Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal malignant tumor, for which new treatment options are urgently required. Lipolysis-stimulated lipoprotein receptor (LSR) is widely expressed in EOC, and it is associated with poor prognosis. In this study, we developed an antibody-drug conjugate (ADC) targeting LSR as a new therapeutic approach to EOC. METHODS: We, herein, developed novel anti-LSR monoclonal antibodies (mAbs) and an LSR-ADC by conjugating monomethyl auristatin E as a payload. We subsequently evaluated the in vitro and in vivo (on xenograft models) antitumor effect of the LSR-ADC. RESULTS: An overexpression of LSR was observed not only in the primary EOC tumor but also in its lymph node and omental metastases. The EOC cell lines NOVC7-C and OVCAR3 strongly expressed LSR (as compared to ES2 cells). Both the anti-LSR mAb and the LSR-ADC were able to specifically bind to LSR-positive cells and were rapidly internalized and trafficked to the lysosomes. The LSR-ADC demonstrated a potent antitumor effect against NOVC-7C and OVCAR3, but little activity against ES2 cells. In vitro, the LSR-ADC exhibited a potent antitumor effect against NOVC-7C and OVCAR3. Moreover, in the OVCAR3 xenograft models as well as in the patient-derived xenograft models of LSR-positive EOC, the LSR-ADC significantly inhibited tumor growth. The LSR-ADC also suppressed the omental/bowel metastases in OVCAR3-Luc xenografts and improved the median survival. CONCLUSION: The developed LSR-ADC demonstrated a significant antitumor activity against LSR-positive EOC cell lines and tumors. Our preclinical data support the use of the LSR-ADC as a novel therapy for patients with LSR-positive ovarian cancer.

Thymus variants on imaging of patients with primary Sjögren's syndrome and polymyositis/dermatomyositis: clinical and immunological significance.

We investigated the presence of radiographic thymus variants using a scoring system and examined their association with clinical and immunological features in primary Sjögren's syndrome (pSS) and polymyositis/dermatomyositis (PM/DM) patients. Cases of 72 patients with pSS and 47 with PM/DM were randomly selected from all visitors to our department who received chest CT scanning, excluding those with thymoma or thymic cyst, or age <30 years. We quantitatively interpreted and assessed thymus size and attenuation score in axial CT images. Thymic enlargement was identified in 16 (22.2%) pSS and 14 (29.8%) PM/DM patients. A thymus attenuation score ≥ 2 was seen in 11 (15.3%) pSS and 9 (19.1%) PM/DM patients. Thymic enlargement showed a significant association with the titre of rheumatoid factor in PM/DM patients. Thymic enlargement and score showed a significant association with body weight in pSS patients. Radiographic thymus variants are often observed in pSS and PM/DM patients, particularly in cases of PM/DM, and may suggest the role of an abnormal immune response in their pathogenesis.

Incidence and baseline characteristics of relapse or exacerbation in patients with pulmonary sarcoidosis in Japan.

BACKGROUND: To identify the incidence and baseline characteristics of relapse and exacerbation in patients with pulmonary sarcoidosis over a long-term period. METHODS: We enrolled 103 patients. The incidence and characteristics of relapse or exacerbation were retrospectively recorded and statistically analysed. RESULTS: Of 103 patients, 79% were women. Mean age at diagnosis was 50.1 ± 16.4 y. Mean observation period was 9.8 ± 8.6 y. Overall relapse or exacerbation was 22.3% (n = 23) and mean time from diagnosis (including diagnosis of ocular disease at another facility) to relapse or exacerbation was 8.7 ± 8.3 y. We analysed the data of 69 -patients who were observed for > 5 y and identified relapse or exacerbation within 5 y in 9 patients. -Comparison of characteristics at diagnosis between the relapse/exacerbation group and the improved/stable group showed that the relapse/exacerbation group had a significantly higher frequency of bilateral hilar lymphadenopathy, longer disease duration, ocular involvement, cardiac involvement, and oral glucocorticoid use at diagnosis (P = 0.014, 0.027, 0.019, 0.035, and 0.0043, respectively). The number of risk factors was positively and significantly associated with the cumulative rate of relapse/exacerbation (P = 0.048). CONCLUSION: Our long-term observational cohort study newly identified the incidence and baseline risk factors for relapse or exacerbation in patients with pulmonary sarcoidosis over a long-term period. Scoring the number of factors at baseline may facilitate the prediction of relapse or exacerbation.

