Prenatal diagnosis of the umbilical cord torsion at the placental cord insertion site: A case report and literature review.

A 35-year-old woman (gravida 1, para 0) was admitted to our hospital at 28 weeks' gestation with vaginal bleeding from placenta previa. Severe fetal bradycardia was observed during fetal heart rate monitoring. Ultrasonography showed widely dilated veins on the fetal surface of the placenta and an extraordinarily low umbilical artery peak systolic velocity in the Doppler study. Umbilical cord torsion was suspected. On the subsequent day, we performed a cesarean section due to worsening fetal heart rate patterns. Umbilical artery blood gas analysis indicated severe acidemia (pH 7.063), and umbilical cord torsion was confirmed at the placental cord insertion site. Diagnosing UCT prenatally is challenging; however, it can be suspected by scanning for the widely dilated veins on the fetal placental surface, termed as the "Sunset Sign," an abnormally low umbilical artery peak systolic velocity, and other fetal Doppler abnormalities.

Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Risk classification system using the detailed positive surgical margin status for predicting biochemical recurrence after robot-assisted radical prostatectomy.

AIM: This study aimed to evaluate the risk classification system using the detailed positive surgical margin (PSM) status to predict biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP). METHODS: We retrospectively analyzed 427 patients who underwent RARP between January 2016 and March 2020. We investigated risk factors for BCR using univariate and multivariate Cox proportional hazard regression models. The biochemical recurrence-free survival (BRFS) rate was assessed using the Kaplan-Meier method. RESULTS: The median follow-up period was 43.4 months and 99 patients developed BCR. In the multivariate analysis, maximum PSM length > 5.0 mm and the International Society of Urological Pathology grade group (ISUP GG) at the PSM ≥3 were predictive factors for BCR in patients with a PSM. In the multivariate analysis, these factors were also independent predictive factors in the overall study population, including patients without a PSM. We classified the patients into four groups using these factors and found that the 1-year BRFS rates in the negative surgical margin (NSM) group, low-risk group (PSM and neither factor), intermediate-risk group (either factor), and high-risk group (both factors) were 94.9%, 94.5%, 83.1%, and 52.9%, respectively. The low-risk group showed similar BRFS to the NSM group (p = 0.985), while the high-risk group had significantly worse BRFS than the other groups (p < 0.001). CONCLUSION: Maximum PSM length > 5.0 mm and ISUP GG at the PSM ≥3 were independent predictive factors for BCR after RARP. Risk classification for BCR using these factors is considered to be useful and might help urologists decide on additional treatment after RARP.

High signal intensity of the intraaneurysmal sac on T1 CUBE imaging as a predictor of aneurysm stability after coil embolization.

OBJECTIVE: Histopathological studies of aneurysms after coil embolization showed that thrombus formation during the first month after endovascular treatment (EVT) played an important role in the healing process. The authors hypothesized that dedicated T1-weighted imaging may be used to predict stable aneurysms by visualizing the thrombus status within coil-treated aneurysms. Therefore, this study investigated the relationship between the signal intensity (SI) of the intraaneurysmal sac after coil embolization and aneurysm stability. METHODS: The study population included 82 patients with 86 aneurysms who underwent T1-weighted 3D black-blood fast spin-echo (T1 CUBE) imaging within 1 month after coil embolization between 2019 and 2022. The relative SI of a coil-treated aneurysm (RSIcoiled) was calculated as follows: the mean SI of the intraaneurysmal sac/the mean SI of the genu of the corpus callosum. Aneurysms with enlarged remnants on MR angiography (MRA) within 6 months after EVT were defined as recurrence, while a decrease of intraaneurysmal flow on MRA was defined as improved embolization status. Stable aneurysms were defined as improvement or no change in embolization status 6 months after coil embolization. The volume embolization ratio (VER) was calculated as the ratio of the packed coil volume to the aneurysm volume. Differences between stable and recurrent aneurysms were examined. All aneurysms were divided into high and low RSIcoiled groups based on the cutoff value of RSIcoiled, and differences between the two groups were also evaluated. RESULTS: Recurrence was confirmed for 26 of 86 aneurysms. A univariable analysis showed that small aneurysms, high VER, and high RSIcoiled were associated with aneurysm stability. In the receiver operating characteristic curve analysis, the optimal cutoff value for RSIcoiled to differentiate stable from recurrent aneurysms was 0.54. The cutoff value for RSIcoiled was selected as 0.50 (sensitivity 0.77, specificity 0.70) because it was half the value of the SI of the corpus callosum and close to the optimal cutoff value. In a multivariable analysis, RSIcoiled > 0.50 (OR 8.1, 95% CI 2.5-27) remained a significant factor for aneurysm stability. The high RSIcoiled group showed a higher rate of an improved embolization status (26% vs 6.1%, p = 0.022) and stable aneurysms (85% vs 15%, p = 0.0002). CONCLUSIONS: RSIcoiled was associated with postcoiling aneurysm stability. High RSIcoiled might imply intraaneurysmal thrombus formation associated with the healing process of coil-treated aneurysms.

