Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.

Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

Prospective validation of the role of PET/CT in detecting disease after neoadjuvant chemotherapy in advanced ovarian cancer.

OBJECTIVES: The study aimed to compare the diagnostic accuracies of 2-[18F]FDG PET/CT and contrast-enhanced CT (ceCT) after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer (OC). MATERIALS AND METHODS: This study consisted historical observational cohort and prospective validation cohort. Patients with newly diagnosed stage III-IV OC scheduled for NACT were recruited, with imaging performed after three to six cycles of NACT before interval debulking surgery. Nineteen regions in the abdominopelvic cavity were scored for the presence and absence of disease, referenced to the intra-operative findings or histological specimens. Diagnostic metrics were compared using McNemar's test. RESULTS: In the historical cohort (23 patients, age 58 ± 13), 2-[18F]FDG PET had an overall accuracy (Acc) 82%, sensitivity (Sen) 38%, specificity (Spe) 97%, positive predictive value (PPV) 79% and negative predictive value (NPV) 82%; ceCT had an overall Acc 86%, Sen 64%, Spe 93%, PPV 75% and NPV 89%. In the prospective cohort (46 patients, age 59 ± 9), 2-[18F] FDG PET had an overall Acc 87%, Sen 48%, Spe 98%, PPV 84% and NPV 88%; ceCT had an overall Acc 89%, Sen 66%, Spe 95%, PPV 77% and NPV 91%. No significant difference was demonstrated between the two imaging modalities (p > 0.05). High false-negative rates were observed in the right subdiaphragmatic space, omentum, bowel mesentery and serosa. High omental metabolic uptake after NACT was associated with histological non-responders (p < 0.05). CONCLUSION: 2-[18F]FDG PET/CT had no additional value over ceCT with comparable diagnostic accuracy in detecting disease after NACT in advanced OC. CLINICAL RELEVANCE STATEMENT: 2-[18F]FDG PET/CT is not superior to contrast-enhanced CT in determining disease after neoadjuvant chemotherapy in advanced ovarian cancer; contrast-enhanced CT should be suffice for surgical planning before interval debulking surgery. KEY POINTS: • Additional value of 2-[18F]FDG PET/CT over contrast-enhanced CT is undefined in detecting disease after neoadjuvant chemotherapy. • 2-[18F]FDG PET/CT has comparable diagnostic accuracy compared to contrast-enhanced CT. • Contrast-enhanced CT will be suffice for surgical planning after neoadjuvant chemotherapy.

Identifying intraoperative events in a simulated laparotomy video: a multinational study of inattentional blindness among anesthesiologists.

PURPOSE: Medical errors may be occasionally explained by inattentional blindness (IB), i.e., failing to notice an event/object that is in plain sight. We aimed to determine whether age/experience, restfulness/fatigue, and previous exposure to simulation education may affect IB in the anesthetic/surgical setting. METHODS: In this multicentre/multinational study, a convenience sample of 280 anesthesiologists watched an attention-demanding video of a simulated trauma patient undergoing laparotomy and (independently/anonymously) recorded the abnormalities they noticed. The video contained four expected/common abnormalities (hypotension, tachycardia, hypoxia, hypothermia) and two prominently displayed unexpected/rare events (patient's head movement, leaky central venous line). We analyzed the participants' ability to notice the expected/unexpected events (primary outcome) and the proportion of expected/unexpected events according to age group and prior exposure to simulation education (secondary outcomes). RESULTS: Anesthesiologists across all ages noticed fewer unexpected/rare events than expected/common ones. Overall, younger anesthesiologists missed fewer common events than older participants did (P = 0.02). There was no consistent association between age and perception of unexpected/rare events (P = 0.28), although the youngest cohort (< 30 yr) outperformed the other age groups. Prior simulation education did not affect the proportion of misses for the unexpected/rare events but was associated with fewer misses for the expected/common events. Self-perceived restfulness did not impact perception of events. CONCLUSION: Anesthesiologists noticed fewer unexpected/rare clinical events than expected/common ones in an attention-demanding video of a simulated trauma patient, in keeping with IB. Prior simulation training was associated with an improved ability to notice anticipated/expected events, but did not reduce IB. Our findings may have implications for understanding medical mishaps, and efforts to improve situational awareness, especially in acute perioperative and critical care settings.

