Endometriosis, a common but enigmatic disease with many faces: current concept of pathophysiology, and diagnostic strategy.

Endometriosis is a benign, common, but controversial disease due to its enigmatic etiopathogenesis and biological behavior. Recent studies suggest multiple genetic, and environmental factors may affect its onset and development. Genomic analysis revealed the presence of cancer-associated gene mutations, which may reflect the neoplastic aspect of endometriosis. The management has changed dramatically with the development of fertility-preserving, minimally invasive therapies. Diagnostic strategies based on these recent basic and clinical findings are reviewed. With a focus on the presentation of clinical cases, we discuss the imaging manifestations of endometriomas, deep endometriosis, less common site and rare site endometriosis, various complications, endometriosis-associated tumor-like lesions, and malignant transformation, with pathophysiologic conditions.

MR Imaging Findings of Uterine Adenomatoid Tumors.

PURPOSE: Adenomatoid tumor is a rare benign genital tract neoplasm of mesothelial origin. Uterine adenomatoid tumors occur in the outer myometrium and may mimic leiomyomas. Because hormonal treatment is not applicable to adenomatoid tumors and laparoscopic enucleation is not easy as myomectomy, it is important to differentiate adenomatoid tumors from leiomyomas for the adequate treatment. The purpose of this study is to evaluate the MRI findings of adenomatoid tumor for the differentiation from leiomyoma. METHODS: MRI findings of surgically proven 10 uterine adenomatoid tumors in 9 women were retrospectively evaluated with correlation to histopathological findings. RESULTS: All 10 tumors appeared as solid myometrial masses and showed heterogeneous signal intensity with admixture of partially ill-defined slight high-intensity areas containing abundant tubular tumor cells and well-defined myoma-like low-intensity areas reflecting smooth muscle hypertrophy on T2WI including 4 lesions with peripheral ring-like high intensity. High-intensity areas on T2WI tended to show high intensity on diffusion-weighted imaging (DWI) with relatively high apparent diffusion coefficient (ADC), suggesting T2 shine-through effect due to abundant tubules. Intra-tumoral hemorrhage revealed on MRI was rare. Early intense contrast-enhanced areas on dynamic contrast-enhanced study were observed dominantly within the high-intensity areas but rarely within the low-intensity areas on T2WI. CONCLUSION: The outer myometrial mass with the admixture of well-defined low- and ill-defined high-intensity areas on T2WI may be suggestive of adenomatoid tumor. Peripheral ring-like high intensity on T2WI and DWI may also be suggestive. Dynamic contrast-enhanced MR study may be helpful for the differentiation from leiomyoma.

Dynamic contrast-enhanced MR imaging of uterine endometrial carcinoma with/without squamous differentiation.

PURPOSE: Endometrial carcinoma with strong enhancement on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is suggestive of high-grade type II endometrial carcinoma. However, low-grade type I endometrial carcinoma may also sometimes show strong enhancement. We hypothesized that squamous differentiation would contribute to the strong enhancement at the early phase on DCE-MRI-like uterine cervical squamous cell carcinoma and compared the DCE-MRI findings of endometrial carcinoma with and without squamous differentiation. METHODS: DCE-MRI of endometrial carcinoma including 41 low-grade type I endometrial carcinomas without squamous differentiation (LG), 39 low-grade type I endometrial carcinomas with squamous differentiation (LGSD), and 20 high-grade type II endometrial carcinomas (HG) was retrospectively evaluated. RESULTS: Significant difference in the time-intensity curves was found between LG and HG and LG and LGSD, whereas no significant difference was seen between HG and LGSD. Curve type 3 (initial signal rise which is steeper than that of the myometrium) was more frequent in HG (60%) and LGSD (77%) than in LG (34%). CONCLUSION: It should be recognized as a pitfall that high-grade type II endometrial carcinoma and low-grade type I endometrial carcinoma with squamous differentiation may show similar early strong enhancement on DCE-MRI.

Magnetic resonance imaging characteristics of polypoid endometriosis and review of the literature.