Distribution of osteoprotegerin in unruptured intracranial aneurysms in humans: association with aneurysm wall protective remodeling.

OBJECTIVE: Aneurysm wall inflammation is associated with lesion instability in unruptured intracranial aneurysms (UIAs). However, most UIAs remain unruptured during lifelong follow-ups because of simultaneous protective remodeling against the inflammatory response. The protective effects of osteoprotegerin (OPG) in intracranial and abdominal aortic aneurysms have been suggested using rodent models; however, the role of this protein in UIAs in humans remains unclear. Herein, the authors examined the relationship between OPG expression and aneurysm wall integrity in intraoperatively resected UIAs by using immunohistochemical and immunofluorescence staining. METHODS: Sixteen UIA wall tissue specimens resected between 2017 and 2022 were analyzed. Aneurysm growth was defined as an enlargement > 1 mm or an obvious morphological change over the course of more than 6 months. Three high-power fields were randomly selected from areas expressing high and low levels of OPG within the same aneurysm. To clarify the role of OPG in the human aneurysm wall, the authors compared averaged values for the following pathological features between the 2 OPG expression groups: aneurysm wall thickness, collagen, macrophages, smooth muscle cells, and transforming growth factor beta 1 (TGF-ß1). Immunohistochemical staining within the entire tissue area was also analyzed to determine the relationships between OPG expression and different aneurysm growth patterns. Pathological findings were compared between high and low OPG expression levels using the Wilcoxon signed-rank test. RESULTS: The heterogeneous expression of OPG was detected in the walls of UIAs. Lesions expressing high OPG levels had thicker aneurysm walls (327 vs 180 µm, p = 0.002) and higher expression levels of TGF-ß1 (8.5% vs 5.4%, p = 0.002) than those expressing low OPG levels. The expression of TGF-ß1 was colocalized with that of OPG mainly in the tunica media. Furthermore, lesions expressing high OPG levels had larger α-SMA+ areas (25% vs 13%, p = 0.002). Aneurysm growth was observed in 6 of 9 UIAs with available data: whole sac expansion in 4 and secondary aneurysm formation in 2. Among the 6 UIAs with aneurysm growth, OPG expression was relatively higher in the UIAs with an internal elastic lamina than in those without (17% vs 6.9%). CONCLUSIONS: Aneurysm wall integrity was associated with OPG expression in the aneurysm wall. Collectively, the study results indicated that OPG is associated with protective remodeling, which may contribute to the retention of aneurysm wall structures.

Inaccessibility, unresponsiveness, inconsistency, and invisibility of informal caregivers of older persons with cognitive impairment: community-based participatory research.

