Rare Hereditary Gynecological Cancer Syndromes.

Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.

Successful pregnancy and term delivery after treatment of unicornuate uterus with non-communicating rudimentary horn pregnancy with local methotrexate injection followed by laparoscopic resection: a case report and literature review.

BACKGROUND: Pregnancy in a rudimentary horn is an extremely rare type of ectopic pregnancy. A rudimentary uterine horn pregnancy is associated with a risk of spontaneous rupture and bleeding during surgery due to the increased uterine blood flow. Recent advances in imaging modalities have enabled laparoscopic surgery to be performed in cases without rupture in the early stages of pregnancy. However, there are few reports of successful pregnancies and deliveries after treatment of rudimentary horn pregnancies. We report the successful management of a case of non-communicating rudimentary horn pregnancy by local injection of methotrexate followed by complete laparoscopic excision along with a review of the literature. CASE PRESENTATION: The patient was a 29-year-old Japanese woman, gravida 2, nullipara. She was diagnosed with a left unicornuate uterus with a right non-communicating rudimentary horn on hysterosalpingography and magnetic resonance imaging. A gestational sac with a heartbeat was observed in the right rudimentary uterine horn at 6 weeks of gestation. A diagnosis of ectopic pregnancy in a non-communicating rudimentary horn was made. Color Doppler detected multiple blood flow signals around the gestational sac, which were clearly increased compared to the left unicornuate uterus. Her serum human chorionic gonadotropin level was 104,619 mIU/ml. A 100 mg methotrexate injection into the gestational sac was administered, and laparoscopic surgery was performed on day 48 after the methotrexate treatment. The right rudimentary horn and fallopian tube were successfully excised with minimal bleeding. A spontaneous normal pregnancy was established 6 months after the surgery. The pregnancy was uneventful, and a baby girl was born by elective cesarean section at 38w0d. CONCLUSION: Combined local methotrexate injection and laparoscopic surgery are safe treatment options for patients with a unicornuate uterus with a non-communicating rudimentary horn pregnancy.

Identification of miR-305, a microRNA that promotes aging, and its target mRNAs in Drosophila.

MicroRNAs (miRNAs) are involved in the regulation of important biological processes. Here, we describe a novel Drosophila miRNAs involved in aging. We selected eight Drosophila miRNAs, displaying high homology with seed sequences of aging-related miRNAs characterized in other species, and investigated whether the over-expression of these miRNAs affected aging in Drosophila adult flies. The lifespan of adults over-expressing miR-305, a miRNA showing high homology with miR-239 in C. elegans, was significantly shorter. Conversely, a reduction in miR-305 expression led to a longer lifespan than that in control flies. miR-305 over-expression accelerated the impairment of locomotor activity and promoted the age-dependent accumulation of poly-ubiquitinated protein aggregates in the muscle, as flies aged. Thus, we show that the ectopic expression of miR-305 has a deleterious effect on aging in Drosophila. To identify the targets of miR-305, we performed RNA-Seq. We discovered several mRNAs encoding antimicrobial peptides and insulin-like peptides, whose expression changed in adults upon miR-305 over-expression. We further confirmed, by qRT-PCR, that miR-305 over-expression significantly decreases the mRNA levels of four antimicrobial peptides. As these mRNAs contain multiple sequences matching the seed sequence of miR-305, we speculate that a reduction in target mRNA levels, caused by ectopic miRNA expression, promotes aging.

Specific increase in serum core-fucosylated haptoglobin in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all malignancies, and its diagnosis in early stages is the most important prognostic factor. Chronic pancreatitis (CP), a common background of PDAC occurrence, is morphologically defined as progressive pancreatic fibrosis and inflammation accompanied by pancreatic exocrine cell atrophy. We recently found that inflammation and fibrosis are independent characteristic histological changes in noncancerous lesions in PDAC patients despite the absence of a past history of clinical CP. Subclinical CP is an important background for PDAC occurrence. Therefore, there is an urgent need to develop a noninvasive and reliable biomarker for CP diagnosis. METHODS: Fifty-nine healthy volunteers (HV), 159 patients with CP, and 83 patients with PDAC were enrolled in this study. We measured serum total fucosylated haptoglobin (Fuc-Hpt) and core-Fuc-Hpt levels using lectin-antibody enzyme-linked immunosorbent assay kits that we developed. In these kits, total Fuc-Hpt and core-Fuc-Hpt were measured using Aleuria aurantia lectin and Pholiota squarrosa lectin, respectively. RESULTS: Serum Fuc-Hpt levels were significantly increased in CP patients compared to HV (P < 0.0001) and were further increased in PDAC patients (P < 0.0001). Interestingly, serum core-Fuc-Hpt levels were significantly higher in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Multivariate analyses demonstrated that total serum core-Fuc-Hpt was an independent determinant for CP diagnosis, but Fuc-Hpt was not. CONCLUSIONS: A dramatic change in oligosaccharides was observed in serum haptoglobin between CP and PDAC. Serum core-Fuc-Hpt may be a novel and useful biomarker for CP diagnosis.

