Although ovarian cancer is the most lethal gynecologic malignancy in women, little is known about how the cancer initiates and metastasizes. In the last decade, new evidence has challenged the dogma ...that the ovary is the main source of this cancer. The fallopian tube has been proposed instead as the primary origin of high-grade serous ovarian cancer, the subtype causing 70% of ovarian cancer deaths. By conditionally deleting Dicer, an essential gene for microRNA synthesis, and Pten, a key negative regulator of the PI3K pathway, we show that high-grade serous carcinomas arise from the fallopian tube in mice. In these Dicer-Pten double-knockout mice, primary fallopian tube tumors spread to engulf the ovary and then aggressively metastasize throughout the abdominal cavity, causing ascites and killing 100% of the mice by 13 mo. Besides the clinical resemblance to human serous cancers, these fallopian tube cancers highly express genes that are known to be up-regulated in human serous ovarian cancers, also demonstrating molecular similarities. Although ovariectomized mice continue to develop high-grade serous cancers, removal of the fallopian tube at an early age prevents cancer formation—confirming the fallopian tube origin of the cancer. Intriguingly, the primary carcinomas are first observed in the stroma of the fallopian tube, suggesting that these epithelial cancers have a mesenchymal origin. Thus, this mouse model demonstrates a paradigm for the origin and initiation of high-grade serous ovarian carcinomas, the most common and deadliest ovarian cancer.
Although named “ovarian cancer,” it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian ...cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53R172H-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.
The existing evidence demonstrates that survivors of SJS/TEN have reported long-lasting psychological effects of their condition. Burns patients experience similar psychological effects. It is ...important to look at ways to help allay the psychological complications of SJS/TEN. As there is an absence of evidence on SJS/TEN psychotherapeutic interventions, it was judged to be beneficial to determine the evidence underpinning psychotherapeutic interventions used with burns patients. The aim of this systematic integrative review was to synthesize the evidence relating to psychotherapeutic interventions used with adult burns patients and patients with SJS/TEN. The systematic review was guided by Whittemore and Knafl's integrative review process and the PRISMA guidelines. Nine databases were searched for English and French language papers published January 2008 to January 2021. The protocol for the review was registered with PROSPERO. Following a screening process, 17 studies were included in the review. Two themes were identified using content analysis, (i) Empirically supported psychotherapeutic treatments, (ii) Alternative psychotherapeutic treatments. This review revealed no evidence on specific psychotherapeutic interventions for patients with SJS/TEN. Some of the interventions used with burns patients, viz. relaxation therapy, hypnosis and cognitive behavioral therapy showed some significant benefits. However, the evidence for burns patients is mainly focused on pain and pain anxiety as outcomes. Following further research, some of the interventions deployed in burns patients may be applicable to SJS/TEN patients, particularly stress reduction techniques. In addition, the caring behaviours such as compassion, respect, and getting to know the patient as a person are important components to psychological care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the ...development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.
Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, ...also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced ...fibrosis.
AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining.
AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p<0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p>0.5) and histological scoring of radiation induced fibrosis (p>0.5).
Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC.
To determine if adding shear-wave elastography (SWE) to second-look ultrasonography (US) after breast dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging helps find or target ...lesions seen on DCE MR images for US-guided biopsy.
This HIPAA-compliant prospective study was approved by the institutional review board, and written informed consent was obtained from patients. From May 2011 to July 2012, 73 women with 96 Breast Imaging Reporting and Data System (BI-RADS) category 4 or 5 lesions after DCE MR imaging prospectively consented to undergo SWE during second-look US. If a lesion was not confidently seen with B-mode US, SWE during real-time scanning was performed to determine if SWE helped find or target lesions for US biopsy. A qualitative SWE six-point color scale was used to record the maximum elasticity in and around lesions. All lesions underwent US or DCE MR imaging-guided core biopsy.
Median participant age was 52 years (range, 21-81 years). In 72 patients who underwent DCE MR imaging, 96 BI-RADS category 4 or 5 lesions were detected in 81 breasts. There were 29 (30%) malignancies (one malignancy was of nonbreast origin), 14 (15%) high-risk lesions, and 53 (55%) benign lesions. US revealed 22 cancers, and seven cancers were detected only with MR imaging. Real-time SWE helped find one lesion and target four lesions that were incompletely assessed with gray-scale US. These five lesions that were localized or targeted for biopsy were invasive cancers, representing 23% of the 22 malignancies detected with US.
Real-time SWE added to second-look US after DCE MR imaging increased the detection rate of cancers and helped target cancers for US-guided biopsy.
Metaplastic breast carcinoma (MBC) and gynecologic carcinosarcoma (GCS) are rare, clinically aggressive cancers that demonstrate epithelial components and mesenchymal or sarcomatoid components. In ...this study, we assessed PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in MBC and GCS. Overall, PD-L1 positivity using the SP142 clone was seen in 50 % of MBC and 51.9 % of GCS cases, with PD-L1 expression in tumor cells significantly higher in MBC cases (p = 0.034), and PD-L1 expression in immune cells similar in MBC and GCS cases. PD-L1 expression was significantly higher in epithelial components than in mesenchymal components in both MBC and GCS cases (p = 0.0005). TILs were low in the majority of MBC and GCS cases (≥ 10 %) and generally correlated with PD-L1 expression; however, many PD-L1 positive cases with low TILs were seen. PD-L1 expression using the 22C3 clone was additionally assessed, with positivity seen in 62.9 % of MBC cases and 30 % of GCS cases. Concordance between SP142 and 22C3 results was seen in 62.5 % of MBC cases and 80 % of GCS cases. Overall, our findings suggest that a subset of MBC and GCS cases may benefit from immune checkpoint inhibitor therapy. Our findings also illustrate unique aspects of PD-L1 expression patterns in these tumors which may harbor additional prognostic and therapeutic significance.
•PD-L1 often positive in metaplastic breast carcinoma and gynecologic carcinosarcoma•PD-L1 expression was higher in epithelial components than mesenchymal components.•Tumor-infiltrating lymphocytes were low in most cases and correlated with PD-L1.•PD-L1 positive cases with low tumor-infiltrating lymphocytes were identified.
Digital whole slide imaging is the anticipated future of anatomic pathology, where sign-out of glass slides will be replaced by scanned images. Whole slide imaging has been successfully used in ...surgical pathology, but its usefulness and clinical application have been limited in cytology for several reasons, including lack of availability of z-axis depth focusing and large file size. Recently, several systems have become available in the United States for whole slide imaging with z-axis technology.
To determine the accuracy and efficiency of whole slide imaging, as compared with traditional glass slides, for use in cervicovaginal diagnostic cytology.
Eleven cervicovaginal cytology cases (ThinPrep and SurePath) scanned at ×20, ×40, and ×40 z-stack magnifications using the BioImagene iScan Coreo Au 3.0 scanner were evaluated by 4 cytotechnologists and 3 pathologists in a blinded study. Different magnification scans were recorded as separate cases and presented in a randomized sequence. Corresponding glass slides were also reviewed. For each case, the diagnoses and total time to reach each diagnosis were recorded.
Diagnostic accuracy was higher and average time per case was lower with glass slides as compared with all digital images. Among the digital images, the ×40 or ×40 z-stack had the highest diagnostic accuracy and lowest interpretation time.
Whole slide imaging is a viable option for the purposes of teaching and consultations, and as a means of archiving cases. However, considering the large file size and total time to reach diagnosis on digital images, whole slide imaging is not yet ready for daily cervicovaginal diagnostic cytology screening use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Yolk-sac tumors account for about 20% of ovarian germ cell tumors and occur predominantly in women below 35 years of age. Modern evidence-based treatment strategies have ensured long term ...post-treatment survival, but with increased survival, attention has been turned to an urgent need for developing fertility sparing treatment strategies. In this report we describe the successful treatment of a young woman who was able to conceive and deliver two children, in spite of the loss of one ovary two years prior to being diagnosed with an ovarian yolk-sac tumor on the remaining ovary.
•Patient with a yolk sac tumor in her only ovary with desire for future fertility.•Fertility-sparing approach used with subsequent successful fertility outcome.•Discussion of current approaches for potential fertility preservation.
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