The Risk Factors of Exacerbation in Interstitial Pneumonia With Autoimmune Features: A Single-Center Observational Cohort Study.

OBJECTIVES: To investigate the long-term outcomes, including risk factors, for exacerbation between monotherapy and combination therapy in patients with interstitial pneumonia with autoimmune features (IPAF). METHODS: We assessed 672 patients between April 2009 and March 2019 who were evaluated using high-resolution computed tomography (HRCT) of the chest. We applied the IPAF criteria. Fifty-two patients who visited our department for at least 6 months were diagnosed with IPAF. Clinical, laboratory, and imaging data were collected from medical records and statistically analyzed. RESULTS: Among the 52 cases of IPAF, we compared the characteristics at diagnosis between treated (n = 28) and untreated patients (n = 24). The exacerbation rates were 42.9% (n = 12) and 8.3% (n = 2) (P = 0.0051), respectively. Among the treated patients, smoking history, high titer of KL-6, and the duration from diagnosis to the start of treatment were significant risk factors for exacerbation (P = 0.0062, 0.011, and 0.019, respectively). The number of risk factors was significantly and positively associated with exacerbation rate (P = 0.0053). Among the treated patients, glucocorticoid (GC) monotherapy was used in 13 cases, and GC and immunosuppressant (IS) combination therapy was used in 14 patients. There was no significant difference in the treatment methods between patients with and without risk factors (P = 0.47). When comparing the long-term outcomes between the monotherapy and combination therapy groups, the 3-year non-exacerbation rates were 72.9 and 45.9% (P = 0.020), respectively. CONCLUSIONS: IPAF patients with risk factors had a high exacerbation rate, regardless of the type of treatment. New interventions aimed at preventing exacerbations in these patients are required.

Steroid-Sparing Effect of Tocilizumab and Methotrexate in Patients with Polymyalgia Rheumatica: A Retrospective Cohort Study.

Polymyalgia rheumatica (PMR) is an inflammatory disorder characterized by pain and stiffness in the shoulders, hips, and proximal limbs; it usually affects elderly patients. The effectiveness of methotrexate and tocilizumab in PMR treatment has not been extensively studied. Thus, we aimed to assess the steroid-sparing effect of tocilizumab and methotrexate in PMR in clinical practice. Consecutive patients with PMR in our hospitals, who were included in our retrospective cohort, were reviewed between 2005 and 2015 and divided into the following groups according to their treatments: prednisolone or none (prednisolone group), methotrexate ± prednisolone (methotrexate group), or tocilizumab ± prednisolone (tocilizumab group). The prednisolone dose at the last follow-up was compared. A total of 227 patients with an average age of 74 years were enrolled. No difference in baseline characteristics was found among the three groups. The prednisolone dose at the last follow-up was lower (0 vs. 3.0 vs. 3.5 mg/day, p < 0.001) and the prednisolone discontinuation rate was higher (80.0% vs. 28.3% vs. 18.8%, p < 0.0001) in the tocilizumab group than in the prednisolone and methotrexate groups. This study suggested that tocilizumab has a steroid-sparing effect in PMR. Tocilizumab can be an option in the management of PMR. Future studies are warranted to confirm our findings.

Thymus variants on imaging in patients with rheumatoid arthritis-clinical and immunological significance.

OBJECTIVES: We sought to clarify the presence of radiographic thymus variants using a scoring system, and their association with clinical and immunological features in RA patients. METHODS: A total of 387 RA patients were randomly selected from all patients visiting our department who underwent chest CT scanning, with exclusion of patients with thymoma or thymic cyst, or age < 30 years. Thymus size and attenuation score in axial CT images were quantitatively interpreted and assessed. Associations between immunophenotype data and clinical and serological features were analysed in a subset of patients. RESULTS: Thymic enlargement was found in 76 (19.6%) patients, and a thymus attenuation score ≥ 2 was found in 50 (12.9%) patients. The score was significantly associated with antibodies to ACPA positivity. Thymic enlargement was significantly associated with the proportions of CD4+ effector memory T cells. CONCLUSION: Radiographic thymus variants were frequently observed in RA patients and may reflect an abnormal immune response involved in the pathogenesis of RA.