BACKGROUND: Studies on informal caregivers in Japan have been limited to family caregivers and largely conducted where family caregivers generally gather. Family caregivers who do not visit such places or non-family caregivers are generally overlooked, and data on these informal caregivers remains scant. Consequently, a framework is needed through which healthcare professionals can approach the informal caregivers of community-dwelling older persons. Therefore, this study approaches such informal caregivers and proposes a classification system for them from the starting point of older persons living in the community with cognitive impairment. METHODS: In 2016, we conducted an epidemiological survey of 7000 + community-dwelling older persons and identified 198 residents with Mini-mental state examination scores less than 23. A team of healthcare professionals contacted them regularly. By 2022, 92 people were still living in the community, and we systematically asked them about their informal caregivers. After approaching the caregivers and obtaining informed consent, we mailed separate questionnaires to older persons and informal caregivers. RESULTS: Among the caregivers, 59%, 34%, and 3% were the child, spouse, and sibling of the older person, while the remaining 4% were non-family caregivers. Except for two daughters-in-laws, all children were biological children of the older person. Male caregivers (46%) tended to have full-time jobs, whereas female caregivers (54%) tended to face financial difficulties. Only 3% of the caregivers had joined a family caregivers' association. Caregivers' reason for not joining such organizations was a lack of time and knowledge. A 3-tiered classification system was developed for these informal caregivers: (1) the household form, (2) accessibility, and (3) the reciprocal awareness of caregiving. Furthermore, family caregivers who lived with the older person or visited them more than once a week with reciprocal awareness of caring and being cared, or "traditional caregivers," accounted for 68% of the caregivers in this study. CONCLUSION: Core family caregivers can be easily approached at places where such caregivers generally gather. However, there also exists a group of informal caregivers who are sometimes inaccessible, unresponsive, and invisible to healthcare professionals. Moreover, their awareness of caregiving is sometimes inconsistent.

'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

Pontine autosomal dominant microangiopathy and leukoencephalopathy is one of hereditary cerebral small vessel diseases caused by pathogenic variants in COL4A1 3'UTR and characterized by multiple small infarctions in the pons. We attempted to establish radiological features of this disease. We performed whole exome sequencing and Sanger sequencing in one family with undetermined familial small vessel disease, followed by clinicoradiological assessment and a postmortem examination. We subsequently investigated clinicoradiological features of patients in a juvenile cerebral vessel disease cohort and searched for radiological features similar to those found in the aforementioned family. Sanger sequencing was performed in selected cohort patients in order to detect variants in the same gene. An identical variant in the COL4A1 3'UTR was observed in two patients with familial small vessel disease and the two selected patients, thereby confirming the pontine autosomal dominant microangiopathy and leukoencephalopathy diagnosis. Furthermore, postmortem examination showed that the distribution of thickened media tunica and hyalinized vessels was different from that in lacunar infarctions. The appearance of characteristic multiple oval small infarctions in the pons, which resemble raisin bread, enable us to make a diagnosis of pontine autosomal dominant microangiopathy and leukoencephalopathy. This feature, for which we coined the name 'raisin bread sign', was also correlated to the pathological changes.

Dual-energy Computed Tomography Iodine Map for Breast Cancer: Comparison With Dynamic Contrast-enhanced Magnetic Resonance Imaging.

BACKGROUND/AIM: The characteristics of different breast cancers imaged using dual-energy computed tomography (DECT) are unknown. Furthermore, the differences between DECT and magnetic resonance imaging (MRI) in the ability to assess tumor extent have not been clarified. Therefore, this study aimed to evaluate the effectiveness of DECT iodine maps compared to contrast-enhanced MRI in patients with operable breast cancer. PATIENTS AND METHODS: Clinicopathological data from 858 patients with breast cancer who underwent resection after DECT (100/140 kv) and MRI during 2012-2021 were collected. Tumoral iodine concentration (IC; max/Δ) was analyzed from iodine maps. Factors associated with the ability of iodine maps and MRI to predict tumor extent were analyzed with reference to resected specimens' pathological diagnosis. RESULTS: IC parameters varied according to the tumors' histological types and were correlated with the estrogen receptor, histological grade, and Ki-67 labeling index. In 86.2% of patients with invasive carcinoma with intraductal extension, images and resected specimen mapping were matched. Iodine maps were less accurate than MRI in identifying tumor borders in 9.8% and more accurate in 2.1% of patients. The discrepancies in assessing tumor borders between imaging modalities were associated with the tumor's IC parameters and mammary gland status. CONCLUSION: Differences in assessment between DECT and MRI in operable breast cancer are associated with IC parameters and background parenchymal enhancement. Therefore, evaluating tumor extent using DECT considering these characteristics appears to be a feasible approach.