RéSUMé: OBJECTIF: Les erreurs médicales peuvent parfois s'expliquer par la cécité d'inattention, soit le fait de ne pas remarquer un événement/objet qui est à la vue de tous et toutes. Notre objectif était de déterminer si l'âge/l'expérience, le repos/la fatigue et l'exposition antérieure à l'enseignement par simulation pouvaient affecter la cécité d'inattention dans le cadre de l'anesthésie/chirurgie. MéTHODE: Dans cette étude multicentrique/multinationale, un échantillon de convenance de 280 anesthésiologistes ont visionné une vidéo exigeant l'attention portant sur un patient de trauma simulé bénéficiant d'une laparotomie et ont enregistré (de manière indépendante/anonyme) les anomalies qu'ils et elles ont remarquées. La vidéo contenait quatre anomalies attendues/courantes (hypotension, tachycardie, hypoxie, hypothermie) et deux événements inattendus/rares bien en vue (mouvement de la tête du patient, fuite du cathéter veineux central). Nous avons analysé la capacité des participant·es à remarquer les événements attendus/inattendus (critère d'évaluation principal) et la proportion d'événements attendus/inattendus selon le groupe d'âge et l'exposition antérieure à l'enseignement par simulation (critères d'évaluation secondaires). RéSULTATS: Les anesthésiologistes de tous âges ont remarqué moins d'événements inattendus/rares que d'événements attendus/courants. Globalement, les anesthésiologistes plus jeunes ont manqué moins d'événements courants que leurs congénères plus âgé·es (P = 0,02). Il n'y avait pas d'association constante entre l'âge et la perception d'événements inattendus ou rares (P = 0,28), bien que la cohorte la plus jeune (< 30 ans) ait surpassé les autres groupes d'âge. La formation antérieure par simulation n'a pas eu d'incidence sur la proportion d'inobservation des événements inattendus ou rares, mais a été associée à moins de cécité d'inattention envers les événements attendus ou courants. Le repos perçu n'a pas eu d'impact sur la perception des événements. CONCLUSION: Les anesthésiologistes ont remarqué moins d'événements cliniques inattendus/rares que d'événements attendus/courants dans une vidéo exigeant l'attention portant sur la simulation d'un patient traumatisé, ce qui s'inscrit dans la cécité d'inattention. La formation préalable par simulation était associée à une meilleure capacité à remarquer les événements anticipés/attendus, mais ne réduisait pas la cécité d'inattention. Nos résultats peuvent avoir des implications pour la compréhension des accidents médicaux et les efforts visant à améliorer la conscience situationnelle, en particulier dans les contextes de soins périopératoires aigus et de soins intensifs.

Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1.

The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.

AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer.

Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.

Anaesthetic depth and delirium after major surgery: a randomised clinical trial.

BACKGROUND: Postoperative delirium is a serious complication of surgery associated with prolonged hospitalisation, long-term cognitive decline, and mortality. This study aimed to determine whether targeting bispectral index (BIS) readings of 50 (light anaesthesia) was associated with a lower incidence of POD than targeting BIS readings of 35 (deep anaesthesia). METHODS: This multicentre randomised clinical trial of 655 at-risk patients undergoing major surgery from eight centres in three countries assessed delirium for 5 days postoperatively using the 3 min confusion assessment method (3D-CAM) or CAM-ICU, and cognitive screening using the Mini-Mental State Examination at baseline and discharge and the Abbreviated Mental Test score (AMTS) at 30 days and 1 yr. Patients were assigned to light or deep anaesthesia. The primary outcome was the presence of postoperative delirium on any of the first 5 postoperative days. Secondary outcomes included mortality at 1 yr, cognitive decline at discharge, cognitive impairment at 30 days and 1 yr, unplanned ICU admission, length of stay, and time in electroencephalographic burst suppression. RESULTS: The incidence of postoperative delirium in the BIS 50 group was 19% and in the BIS 35 group was 28% (odds ratio 0.58 [95% confidence interval: 0.38-0.88]; P=0.010). At 1 yr, those in the BIS 50 group demonstrated significantly better cognitive function than those in the BIS 35 group (9% with AMTS ≤6 vs 20%; P<0.001). CONCLUSIONS: Among patients undergoing major surgery, targeting light anaesthesia reduced the risk of postoperative delirium and cognitive impairment at 1 yr. CLINICAL TRIAL REGISTRATION: ACTRN12612000632897.