Predictors of silent brain infarction on magnetic resonance imaging in patients with nonvalvular atrial fibrillation: A transesophageal echocardiographic study.

BACKGROUND: Silent brain infarction (SBI) is often found in patients with atrial fibrillation (AF) and may be related to cognitive decline. We investigated the predictors of SBI on brain magnetic resonance imaging (MRI) using transesophageal echocardiography (TEE) in patients with nonvalvular AF. METHODS: The study population consisted of 103 neurologically asymptomatic patients with nonvalvular AF who underwent TEE before transcatheter AF ablation (76 men; mean age 63 ± 10 years). Left atrial (LA) abnormalities such as LA thrombus, spontaneous echo contrast, or abnormal LA appendage emptying velocity (<20 cm/s) and complex plaques in the aortic arch defined as large plaques ≥4 mm thickness, ulcerated plaques, or mobile plaques were evaluated by TEE. All patients were screened for SBI by brain MRI. RESULTS: Of 103 patients, 31 (30%) showed SBI on brain MRI. Most lesions were multiple (61%) and small (<15 mm) in diameter (84%). Patients with SBI had a higher prevalence of LA abnormalities (45% vs 14%; P < .001) and complex arch plaques (45% vs 7%; P < .001) compared with those without SBI. In a multivariate logistic regression analysis including age and CHADS2 score ≥2, LA abnormalities (odds ratio 4.13; 95% CI 1.34-12.72; P = .014) and complex arch plaques (odds ratio 4.82; 95% CI 1.23-18.92; P = .024) were independent predictors of SBI. CONCLUSIONS: Left atrial abnormalities and complex arch plaques detected by TEE were closely associated with the presence of SBI on brain MRI, suggesting that microembolization of small thrombi derived from the fibrillating LA or advanced aortic atherosclerotic lesions may be important causes of SBI in patients with nonvalvular AF.

[Vascular Calcification - Pathological Mechanism and Clinical Application - . The significance of arterial calcification in unstable plaques].

Plaque rupture or erosion with subsequent thrombus formation is the principal mechanism underlying the sudden onset of acute coronary syndromes. Plaque inflammation and increased oxidative stress play important roles in the pathogenesis of plaque destabilization. Macrophages, T lymphocytes, and neutrophils are the dominant types of inflammatory cells at human coronary unstable plaques, such as ruptured plaques or eroded plaques. Calcification is a common finding in human atherosclerotic lesions, and arterial calcification is generally classified into calcification within an atherosclerotic plaque, and Mönckeberg's medial calcific sclerosis characterized by calcific deposits within the media of small and medium-sized muscular arteries. It has been reported that a spotty pattern of calcification is associated with coronary unstable ruptured plaques in patients with acute myocardial infarction. Patients undergoing hemodialysis (HD) have a high prevalence of arterial calcification and cardiovascular events. We recently demonstrated that plasma oxidized low density lipoprotein (LDL) levels significantly increased after a single HD session. This HD session-related increase in plasma oxidized LDL levels could contribute to the progression and acceleration of atherosclerosis and arterial calcification, leading to the development of cardiovascular events in HD patients.

Diaphragmatic clear cell carcinoma with Lynch syndrome after surgery for atypical endometrial hyperplasia and ovarian endometriosis: A case report.