Genome-Wide Gene Expression Profiling Reveals the Direct Effect of Dienogest on Ovarian Endometriotic Stromal Cells.

Endometriosis affects up to 10% of women of reproductive age, causing dysmenorrhea, chronic pelvic pain, and infertility. The current key drug for endometriosis is dienogest, a progestin with high specificity for the progesterone receptor. To reveal the direct anti-endometriotic effect of dienogest on ovarian endometriotic cells, we investigated the genome-wide gene expression profiles of ovarian endometriotic stromal cells with (Dienogest group) or without dienogest treatment (Control group) and compared the groups' gene expression profiles. We performed a gene ontology (GO) analysis and Ingenuity pathway analysis using these data. To validate the microarray data, we performed real-time RT-PCRs and immunohistochemistry for the differentially expressed genes between the two groups. Of 647 genes differentially expressed between the two groups, 314 genes were upregulated and 333 were downregulated in the Dienogest group versus the Control group. The GO analysis showed that the regulation of macrophage chemotaxis, the collagen catabolic process, and the proteoglycan biosynthetic process are the main biological processes closely associated with the differentially expressed genes. We identified 20 canonical pathways that were most significantly differentially expressed in the Dienogest group versus the Control group. We observed that matrix metalloproteinases (MMPs) are the genes in these pathways that are most closely associated with dienogest treatment. Of components involved in the regulation of macrophage chemotaxis, colony-stimulating factor 1 and macrophage-stimulating 1 are potential upstream regulators of MMPs and were observed herein to be suppressed by dienogest. Our results suggest that dienogest may thus exert its anti-endometriotic effect by directly suppressing MMPs.

Ischemic Necrosis of the Gastric Remnant Treated Successfully Using Total Remnant Gastrectomy.

Distal gastrectomy (DG) with lymph node dissection is considered as the standard treatment for gastric cancer. Ischemic necrosis of the gastric remnant is a rare but serious complication of DG that requires careful consideration for early diagnosis and treatment to lower the associated mortality rate. A 71-year-old male presented to our hospital with hyperglycemia and was evaluated for suspected diabetes. The patient's medical history was otherwise unremarkable. Computed tomography (CT) revealed a thickening of the stomach wall, with follow-up esophagogastroduodenoscopy revealing type 3 gastric cancer in the greater curvature of the antrum. Biopsy specimen confirmed a pathological diagnosis of mucinous adenocarcinoma, with a clinical diagnosis of cT3N0M0, cStageIIB. An open DG with Billroth I reconstruction was performed, without incident. On postoperative day 1, the patient developed a high fever, abdominal pain, and elevated white blood cell count (12,200/µL). On postoperative day 2, his C-reactive protein level increased to >30 mg/dL. CT revealed an edematous thickening of the stomach wall, with poor mucosal enhancement of the remnant stomach and thinning of the anastomosis wall, with air nearby. Emergency surgery was performed for suspected leakage. Intraoperative findings showed no evidence of leakage. Intraoperative endoscopy revealed a necrotic gastric remnant, and we performed a total remnant gastrectomy with Roux-en Y reconstruction. The patient was discharged in a stable condition, 25 days after the first surgery. Although ischemic necrosis of the gastric remnant is a rare complication, its possibility should be carefully considered after DG, for early diagnosis and treatment.

Squamous Metaplasia of the Colon Following Severe COVID-19.