Primary HPV testing with cytology versus cytology alone in cervical screening-A prospective randomized controlled trial with two rounds of screening in a Chinese population.

We conducted a prospective randomized controlled trial with two screening rounds to evaluate the effectiveness of combining HPV testing with liquid-based cytology (LBC) as a co-test, compared to LBC only in cervical cancer screening of a Chinese population. First, 15,955 women aged 30-60 were randomized at a 1:1 ratio into an intervention group (Digene Hybrid Capture 2 HPV test with LBC) and a control group (LBC alone). Women in the intervention group would be referred for colposcopy and biopsy immediately if they were found to have high-risk HPV regardless of cytology results. The detection of cervical intraepithelial neoplasia grade 2 or above (CIN2+) lesions was significantly higher in the intervention group compared to the control (0.95% vs. 0.38%, OR 2.50, 95% CI 1.65-3.88). At the subsequent round of screening approximately 36 months later, CIN2+ detection was significantly lower in the intervention group (0.08% vs. 0.35%, OR 0.23, 95% CI 0.08-0.57). Over the two rounds of screening, the total detection of CIN2+ was higher in the intervention group (1.01% vs. 0.66%, OR 1.53, 95% CI 1.09-2.19). There was a fourfold increase (10.6% vs. 2.4%, p < 0.001) in the number of colposcopies performed in the intervention arm. Adding a high-risk HPV test to cytology for primary cervical screening led to earlier detection of clinically significant preinvasive lesions, resulting in a reduced detection of CIN2+ lesions in subsequent rounds and an increased rate of colposcopy.

Anaesthetic depth and complications after major surgery: an international, randomised controlled trial.

BACKGROUND: An association between increasing anaesthetic depth and decreased postoperative survival has been shown in observational studies; however, evidence from randomised controlled trials is lacking. Our aim was to compare all-cause 1-year mortality in older patients having major surgery and randomly assigned to light or deep general anaesthesia. METHODS: In an international trial, we recruited patients from 73 centres in seven countries who were aged 60 years and older, with significant comorbidity, having surgery with expected duration of more than 2 h, and an anticipated hospital stay of at least 2 days. We randomly assigned patients who had increased risk of complications after major surgery to receive light general anaesthesia (bispectral index [BIS] target 50) or deep general anaesthesia (BIS target 35). Anaesthetists also nominated an appropriate range for mean arterial pressure for each patient during surgery. Patients were randomly assigned in permuted blocks by region immediately before surgery, with the patient and assessors masked to group allocation. The primary outcome was 1-year all-cause mortality. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000632897, and is closed to accrual. FINDINGS: Patients were enrolled between Dec 19, 2012, and Dec 12, 2017. Of the 18 026 patients screened as eligible, 6644 were enrolled, randomly assigned to treatment or control, and formed the intention-to-treat population (3316 in the BIS 50 group and 3328 in the BIS 35 group). The median BIS was 47·2 (IQR 43·7 to 50·5) in the BIS 50 group and 38·8 (36·3 to 42·4) in the BIS 35 group. Mean arterial pressure was 3·5 mm Hg (4%) higher (median 84·5 [IQR 78·0 to 91·3] and 81·0 [75·4 to 87·6], respectively) and volatile anaesthetic use was 0·26 minimum alveolar concentration (30%) lower (0·62 [0·52 to 0·73] and 0·88 [0·74 to 1·04], respectively) in the BIS 50 than the BIS 35 group. 1-year mortality was 6·5% (212 patients) in the BIS 50 group and 7·2% (238 patients) in the BIS 35 group (hazard ratio 0·88, 95% CI 0·73 to 1·07, absolute risk reduction 0·8%, 95% CI -0·5 to 2·0). Grade 3 adverse events occurred in 954 (29%) patients in the BIS 50 group and 909 (27%) patients in the BIS 35 group; and grade 4 adverse events in 265 (8%) and 259 (8%) patients, respectively. The most commonly reported adverse events were infections, vascular disorders, cardiac disorders, and neoplasms. INTERPRETATION: Among patients at increased risk of complications after major surgery, light general anaesthesia was not associated with lower 1-year mortality than deep general anaesthesia. Our trial defines a broad range of anaesthetic depth over which anaesthesia may be safely delivered when titrating volatile anaesthetic concentrations using a processed electroencephalographic monitor. FUNDING: Health Research Council of New Zealand; National Health and Medical Research Council, Australia; Research Grant Council of Hong Kong; National Institute for Health and Research, UK; and National Institutes of Health, USA.