AIM: Polypoid endometriosis is a rare variant of endometriosis and may mimic malignancy. The purpose of this study is to evaluate magnetic resonance (MR) imaging characteristics of polypoid endometriosis for the differential diagnosis with malignancy. METHODS: MR imaging findings of four histologically proven polypoid endometriosis were retrospectively evaluated with the review of the literature. RESULTS: All polypoid endometriosis exhibited high signal intensity on T2-weighted images reflecting abundant dilated endometrial glands. Peritoneal lesions were surrounded by low signal intensity rim represented the "black rim sign" reflecting endometriotic fibrous adhesion. Two cases arising from endometriotic cysts showed transmural extension (peritoneal extension and myometrial infiltration). Endometriotic hemorrhagic foci were demonstrated in four lesions as high signal intensity on T1-weighted images and/or susceptibility-induced signal voids on susceptibility-weighted MR sequence. Diffusion-weighted images showed high signal intensity with relatively high apparent diffusion coefficient (ADC) due to T2 shine-through effect but no diffusion restriction, and dynamic contrast-enhanced (DCE) MR imaging showed gradually increasing contrast-enhancement pattern like benign pathologies. CONCLUSIONS: Polypoid endometriosis may mimic malignancy; however, black rim sign may be a characteristic MR imaging finding for the peritoneal lesions, and no diffusion restriction and gradually increasing contrast-enhancement pattern may reflect its benign nature.

The feasibility of reduced field-of-view diffusion-weighted imaging in evaluating bladder invasion of uterine cervical cancer.

OBJECTIVES: Uterine cervical cancer with bladder mucosal invasion is classified as FIGO stage IVA with poor prognosis. MRI can rule out the bladder invasion and skipping cystoscopy may be possible; however, high false-positive rate may be problematic. The purpose of this study is to evaluate the diagnostic performance of reduced field-of-view (FOV) diffusion-weighted imaging (DWI) in evaluating bladder mucosal invasion of cervical cancer. METHODS: 3T MRI including T2WI and reduced FOV DWI in 15 women with histologically proven cervical cancer (two stage IIIB, six stage IVA, seven stage IVB) were retrospectively evaluated compared with cystoscopic findings. RESULTS: Cystoscopy revealed mucosal invasion in 13 of 15 cases. The border between the tumor and the bladder wall was unclear on T2WI and clear on reduced FOV DWI in all 15 cases. The diagnosis of mucosal invasion on reduced FOV DWI had a sensitivity of 100%, specificity of 50%, accuracy of 93%, PPV of 93%, and NPV of 100%. CONCLUSIONS: Addition of reduced FOV DWI may improve the staging accuracy of MRI for cervical cancer in assessing the bladder mucosal invasion. ADVANCES IN KNOWLEDGE: Reduced FOV DWI may improve the staging accuracy of cervical cancer in assessing bladder mucosal invasion with high NPV and PPV, which may be helpful for avoiding unnecessary cystoscopy.

The Impact of VEGF Inhibition on Clinical Outcomes in Patients With Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy: A Retrospective Cohort Study.

BACKGROUND: In recent years, immune checkpoint inhibitors (ICIs) in combination with chemotherapy have increased survival in patients with advanced non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF), which plays a key role in tumor angiogenesis, is an immunological modulator; therefore, it is expected that anti-VEGF therapy in combination with ICIs enhances the antitumor effect of ICIs. In the present study, we investigated the impact of VEGF inhibition on clinical outcomes of NSCLC patients, including the efficacy of ICI treatment. METHODS: A total of 105 patients with advanced NSCLC who had been treated with ICIs were retrospectively analyzed to examine the relationship between the history of treatment with anti-VEGF agents and the clinical outcomes with ICI monotherapy. RESULTS: Patients who had received anti-VEGF therapy prior to ICIs showed shortened progression-free survival of ICI treatment and a decreased overall response rate to ICI treatment. By contrast, anti-VEGF therapy after ICI treatment was associated with increased survival, especially in patients who had also received anti-VEGF therapy prior to ICI therapy. CONCLUSIONS: These retrospective observations suggest that anti-VEGF therapy prior to ICIs might be a negative predictor of response to ICIs. The sequence of anti-VEGF therapy might play a role in its ability to predict survival in NSCLC patients. Further investigation is warranted to identify the role of VEGF inhibition in altering clinical outcomes after immunotherapy.

Clinical value of N-acetyl mucinous compounds and lipid peaks in differentiating benign and malignant ovarian mucinous tumors by MR spectroscopy.