Clear cell carcinoma (CCC) of the diaphragm is rare, with an origin that is reported to be associated with malignant transformation of extraperitoneal endometriosis. Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. Women with LS have a significantly increased lifetime risk of endometrial and ovarian cancer. CCC is a common histology of endometriosis- and LS-associated malignancy. The present study describes the case of a 51-year-old woman with an intra-abdominal mass found during a routine physical examination. The patient had undergone total hysterectomy and bilateral adnexectomy for atypical endometrial hyperplasia (AEH) and ovarian endometriosis, respectively, 3 years previously. Enhanced computed tomography showed a mass on the surface of the liver. Laparoscopic examination of the abdominal cavity revealed a tumor on the underside of the right diaphragm, which was then surgically excised. Pathological examination of the excised tumor, along with immunohistochemistry, led to a diagnosis of CCC. Since LS was suspected due to the genetic family history of the patient, microsatellite instability analysis was performed on the diaphragmatic tumor, and the results were positive. Immunohistochemistry was performed for MMR proteins in AEH and CCC cells, both of which revealed loss of MSH2 and MSH6 expression. Following detailed genetic counseling, genetic testing of MMR genes was performed, revealing a germline pathogenic variant in MSH2 (c.1000C>T, p.Gln344*), thus confirming the diagnosis of LS. To the best of our knowledge, this is the first case report of concurrent diaphragmatic CCC and LS. Patients with LS and endometriosis are at risk of developing ovarian cancer or intra-abdominal malignant tumors. In addition, immunohistochemistry screening for MMR proteins should be considered in patients with AEH and a family history of LS-related cancer, to enable early clinical intervention in cases of endometrial cancer.

Enhanced expression of neopterin in valve tissue of bicuspid aortic stenosis.

Background: Aortic valve stenosis (AS) occurs in bicuspid aortic valve (BAV) patients at a relatively young age compared to tricuspid aortic valve (TAV) patients. However, the underlying cause of this phenomenon remains unknown. Neopterin, which is a by-product of the guanosine triphosphate (GTP) pathway, enhances the oxidative potential of reactive oxygen species. To clarify the role of neopterin in the aortic valve, we immunohistochemically studied the presence of neopterin in aortic valve specimens from patients with AS harboring either TAV or BAV. Methods: Frozen aortic valve samples were surgically obtained from 68 patients with severe AS with TAV (n=34) and BAV (n=34). Normal aortic valves were obtained from cadavers who died of non-cardiovascular causes as controls (n=9). Samples were immunohistochemically stained with antibodies against smooth muscle cells, macrophages, T lymphocytes, neopterin, and 4-hydroxy-2-nonenal (4-HNE). Results: Quantitative analysis showed that the percentage of macrophages, 4-HNE- and neopterin-positive macrophage score, and the number of T lymphocytes were significantly higher in BAV patients than in TAV patients (macrophages, P=0.013; T lymphocytes, P=0.011; neopterin, P<0.001; 4-HNE, P=0.008). Double immunostaining for neopterin and macrophages demonstrated that most neopterin-positive cells were macrophages in BAV patients. Conclusions: Neopterin accumulation in macrophages may increase oxidative stress and contribute to the early onset of AS in BAV.

Myeloperoxidase and progression of aortic valve stenosis in patients undergoing hemodialysis.

BACKGROUND AND AIM OF THE STUDY: Currently, there is an increased incidence of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD), though the exact mechanisms are not fully understood. Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of reactive oxygen species and is an index of oxidative stress. The study aim was to examine, immunohistochemically, the expression of MPO, using surgically resected aortic valve specimens from AS patients undergoing HD. METHODS: The study population consisted of 15 HD patients and 19 non-HD patients with severe AS undergoing aortic valve replacement. Frozen aortic valve samples obtained surgically from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, neutrophils, macrophages, T lymphocytes, CD31, MPO and 4-hydroxy-2-nonenal (4-HNE). RESULTS: Quantitative analyses showed that the macrophage-positive area, and numbers of T lymphocytes, neutrophils, CD31-positive microvessels and MPO-positive cells in HD patients were significantly higher than in non-HD patients (macrophages, p < 0.0001; T lymphocytes, p < 0.0001; neutrophils, p < 0.0001; CD31, p < 0.0001; MPO, p < 0.0001). Moreover, the number of MPO-positive cells was positively correlated with CD31-positive microvessels and the 4-HNE-positive macrophage score (CD31, R = 0.73, p < 0.0001; 4-HNE, R = 0.49; p < 0.005). CONCLUSION: These findings suggest that MPO is highly expressed in the aortic valves of AS patients undergoing HD. Furthermore, MPO is positively associated with neovascularization and oxidative stress, which contribute to a rapid progression of AS in HD patients.

Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion.