MRI texture features differentiate clinicopathological characteristics of cervical carcinoma.

OBJECTIVES: To evaluate MRI texture analysis in differentiating clinicopathological characteristics of cervical carcinoma (CC). METHODS: Patients with newly diagnosed CC who underwent pre-treatment MRI were retrospectively reviewed. Texture analysis was performed using commercial software (TexRAD). Largest single-slice ROIs were manually drawn around the tumour on T2-weighted (T2W) images, apparent diffusion coefficient (ADC) maps and contrast-enhanced T1-weighted (T1c) images. First-order texture features were calculated and compared among histological subtypes, tumour grades, FIGO stages and nodal status using the Mann-Whitney U test. Feature selection was achieved by elastic net. Selected features from different sequences were used to build the multivariable support vector machine (SVM) models and the performances were assessed by ROC curves and AUC. RESULTS: Ninety-five patients with FIGO stage IB~IVB were evaluated. A number of texture features from multiple sequences were significantly different among all the clinicopathological subgroups (p < 0.05). Texture features from different sequences were selected to build the SVM models. The AUCs of SVM models for discriminating histological subtypes, tumour grades, FIGO stages and nodal status were 0.841, 0.850, 0.898 and 0.879, respectively. CONCLUSIONS: Texture features derived from multiple sequences were helpful in differentiating the clinicopathological signatures of CC. The SVM models with selected features from different sequences offered excellent diagnostic discrimination of the tumour characteristics in CC. KEY POINTS: • First-order texture features are able to differentiate clinicopathological signatures of cervical carcinoma. • Combined texture features from different sequences can offer excellent diagnostic discrimination of the tumour characteristics in cervical carcinoma.

Functional tumour burden of peritoneal carcinomatosis derived from DWI could predict incomplete tumour debulking in advanced ovarian carcinoma.