PURPOSE: To retrospectively evaluate the clinical significance of the peaks of N-acetyl mucinous compounds (NAMC) at 2 ppm and lipid at 1.3 ppm in in-vivo proton magnetic resonance (MR) spectroscopy for distinguishing benign and malignant mucinous tumors in patients with ovarian masses. METHODS: MR spectroscopy was performed in patients with pathologically diagnosed mucinous ovarian tumors at 3 T MRI system. The peaks of NAMC, lipid, and total choline compounds (tCho) were classified into three classes in comparison with the noise level by visual estimation. The NAMC concentration was quantified relative to unsuppressed water by using LCModel analysis. RESULTS: A total of 27 ovarian mucinous tumors in 27 patients were included in this study. The NAMC peak was observed in all 27 mucinous tumors, and the lipid peak was observed in 14 of 27 tumors: 1 of 9 benign tumors (11%), and 13 of 18 malignant tumors (11 borderline malignancies and 7 carcinomas) (72%). The presence of the lipid peak for the diagnosis of malignant mucinous tumor showed generally better diagnostic ability than MR imaging, with a sensitivity of 72%, specificity of 89%, accuracy of 78%, PPV of 93%, and NPV of 62%. The concentration of the NAMC in malignant mucinous tumors tended to be higher than that in benign mucinous tumors, but there was no statistically significant difference. CONCLUSIONS: The bimodal peaks of NAMC and lipid are suggestive of malignant mucinous tumors, and the presence of the lipid peak may be useful in distinguishing benign from malignant ovarian mucinous tumors.

Susceptibility-weighted MR sequence for the evaluation of ovarian masses with torsion.

OBJECTIVE: Adnexal torsion is a rare gynecologic emergency caused by twisting of an adnexal mass. Twisted vascular pedicle is the most specific imaging finding for adnexal torsion, however, identification of twisted vascular pedicle can be challenging. The purpose of this study is to evaluate the feasibility of susceptibility-weighted MR sequence (SWS) for the diagnosis of adnexal torsion. METHODS: MR imaging including SWS (SWAN: susceptibility-weighted angiography) of surgically proven four benign ovarian masses with torsion (one acute and three subacute to chronic torsions) were retrospectively evaluated. Three cystic masses and one solid mass were included in this study. RESULTS: High signal intensity venous thrombus within the twisted vascular pedicle on T1-weighted imaging (T1WI) was detected in three lesions with subacute to chronic torsion (75%) but not in one lesion with acute torsion, whereas susceptibility-induced signal voids within the twisted vascular pedicle on SWAN were detected in all four lesions (100%). CONCLUSION: The demonstration of venous thrombus in the twisted vascular pedicle by SWS may be diagnostic for adnexal torsion. ADVANCES IN KNOWLEDGE: SWS can detect blood products sensitively and can reveal venous thrombus in the twisted vascular pedicle, which may be helpful for the diagnosis of adnexal torsion.

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer.

LESSONS LEARNED: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. BACKGROUND: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. METHODS: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.

Integrative genome analysis identified the KANNO blood group antigen as prion protein.

BACKGROUND: Anti-KANNO, a broadly reactive RBC alloantibody, is found among some Japanese pregnant women, but the genetic basis of the corresponding antigen remains unclear. STUDY DESIGN AND METHODS: We integrated a statistical approach to identify the coding gene for KANNO antigen by conducting a genome-wide association study (GWAS) on four KANNO-negative individuals and 415 healthy Japanese. We also applied whole-exome sequencing to them and performed a replication study to confirm the identified genome variation using independent 14 KANNO-negative individuals. A monoclonal antibody-specific immobilization of erythrocyte antigens (MAIEA) assay was used to locate KANNO antigen on RBC-specific membrane protein. In vivo and in vitro binding assays of anti-KANNO were further applied to the cells expressing a candidate protein. RESULTS: The GWAS revealed a genome-wide significant association of chromosome 20p13 locus (p = 2.76E-08; odds ratio > 1000 [95% confidence interval = 48-23,674]). The identified single-nucleotide polymorphism located in an intronic region of the prion protein (PRNP) gene. Whole-exome sequencing revealed a missense variant in the PRNP gene (rs1800014, E219K), which is in linkage disequilibrium with the single-nucleotide polymorphism identified in the GWAS. All 18 KANNO-negative individuals possessed the homozygous genotype of the missense variant. The MAIEA assay using anti-KANNO and mouse antihuman prion protein showed a clear difference between KANNO-positive and KANNO-negative RBCs. Anti-KANNO showed direct binding to CHO-K1 cells expressing wild-type PRNP but not to those expressing E219K PRNP. CONCLUSION: We first identified the coding gene of the high-frequency antigen KANNO located in PRNP and the missense variation (E219K) that affects the seropositivity of the KANNO antigen, which were confirmed by PRNP overexpressed cells.

Evaluation of Red Degeneration of Uterine Leiomyoma with Susceptibility-weighted MR Imaging.