AIMS: Recent studies have demonstrated that erythrocytes are a potential component in atheromatous lesions and thrombus formation in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to determine the associations of red blood cell (RBC) component of coronary thrombi with oxidative stress and myocardial reperfusion. METHODS AND RESULTS: Aspirated thrombi from 178 STEMI patients within 12 h of symptom onset were investigated immunohistochemically using antibodies against platelets, RBCs, fibrin, macrophages, and neutrophils [myeloperoxidase (MPO)]. The thrombi were divided into tertiles according to the percentage of glycophorin-A-positive area: low (glycophorin-A-positive area <33%; n = 60), intermediate (<54 to 33%; n = 59), and high group (≥54%; n = 59). We also measured plasma MPO levels on admission. In the thrombi, the number of MPO-positive cells in the high-RBC group was significantly greater than that in the low-RBC group (high, 927 ± 385; intermediate, 765 ± 406; low, 279 ± 220 cells/mm(2); P< 0.0001). Plasma MPO levels were significantly higher in the high-RBC group than that in the low-RBC group [low 43.1 (25.0-71.6); intermediate 71.0 (32.9-111.2); high 74.3 (31.1-126.4)ng/mL; P< 0.005]. Distal embolization occurred more frequently in the high-RBC group (P= 0.0009). Moreover, the signs of impaired myocardial reperfusion, as indicated by incomplete ST-segment resolution (STR) and lower myocardial blush grades (MBG), and progression of left ventricular remodelling at 6 months were frequently observed in the high-RBC group (high vs. low: STR, P= 0.056; MBG, P< 0.01; remodelling, P< 0.01). CONCLUSION: The present study demonstrated that erythrocyte-rich thrombi contain more inflammatory cells and reflect high thrombus burden, leading to impaired myocardial reperfusion in STEMI patients.

Relationship between oxidative stress and aortic valve stenosis in humans: an immunohistochemical study.

BACKGROUND: Oxidative stress contributes to plaque formation and the destabilization of coronary atherosclerotic lesions. It has been reported that disease processes and clinical risk factors of aortic valve stenosis (AS) are similar to those of atherosclerosis. In this study, we immunohistochemically examined the expression of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress-related molecule, by using surgically resected aortic valve specimens from AS patients. METHODS: The study was conducted using aortic valve specimens, surgically obtained from 24 patients with severe AS undergoing aortic valve replacement. We immunohistochemically investigated frozen aortic valve samples with antibodies against smooth muscle cells, macrophages, CD31 and 4-HNE. RESULTS: Morphometric analysis showed that the percentage of the macrophage-positive area and the number of CD31-positive microvessels were significantly higher in AS patients than those in reference cases (macrophages, p < 0.005 and CD31, p < 0.0001). Furthermore, the 4-HNE-positive macrophage score was also significantly higher in AS patients than in reference cases (p < 0.005). CONCLUSIONS: 4-HNE was expressed in the stenotic aortic valves in patients with severe AS, suggesting a close relationship between oxidative stress and the progression of calcific AS.

5'­isomiR is the most abundant sequence of miR­1246, a candidate biomarker of lung cancer, in serum.

MicroRNA (miRNA/miR) 5'­isoforms (5'­isomiRs) differ from canonical sequences registered in the microRNA database in the length of their 5' ends. The 'seed sequence' of miRNAs that bind to target mRNAs is 2­8 nucleotides from the 5' end; thus, shifts at the 5' end can cause a 'seed shift'. Accumulating data from miRNA deep sequencing have revealed that, in a substantial number of miRNAs, sequences corresponding to specific isomiRs, not the canonical form, are the most abundant. Studies have so far focused on circulating miRNAs as either markers or intercellular communication factors. miR­1246 is abundant in the serum and is a candidate diagnostic and prognostic marker for esophageal squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma, colorectal adenocarcinoma and non­small cell lung cancer (NSCLC). The present study analyzed the 5'­end of serum miR­1246 by fragment analysis and found that a 5'­isomiR, which is two bases shorter than the canonical sequence, was the most abundant sequence in patients with NSCLC as well as healthy donors. To quantify the 5'­isomiR, 5'­isomiR­specific primers based on primers for allele specific­PCR were used, primarily because commercially available methods for miRNA Reverse transcription­quantitative PCR cannot discriminate among sequences, especially those located at the 5' end of miRNA. The total miR­1246 levels were significantly increased in patients with NSCLC; by contrast, the level of the canonical sequence was significantly decreased. Significant positive correlations were observed between the total miR­1246 levels and the 5'­isomiR levels, but not that of the canonical sequence. These results imply that the increase in levels of serum miR­1246 in patients with NSCLC depends on increase of the 5'­isomiR.

A rare case of recurrent ovarian cancer with TPM3-NTRK1 gene rearrangement: A case report.