A case of bone marrow involvement in sarcoidosis with crescentic glomerular lesions.

Renal and bone marrow involvements in sarcoidosis are rare. We experienced the case of a 67-year-old man with systemic sarcoidosis, with bone marrow involvement, hepatic involvement and a unique constellation of renal lesion with cellular crescent formation. Immunosuppressive therapy was helpful for maintaining the stability of his pancytopenia, hepatic function and renal function. To the best of our knowledge, the association between sarcoidosis, bone marrow involvement and crescentic glomerulonephritis has been reported in only few cases in literature.

Detection of cerebral microvascular lesions using 7 T MRI in patients with neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is speculated to be caused by disturbed microcirculation of the central nervous system. However, characteristic imaging findings of NPSLE have not been established. Hence, we investigated whether high-resolution images obtained using ultrahigh field MRI at 7 T can detect microcerebrovascular lesions in patients with NPSLE that have never been detected by conventional MRI. We prospectively examined 20 patients with SLE, including five with NPSLE, using a 7 T MRI scanner. High-resolution two-dimensional T2-weighted images and high-resolution three-dimensional T1-weighted images (T1WIs) before and after the administration of contrast agents were obtained. On the high-resolution T1WIs obtained at 7 T, minute punctate/linear hyperintense lesions in subcortical and/or cortical areas were found in four (80%) NPSLE patients and one (7%) non-NPSLE patient. Further, the minute punctate enhanced lesions in these areas were found on contrast-enhanced T1WIs in only three (60%) NPSLE patients. These findings suggesting microvascular thrombi or inflammation were significantly more frequent in NPSLE than in non-NPSLE patients (P=0.001). In contrast, other imaging findings, laboratory findings, and clinical characteristics were not different between the two groups. High-resolution T1WIs obtained at 7 T can detect minute lesions, indicating intracerebral microvascular lesions in patients with NPSLE.

Scedosporium aurantiacum brain abscess after near-drowning in a survivor of a tsunami in Japan.

Many victims of the tsunami that occurred following the Great East Japan Earthquake on March 11, 2011 developed systemic disorders owing to aspiration pneumonia. Herein, we report a case of tsunami lung wherein Scedosporium aurantiacum was detected in the respiratory tract. A magnetic resonance image of the patient's head confirmed multiple brain abscesses and lateral right ventricle enlargement. In this case report, we describe a potential refractory multidrug-resistant infection following a tsunami disaster.

Multiple Scedosporium apiospermum abscesses in a woman survivor of a tsunami in northeastern Japan: a case report.

INTRODUCTION: Scedosporium apiospermum is increasingly recognized as a cause of localized and disseminated mycotic infections in near-drowning victims. CASE PRESENTATION: We report the case of a 59-year-old Japanese woman who was a survivor of a tsunami in northeastern Japan and who had lung and brain abscesses caused by S. apiospermum. Initially, an aspergillus infection was suspected, so she was treated with micafungin. However, computed tomography scans of her chest revealed lung abscesses, and magnetic resonance images demonstrated multiple abscesses in her brain. S. apiospermum was cultured from her bronchoalveolar lavage fluid, and antimycotic therapy with voriconazole was initiated. Since she developed an increase in the frequency of premature ventricular contractions, an adverse drug reaction to the voriconazole was suspected. She was started on a treatment of a combination of low-dose voriconazole and liposomal amphotericin B. After combination therapy, further computed tomography scans of the chest and magnetic resonance images of her brain showed a demarcation of abscesses. CONCLUSIONS: Voriconazole appeared to have a successful record in treating scedosporiosis after a near drowning but, owing to several adverse effects, may possibly not be recommended. Thus, a combination treatment of low-dose voriconazole and liposomal amphotericin B may be a safe and effective treatment for an S. apiospermum infection. Even though a diagnosis of scedosporiosis may be difficult, a fast and correct etiological diagnosis could improve the patient's chance of recovery in any case.