PURPOSE: Red degeneration of uterine leiomyoma (RDL) is a hemorrhagic infarction caused by peripheral venous thrombosis. The peripheral high-intensity rim on T1-weighted MRI is characteristic for RDL; however, it may not be observed at all the phases of RDL. Susceptibility-weighted MR sequences (SWS) have exquisite sensitivity to blood products, and we hypothesized that the low-intensity rim due to the T2* shortening effects of blood products may be more clearly demonstrated on SWS. The purpose of this study is to evaluate the capability of SWS for the diagnosis of RDL. METHODS: Surgically proven 15 RDL, which showed suggestive MRI findings (high-intensity rim or entirely high signal intensity on T1-weighted imaging) were retrospectively evaluated. MRI was qualitatively evaluated for the presence of high-intensity rim around a mass on fat-saturated T1-weighted images, and low-intensity rim on T2-weighted images and on SWS (susceptibility-weighted imaging [SWI] or T2-star-weighted angiography [SWAN]). RESULTS: The high-intensity rim on T1-weighted images, low-intensity rim on T2-weighted images and on SWS were observed in 47%, 47%, and 100% of RDL, respectively. The other 53% of lesions showed entirely high signal intensity on T1-weighted images. Pathological examination revealed coagulative necrosis in all 15 lesions. CONCLUSION: SWS may be helpful for the diagnosis of RDL by revealing characteristic peripheral low-intensity rim.

Clinical utility of susceptibility-weighted MR sequence for the evaluation of uterine sarcomas.

PURPOSE: High intensity intra-tumoral hemorrhagic necrosis on T1-weighted images is a suggestive finding for uterine sarcomas, however, the reported prevalence varies. The purpose of this study is to evaluate the capability of susceptibility-weighted MR sequences (SWS) for the diagnosis of uterine sarcomas. MATERIALS AND METHODS: MR imaging of surgically proven 10 uterine sarcomas and 24 benign leiomyomas were retrospectively evaluated for the presence of high intensity areas on T1-weighted images and signal voids on SWS (T2 star-weighted angiography: SWAN). RESULTS: High intensity areas on T1-weighted images and signal voids on SWS were observed in 40% and 100% of sarcomas, whereas 0% and 4% of leiomyomas, respectively. The accuracy, sensitivity, and specificity for T1-weighted images were 82%, 40%, and 100%, and for SWS were 97%, 100%, and 96%, respectively. CONCLUSION: The demonstration of intra-tumoral hemorrhage in patients suspected with uterine sarcomas by SWS may provide valuable diagnostic findings.

Neutrophil-to-lymphocyte ratio after four weeks of nivolumab administration as a predictive marker in patients with pretreated non-small-cell lung cancer.

BACKGROUND: Although phase III trials have shown improved overall and progression-free survival (PFS) using nivolumab compared to docetaxel in patients with non-small-cell lung cancer, the progressive disease ratio of nivolumab is higher than docetaxel. Furthermore, nonconventional response patterns of nivolumab make it difficult to determine the time point for nivolumab discontinuation. Therefore, a method to detect non-responders to nivolumab at an early time point is crucial. This retrospective study was conducted to identify immunological and nutritional markers, including neutrophil-to-lymphocyte ratios (NLR), which would predict the efficacy of nivolumab treatment. Because the expression of these markers fluctuates dramatically during treatment, repeat evaluation was performed. METHODS: We retrospectively investigated 30 patients with non-small-cell lung cancer who were treated with nivolumab. The stratified data of each marker obtained during four weeks after nivolumab treatment were evaluated by Cox proportional hazards regression to verify the differences in PFS. RESULTS: One and four patients experienced progressive disease within two and four weeks, respectively. Therefore, 29 and 26 patients were analyzed two and four weeks after nivolumab administration, respectively. The results showed that the NLR after four weeks could predict PFS. The median PFS in 21 patients with NLR < 5 after four weeks of nivolumab administration was 95 days (95% confidence interval [CI] 50-NA), while the mPFS in five patients with NLR ≥ 5 was 10 days (95% CI 6-NA). NLR ≥ 5 showed a hazard ratio of 5.995 (95% CI 1.225-29.35). CONCLUSION: Clarifying NLR four weeks after nivolumab administration may be useful to predict outcomes in nivolumab-treated patients.