NTRK gene fusion is rare in gynecological cancer. Entrectinib is a novel targeted drug, which is a potent inhibitor of TRK A, B and C. The present case report described a case of recurrent ovarian cancer with TPM3-NTRK1 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. A 56-year-old woman was diagnosed as having stage IV ovarian cancer with positive pleural fluid cytology. Neoadjuvant chemotherapy and interval debulking surgery, followed by chemotherapy, were performed. A total of 10 months after completion of chemotherapy, the disease recurred and the patient was treated with multimodal therapy for recurrence. DNA-based NGS detected TPM3-NTRK1 rearrangement and entrectinib therapy was initiated; however, the disease progressed despite 6 weeks of entrectinib administration, and 1 month after discontinuation of entrectinib, the patient died. After their death, immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression levels of TRK; however, immunohistochemistry was negative for TRK. In conclusion, the present case report described a rare case of recurrent ovarian cancer with TPM3-NTRK1 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for TRK. These findings indicated that immunohistochemistry may be required for confirmation of TRK protein expression prior to entrectinib administration.

Successful management of pelvic recurrence of MSI-High endometrial cancer by total pelvic exenteration followed by administration of pembrolizumab:A case report.

Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.

Extrapulmonary lymphangioleiomyomatosis in pelvic and paraaortic lymph nodes associated with uterine cancer: a report of 3 cases.

We report 3 cases of extrapulmonary lymphangioleiomyomatosis incidentally found in pelvic and paraaortic lymph nodes in association with uterine cancers. Three women, 47-year-old, 59-year-old, and 71-year-old, respectively, had uterine cancers and underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymph node excision. None of the 3 patients had tuberous sclerosis complex or lymphangioleiomyomatosis in other organs. None had any history of extrinsic hormonal administration. The postoperative pathologic diagnoses were uterine cervical squamous cell carcinoma for the first patient and endometrioid adenocarcinomas for the second and the third patients. Besides these malignant lesions, all 3 patients showed spindle cell proliferation, 2 to 5 mm in size, in 1 to 8 foci of the pelvic and paraaortic lymph nodes. The spindle cells having small polygonal nuclei and inconspicuous nucleoli with palely eosinophilic cytoplasm, reminiscent of immature smooth muscle cells, proliferated in nested and whorling patterns. Neither cellular atypia nor mitotic figures were observed. Immunohistochemically, these spindle cells were positive for α-Smooth Muscle Actin, Desmin, HMB45, Microphthalmia Transcription Factor, Estrogen receptor, and Progesterone receptor. And the network of the vascular-like channels surrounded by these spindle cells was positive for D2-40. From the pathologic and immunohistochemical findings, the spindle cell proliferation in the lymph nodes is best interpreted as lymphangioleiomyomatosis.

Enhanced expression of the S100A8/A9 complex in acute myocardial infarction patients.

BACKGROUND: S100A8/A9 complex (S100A8/A9) is expressed in activated human neutrophils and macrophages. Enhanced expression of S100A8/A9 in atherosclerotic plaque of patients with unstable angina pectoris (UAP) has been demonstrated, but its profile in acute myocardial infarction (AMI) has not been clarified. METHODS AND RESULTS: Serum S100A8/A9 levels were serially measured in patients with AMI (n=55) and UAP (n=16) during the acute period. The expression of S100A8/A9 was examined immunohistochemically in the infarcted myocardium of 7 autopsied patients with AMI. Serum S100A8/A9 levels on the 1st day were 1,118+/-115 (SE) ng/ml in AMI patients as compared with 787+/-147 ng/ml in UAP patients. On days 3-5, serum S100A8/A9 levels in AMI patients reached a peak value and were significantly higher than the values in UAP patients (1,690+/-144 ng/ml vs 844+/-100 ng/ml; P<0.0001). In AMI patients, peak S100A8/A9 levels positively correlated with peak white blood cell and neutrophil counts, and peak creatine kinase-MB and peak C-reactive protein levels. Double immunostaining revealed that S100A8/A9 was specifically expressed in neutrophils and macrophages infiltrating the infarcted myocardium. CONCLUSIONS: S100A8/A9 is implicated in the pathophysiology of AMI and may be an additional biomarker of the local inflammatory response following AMI.

Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes.