A 53-year-old man was admitted for respiratory failure due to severe acute respiratory syndrome caused by a severe acute respiratory syndrome coronavirus 2 infection. The patient required prolonged artificial ventilation and extracorporeal membrane oxygenation (ECMO) for respiratory support. Despite successful discontinuation of ECMO, the patient experienced profuse watery diarrhea (5-10 L/day). A colonoscopy revealed an inflamed surface without undulation that uniformly extended throughout the colon. Biopsy specimens revealed complete disappearance of existing crypts and replacement with squamous or transitional epithelium normally observed in the anal transitional zone mucosa, with granulation tissue proliferation in the lamina propria. Watery diarrhea persisted despite corticosteroid and infliximab administration. Although diarrhea due to atrophy of the surface and cryptic epithelium as an intestinal manifestation of coronavirus disease 2019 usually responds to corticosteroids, refractory diarrhea can be attributed to squamous metaplasia with complete disappearance of the surface and cryptic epithelium.

Association of Neutrophil Extracellular Traps with Plaque Instability in Patient with Carotid Artery Stenosis.

BACKGROUND: Vulnerable carotid plaques are related to cerebral thromboembolic and ischemic events. Neutrophil extracellular traps (NETs) can induce endothelial dysfunction and induce inflammation and coagulation. The aim of the present study was to investigate NETs in patients with carotid artery plaques. METHODS: Carotid plaques were collected by carotid endarterectomy (CEA) from 26 symptomatic and 8 asymptomatic patients between August 2017 and January 2021. The specimens were stained with hematoxylin-eosin and Elastica-van Gieson. Immunohistochemistry was performed staining by CD31 for identifying endothelial cells. NETs were detected by digoxigenin-labeled antihistone H3 (HH3) (citrulline R2+R8+R17). The relationships between the presence of NETs and patient profile and histopathological findings were assessed. RESULTS: HH3-positive cells were detected in 17 (asymptomatic = 2 symptomatic = 15) of 34 carotid plaques (median = 9.7/mm). The number of NETs was correlated with the number of diffusion-weighted imaging high-intensity lesions [P = 0.01], plaque rupture [P = 0.001], intraplaque hemorrhage [P = 0.02], intra luminal thrombus [P = 0.001], and thin fibrous cap [P = 0.001]. CONCLUSIONS: The presence of NETs was associated with the instability of carotid plaques, intraluminal thrombus, which may lead to subsequent cerebral infarction. Clarifying the roles of NETs in carotid plaques may improve the treatment of carotid artery disease.

Pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia treated by radical resection: a case report.

We here report a case of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia treated by radical resection. A 71-year-old man presented to our hospital because of abdominal bloating. Diagnoses of early-stage pancreatic body cancer with pancreatic duct rupture, pancreatic ascites, and formation of a pseudocyst were made on the basis of blood tests, multidetector dynamic computed tomography, endoscopic ultrasonography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography. After achieving control of the ascites by placement of a pancreatic duct stent and aspiration of the pseudocyst, distal pancreatectomy with D2 lymph node dissection was performed. Intraoperative cytologic examination of the ascites was negative. The pathological diagnosis was high-grade pancreatic intraepithelial neoplasia in the pancreatic body. The branched pancreatic duct was occluded and dilated by acute inflammation around the pancreatic neoplasm, the inflammation being in the region of the dilated branched pancreatic duct and having caused its rupture. To the best of our knowledge, this is the first published report of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia.

Clinical Behavior of Combined Versus Pure High-Grade Neuroendocrine Carcinoma.