Improvement in Patient-Reported Outcomes and Forced Vital Capacity during Nintedanib Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable disease with limited overall survival. Nintedanib is a multikinase inhibitor, and its efficacy on IPF was demonstrated in phase III trials. However, a discrepancy exists between forced vital capacity (FVC) and patient-reported outcomes during nintedanib treatment. Accordingly, we retrospectively analyzed the effects of nintedanib on FVC and patient-reported outcomes among 25 IPF patients. Patient-reported outcomes were evaluated with modified medical research council (mMRC) grade and COPD assessment test (CAT) score. The changes in mMRC grade, CAT score, and FVC data were obtained 6 months before, at the time of, and 6 and 12 months after nintedanib introduction. Significant difference in the mMRC grade was observed only between the baseline and 6 months after treatment (improvement: p = 0.0429). By contrast, there were significant deterioration (p < 0.001) in the CAT scores between 6 months before and the baseline and significant improvement (p < 0.001) between the baseline and 6 months or 12 months after treatment. Overall, 14 patients were judged as efficient with CAT scores after 6-month treatment. Among these 14 patients, only 4 patients (28.6%) were also judged as efficient with mMRC grade. Thus, the CAT score could be more useful in the subjective assessment of IPF. Moreover, FVC was improved 6 months after nintedanib introduction in 12 out of 24 patients with the complete set of the relevant data. These results indicate that nintedanib exhibits favorable effects in IPF from both subjective and objective evaluations.

Successful management of malignant carinal involvement by "side-by-side" method of self-expandable metallic stents followed by chemotherapy.

Bilateral self-expandable metallic stents may be useful in the management of malignant carinal involvement and may improve the performance status of patients. This strategy may allow patients with poor performance status to receive additional chemotherapy.

Evaluating Myometrial Invasion in Endometrial Cancer: Comparison of Reduced Field-of-view Diffusion-weighted Imaging and Dynamic Contrast-enhanced MR Imaging.

PURPOSE: To compare the diagnostic ability of reduced FOV diffusion-weighted (DW) MR imaging with that of 3D dynamic contrast-enhanced (DCE) MR imaging in evaluating the depth of myometrial invasion in patients with endometrial cancer. METHODS: Three tesla MR images including T2-weighted imaging, reduced FOV DW imaging and 3D DCE MR imaging in sagittal and oblique axial (short axis) planes in 25 women with surgically proven endometrial cancer were retrospectively evaluated. The depth of myometrial invasion (stage S: < 50% vs stage D: ≥ 50%) on MR imaging was correlated with surgical pathology results. RESULTS: The 25 endometrial cancers included 16 stage S and 9 stage D tumors. The depth of myometrial invasion could be accurately evaluated in 68% of the cases for T2-weighted imaging, 92% for 3D DCE MR imaging, and 96% for reduced FOV DW imaging. In two patients with coexisting adenomyosis, both T2-weighted imaging and 3D DCE MR imaging failed to reveal the deep myometrial invasion, and reduced FOV DW imaging clearly demonstrated the tumor margin in the cases. Combination of reduced FOV DW imaging reading together with T2-weighted imaging improved the assessment of myometrial invasion with a diagnostic accuracy of up to 100%. CONCLUSIONS: Addition of reduced FOV DW imaging may improve the staging accuracy of MR imaging for endometrial cancer in assessing the depth of myometrial invasion. Especially, reduced FOV DW imaging has an advantage in assessing the depth of myometrial invasion for patients with coexisting adenomyosis. Reduced FOV DW imaging can be an alternative to 3D DCE MR imaging in evaluating myometrial invasion of endometrial cancer without the use of contrast medium.

Successful treatment of limited-stage small-cell lung cancer in the right mainstem bronchus by a combination of chemotherapy and argon plasma coagulation.

The current standard-of-care treatment for patients with limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy for local and systemic control. However, standard-of-care treatment strategies have not been established for those with limited-stage SCLC who have a history of thoracic radiotherapy due to concerns with complications associated with radiation overdose. A 37-year-old male developed an aspergilloma in the postoperative left thoracic space after he was treated with concurrent chemoradiotherapy for mediastinal type lung adenocarcionoma and subsequent left upper lobectomy for heterochronous dual adenocarcinoma. Fiberoptic bronchoscopy was performed to examine the status of the suspected bronchopleural fistula when a polypoid mass was observed in the right mainstem bronchus. A histological examination showed that the mass was SCLC at a clinical stage of cTisN0M0, stageIA, without local invasion. Since thoracic radiotherapy was not an option due to a previous history of thoracic irradiation, a combination treatment of carboplatin and etoposide was administered for 4 cycles and resulted in good partial response. In addition, argon plasma coagulation (APC) was performed as an alternative to curative radiotherapy on day 22 of the 4th cycle. The 5th cycle was administered 7 days after APC at which the anticancer therapy was completed. The patient remains disease-free 60 months after the completion of treatment, which suggests that this combination therapy may resolve very early-stage SCLC.