AIMS: Effective clearance of extracellular haemoglobin (Hb) is thought to limit systemic oxidative heme toxicity, which is presumed to contribute to the pathogenesis of plaque instability. We immunohistochemically examined the relationship between intraplaque haemorrhage, 4-HNE (4-hydroxy-2-nonenal), an index of lipid peroxidation, and the Hb scavenger receptor (CD163), using coronary atherectomy specimens from 74 patients with stable angina pectoris (SAP, n = 39) or unstable angina pectoris (UAP, n = 35). METHODS AND RESULTS: Atherectomy samples were stained with antibodies against glycophorin A (a protein specific to erythrocyte membranes), CD31, 4-HNE, and CD163. Quantitative analysis demonstrated that glycophorin A-positive areas, 4-HNE-positive macrophage score, and CD163-positive macrophage score in UAP patients were significantly higher (glycophorin A, P < 0.0001; 4-HNE-positive macrophage score, P < 0.0001; CD163-positive macrophage score, P < 0.0005) than in SAP patients. The percentage of the glycophorin A-positive area showed a significant positive correlation with the number of CD31-positive microvessels and the 4-HNE-positive macrophage score (microvessels, R = 0.59, P < 0.0001; 4-HNE, R = 0.59, P < 0.0001). Moreover, the CD163-positive macrophage score was positively correlated with glycophorin A-positive area and the 4-HNE-positive macrophage score (glycophorin A, R = 0.58, P < 0.0001; 4-HNE, R = 0.53, P < 0.0001). CONCLUSION: These findings suggest a positive association among intraplaque haemorrhage, enhanced expression of Hb scavenger receptor, and lipid peroxidation in human unstable plaques.

[Clinical relevance of coronary artery calcification, as a risk factor for plaque rupture: viewpoint from pathology].

Atherosclerotic calcification is usually associated with long - standing atherosclerosis. There is accumulating evidence that both apoptosis and osteogenic differentiation of vascular smooth muscle cells contribute to arterial calcification. Our long experience of cardiovascular pathology over many years revealed that ruptured plaques were closely associated with areas of small calcium deposits. To further clarify the association between patterns of coronary arterial calcification and morphology of atherosclerotic plaques, we studied preinterventional intravascular ultrasound (IVUS) images at the site of culprit lesions in patients with acute myocardial infarction (AMI), unstable angina pectoris, or stable angina pectoris. Our study demonstrated that small calcium deposits within an arc of < 90° significantly more frequent in the culprit lesion segments of AMI patients. Thus, our study revealed that the spotty calcification pattern of the coronary culprit segment is associated with unstable plaques in AMI patients.

Successful Management of Platinum-resistant Ovarian Cancer by Weekly Nedaplatin Followed by Olaparib: Three Case Reports.

BACKGROUND: Treatment for platinum-resistant ovarian cancer is difficult and challenging because available chemotherapeutic agents only offer short survival improvements. The efficacy of re-treatment with platinum-based agents including nedaplatin for platinum-resistant patients has not been fully investigated. CASE REPORT: We describe herein three cases of heavily treated platinum-resistant ovarian cancer that were successfully treated with weekly nedaplatin followed by olaparib. After becoming platinum-resistant, the cases were treated with non-platinum chemotherapies. Following these regimens, weekly nedaplatin was introduced, followed by olaparib. At the time of writing, survival since the start of weekly nedaplatin was 30 months for case 1, 20 months for case 2, and 17 months for case 3, with all patients showing no evidence of disease. CONCLUSION: Weekly nedaplatin followed by olaparib might represent a good treatment option for platinum-resistant ovarian cancer and is a solid candidate for further evaluation.

Successful management of preoperatively diagnosed torsion of a subserosal uterine fibroid by pneumoperitoneum laparoscopic single-port surgery.

OBJECTIVE: Preoperative diagnosis and successful management of acute torsion of a subserosal fibroid by using appropriate imaging modalities and single-port laparoscopic surgery. CASE REPORT: A 44-year-old nulliparous woman presented with lower abdominal pain. Computed tomography and magnetic resonance imaging with contrast enhancement revealed a tumor in the pouch of Douglas with a low contrast at the center and thin-rim enhancement. Torsion of a uterine subserosal fibroid was diagnosed preoperatively. Laparoscopic single-port surgery by pneumoperitoneum was performed. Torsion of the pedicle attached to the uterine wall was excised by bipolar coagulation and cut with scissors. The extirpated fibroid was extracted from the umbilical wound. The pneumoperitoneum single-port laparoscopic surgery was completed as a gynecologic emergency operation. CONCLUSION: Torsional uterine fibroids are difficult to diagnose preoperatively as symptoms are nonspecific and need emergent surgical management as an acute abdomen. Preoperative diagnosis using appropriate imaging modalities is important to perform single-port laparoscopic surgery.