BACKGROUND: The aim of this study was to investigate and compare the clinical behaviors of combined and pure high-grade neuroendocrine carcinoma (large-cell neuroendocrine carcinoma [LCNEC] and small-cell lung carcinoma [SCLC]). PATIENTS AND METHODS: Data of 132 patients who underwent complete resection for combined or pure high-grade neuroendocrine carcinoma (combined group, 67; pure group, 65) between January 2001 and December 2015 were retrospectively reviewed. The clinicopathological features were analyzed and compared, and the prognoses were assessed by performing the Kaplan-Meier method and Cox regression analysis. RESULTS: The combined and pure groups had nearly equivalent clinicopathological characteristics, specifically, older males with smoking history, almost the same percentage of pleural/lymphatic/vascular invasion, and nearly the same recurrence rates and relapse patterns. The combined group had prognosis equivalent to that of the pure group (5-year overall survival [OS] rates: 61.8% vs. 52.2%, respectively; P = .82 and 5-year recurrence-free survival [RFS] rates: 42.4% vs. 43.9%, respectively; P = .96), and this trend was identified in sub-analyses only for patients with LCNEC, SCLC, and the same pathological stage. Multivariable Cox regression analysis in patients with high-grade neuroendocrine carcinoma revealed that vascular invasion and pathological stage were independent prognostic factors for OS; more importantly, combined and pure histologies were proven to have nearly equivalent associations with prognosis (hazard ratio, 0.96; 95% confidence interval, 0.22to 1.66; P = .96). RESULTS: Combined high-grade neuroendocrine carcinoma had clinical behavior equivalent to those of pure high-grade neuroendocrine carcinoma, with similar clinicopathological characteristics.

Segmentation of aneurysm wall enhancement in evolving unruptured intracranial aneurysms.

OBJECTIVE: Morphological changes in unruptured intracranial aneurysms (UIAs) are an imaging marker of aneurysm instability. Recent studies have indicated the ability of MR vessel wall imaging (VWI) to stratify unstable UIAs based on a correlation with histopathological aneurysm wall inflammation. In the present study the authors investigated the relationships between aneurysm growth patterns and the segmentation of aneurysm wall enhancement (AWE) in VWI. METHODS: A total of 120 aneurysms with serial angiography from a follow-up period of at least 2 years (mean 65 months, range 24-215 months) were assessed by VWI. Two readers independently evaluated the patterns of morphological changes (stable, whole sac expansion, and secondary aneurysm formation) and the segmentation of AWE (no, focal, and circumferential AWE). The contrast enhancement ratio of the aneurysm wall versus the pituitary stalk (CRstalk) was calculated for the quantitative assessment of AWE. Statistical analyses were performed to investigate the relationships between AWE patterns and patient baseline profiles, aneurysm characteristics, and morphological modifications. RESULTS: Forty-one of 120 UIAs (34%) exhibited aneurysm growth (whole sac expansion in 19 and secondary aneurysm formation in 22). AWE was detected in 35 of 120 UIAs (focal AWE in 25 and circumferential AWE in 10). The maximum diameter of, irregularities in, and morphological modifications in aneurysms were associated with the segmentation of AWE. Focal AWE correlated with secondary aneurysm formation, and circumferential AWE correlated with whole sac expansion. In focal AWE, CRstalk was significantly higher in secondary aneurysm formation than in stable UIAs. UIAs without AWE (categorized as no AWE) correlated with aneurysm stability. CONCLUSIONS: The segmentation of AWE was associated with aneurysm growth scenarios and may provide a novel insight into the evaluation of unstable UIAs.

CD44 Is Involved in Sunitinib Resistance and Poor Progression-free Survival After Sunitinib Treatment of Renal Cell Carcinoma.

BACKGROUND/AIM: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study aimed to examine the role of CD44 in sunitinib resistance and as a predictive marker in mRCC. MATERIALS AND METHODS: We analyzed the effect of CD44 knockdown on sunitinib resistance in RCC cell lines using WST-1 assays. CD44 expression in mRCC patients treated with first-line sunitinib was determined by immunohistochemistry. We validated the findings of this study by in silico analysis. RESULTS: CD44 knockdown increased sensitivity to sunitinib. Immunohistochemical analysis revealed that 19 (34.5%) of 55 mRCC cases were positive for CD44. CD44-positive cases were associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, high CD44 expression was significantly associated with poor PFS after sunitinib but not after avelumab + axitinib therapy. CONCLUSION: CD44 is involved in sunitinib resistance and may be a promising marker for sunitinib treatment in mRCC.

P53 Is Involved in Sunitinib Resistance and Poor Progression-free Survival After Sunitinib Treatment of Renal Cell Carcinoma.

BACKGROUND/AIM: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC. MATERIALS AND METHODS: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC. RESULTS: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan-Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment. CONCLUSION: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC.