the type A scavenger receptor (SR-A) on the uptake of Ac-LDL, we further generated mice lacking both SR-A and SREC-I (SR-A(-/-);SREC-I(-/-)) by cross-breeding and compared the uptake and degradation of Ac-LDL in the isolated macrophages. The contribution of SR-A and SREC-I to the overall degradation of Ac-LDL was 85 and 5%, respectively, in a non-stimulated condition. LPS increased the uptake and degradation of Ac-LDL by 1.8-fold. In this condition, the contribution of SR-A and SREC-I to the overall degradation of Ac-LDL was 90 and 6%, respectively. LPS increased the absolute contribution of SR-A and SREC-I by 1.9- and 2.3-fold, respectively. On the other hand, LPS decreased the absolute contribution of other pathways by 31%. Consistently, LPS did not increase the expression of other members of the scavenger receptor family such as CD36. In conclusion, SREC-I serves as a major endocytic receptor for Ac-LDL in LPS-stimulated macrophages lacking SR-A, suggesting that it has a key role in the development of atherosclerosis in concert with SR-A.

[Lymphangioleiomyomatosis (LAM) causing chylothorax].

A 28-year-old woman was admitted to our hospital complaining of chest pain and dyspnea. Chest radiographs showed left pleural effusion. The effused fluid obtained by thoracocentesis was milky, and so chylothorax was diagnosed. A high-resolution chest CT (HRCT) scan demonstrated diffuse multiple cystic lesions, which were undetectable by conventional CT. An abdominal CT scan showed a retroperitoneal tumor. Since the effusion was resistant to conservative therapy, we performed clipping of the thoracic duct under the diaphragm. Since the effusion disappeared after continuous aspiration, 10 KE of OK-432 was administered into the pleural cavity, and the chylorrhea disappeared. The clinical diagnosis, based on the biopsy of the abdominal tumor, was lymphangioleiomyomatosis. Chylothorax developing from lymphangioleiomyomatosis is rare in Japan. However, we must consider the possibility of lymphangioleiomyomatosis in patients with chylothorax, and always perform chest HRCT.

Primary seminoma in the middle mediastinum.

Primary mediastinal seminoma is a relatively rare tumor usually located in the anterior mediastinum. We report here an extremely rare case of a 66-year-old man with primary seminoma in the middle mediastinum. A physical examination showed lymphadenopathy in the right supraclavicular area. A chest CT confirmed the presence of a tumor occupying the retrotracheal space. A histological examination demonstrated metastatic seminoma from the open biopsy of the lymph node. Abdominal, pelvis, and cerebral CT scan and testicular ultrasound were negative. Thus, primary mediastinal seminoma in the middle mediastinum with supraclavicular lymph node metastasis was diagnosed.