OBJECTIVES: To investigate the predictive value of peritoneal carcinomatosis (PC) quantification by DWI in determining incomplete tumour debulking in ovarian carcinoma (OC). METHODS: Prospective patients with suspected stage III-IV or recurrent OC were recruited for DWI before surgery. PC on DWI was segmented semi-automatically by k-means clustering, retaining voxels with intermediate apparent diffusion coefficient (ADC) to quantify PC burden. A scoring system, functional peritoneal cancer index (fPCI), was proposed based on the segmentation of tumour volume in 13 abdominopelvic regions with additional point given to involvement of critical sites. ADC of the largest PC was recorded. The surgical complexity and outcomes (complete vs. incomplete tumour debulking) were documented. fPCI was correlated with surgical PCI (sPCI), surgical complexity, and its ability to predict incomplete tumour debulking. RESULTS: Fifty-three patients with stage III-IV or recurrent OC were included with a mean age of 56.1 ± 11.8 years old. Complete tumour debulking was achieved in 38/53 patients (71.7%). Significant correlation was found between fPCI and sPCI (r > 0.757, p < 0.001). Patients with high-fPCI (fPCI ≥ 6) had a high surgical complexity score (p = 0.043) with 84.2% received radical or supra-radical surgery. The mean fPCI was significantly higher in patients with incomplete tumour debulking than in those with complete debulking (10.27 vs. 4.71, p < 0.001). fPCI/ADC combined with The International Federation of Gynecology and Obstetrics stage achieved 92.5% accuracy in predicting incomplete tumour debulking (AUC 0.947). CONCLUSIONS: DWI-derived fPCI offered a semi-automated estimation of PC burden. fPCI/ADC could predict the likelihood of incomplete tumour debulking with high accuracy. KEY POINTS: • Functional peritoneal cancer index (fPCI) derived from DWI offered a semi-automated estimation of tumour burden in ovarian carcinoma. • fPCI was highly correlated with surgical PCI (sPCI). • fPCI/ADC could predict the likelihood of incomplete tumour debulking with high accuracy.

Nurse-led follow-up in survivorship care of gynaecological malignancies-A randomised controlled trial.

OBJECTIVE: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies. METHODS: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist. RESULTS: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms. CONCLUSIONS: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care.

Placental Site Trophoblastic Tumor: A Distinct Entity of Gestational Trophoblastic Disease Experience from a Tertiary Referral Center in Hong Kong.

OBJECTIVE: To review the clinical and pathological characteristics of patients with placental site trophoblastic tumor (PS TT) managed in a tertiary referral center in Hong Kong. STUDY DESIGN: Patients with a diagnosis of PSTT from 1995 to 2012 were identified from a computer database. Clinical and patho- logical data were obtained from medical records and the electronic database. RESULTS: Ten patients with PSTT were identified. Only 4 patients (40%) had disease confined to the uterus at presentation (Stage I). The most common site of metastasis was the lung. Four patients had pretreatment serum hCG levels <1,000 IU/L, and all of them had disease 'confined to the uterus. Of the 4 patients with Stage I disease 3 had hysterectomy only and 1 had both hysterectomy and chemotherapy. All 4 patients achieved complete remission; although 1 of them had a recurrence successfully treated with che- motherapy. For patients with Stage III/IV disease most of them had both hysterectomy and chemotherapy. Only 1 patient (20%) was alive without evidence of disease. CONCLUSION: Patients with Stage I disease have excellent prognosis after hysterectomy, and adjuvant treatment is not recommended. A low pretreatment serum hCG level (<1,000 IU/L) was a good predictor of early stage disease. The prognosis for patients with metastatic disease was poor despite surgery and com- bination chemotherapy.

HPV 16 E2 binding sites 1 and 2 become more methylated than E2 binding site 4 during cervical carcinogenesis.

E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer.

The Significance of Mismatch Repair Deficiency in Young Patients With Endometrial Cancer.

The objective of this study was to identify the tumor characteristics associated with mismatch repair deficiency in young patients with endometrial carcinoma. Young patients (45 yr old or younger) with endometrial carcinoma treated by hysterectomy in our institution between July 2001 and June 2009 were identified. The clinical and pathologic data were obtained by review of clinical records. Among the 122 cases identified, paraffin sections were available in 67 cases for immunohistochemical staining and frozen tissue available in 62 cases for microsatellite instability (MSI) analysis. Both paraffin sections and frozen tissue were available in 36 cases. Among the 67 cases with immunohistochemical staining, 22 (32.8%) showed loss of expression of at least 1 mismatch repair protein. Defective MLH1 or MSH2 expression was associated with poor prognostic factors, including a higher incidence of pelvic lymph nodes metastasis (P=0.018) and higher stage (P=0.022) for MLH1, and an increased risk of lymphovascular permeation (P=0.015) for MSH2. On the contrary, defective MSH6 protein expression was associated with a lower incidence of high-grade tumors (P=0.04). Among the 62 cases with MSI analysis, 12 (19.4%) tumors were classified as microsatellite-high (MSI-H), whereas 2 (3.2%) were classified as microsatellite-low (MSI-L). There was no difference in the pathologic characteristics between MSI-stable and MSI-H tumor. We concluded that defective mismatch repair expression is important in young patients with endometrial carcinoma, with MSH6 protein being most commonly affected. The phenotype resulting from defective MSH6 expression was different from that caused by MLH1 or MSH2 loss.

Cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine in the treatment of gestational trophoblastic neoplasia.

OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity profile of the cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, and vincristine (CHAMOC) regimen in the treatment of high-risk gestational trophoblastic neoplasia (GTN). METHODS: We conducted a retrospective study of all patients with GTN treated with the CHAMOC regimen between 1985 and 2012 in a tertiary referral center in Hong Kong. Medical records were reviewed, and data were analyzed. Response rate and toxicity profile were assessed. RESULTS: The CHAMOC regimen was given to 79 patients from 1985 to 2012, with a total of 388 cycles administered. Among the 79 patients, CHAMOC was given to 68 as the primary treatment of high-risk GTN, whereas it was used as the salvage chemotherapy in 11 patients for failure with other chemotherapy regimens or recurrent disease. Complete remission was achieved in 58 patients (85.3%) in the primary treatment group and 8 patients (72.7%) in the salvage treatment group. Grade 3 and grade 4 neutropenia were observed in 13.0% and 3.4% of the chemotherapy cycles, respectively. Grade 3 or 4 thrombocytopenia was rare (1.3% of all treatment cycles). No secondary malignancy was observed in our patients with a mean duration of follow-up of 9.7 to 13 years, except 1 patient with advanced colon cancer diagnosed shortly after chemotherapy, which was unlikely to represent a secondary malignancy from the chemotherapy. CONCLUSIONS: The CHAMOC regimen should be considered as an alternative to other chemotherapy regimens in the primary treatment of high-risk gestational trophoblastic disease, with comparable efficacy, similar short-term side-effects profile, and potentially fewer long-term complications.

Perfusion and diffusion characteristics of cervical cancer based on intraxovel incoherent motion MR imaging-a pilot study.

OBJECTIVES: To investigate the tissue characteristics of cervical cancer based on the intravoxel incoherent motion (IVIM) model and to assess the IVIM parameters in tissue differentiation in the female pelvis. METHODS: Sixteen treatment-naïve cervical cancer and 17 age-matched healthy subjects were prospectively recruited for diffusion-weighted (b = 0-1,000 s/mm(2)) and standard pelvic MRI. Bi-exponential analysis was performed to derive the perfusion parameters f (perfusion fraction) and D* (pseudodiffusion coefficient) as well as the diffusion parameter D (true molecular diffusion coefficient) in cervical cancer (n = 16), normal cervix (n = 17), myometrium (n = 33) and leiomyoma (n = 14). Apparent diffusion coefficient (ADC) was calculated. Kruskal-Wallis test and receiver operating characteristics (ROC) curves were used. RESULTS: Cervical cancer had the lowest f (14.9 ± 2.6%) and was significantly different from normal cervix and leiomyoma (p < 0.05). The D (0.86 ± 0.16 x 10(-3) mm2/s) was lowest in cervical cancer and was significantly different from normal cervix and myometrium (p < 0.05) but not leiomyoma. No difference was observed in D*. D was consistently lower than ADC in all tissues. ROC curves indicated that f < 16.38%, D < 1.04 × 10(-3) mm(2)/s and ADC < 1.13 × 10(-3) mm(2)/s could differentiate cervical cancer from non-malignant tissues (AUC 0.773-0.908). CONCLUSIONS: Cervical cancer has low perfusion and diffusion IVIM characteristics with promising potential for tissue differentiation. KEY POINTS: • Diffusion-weighted MRI is increasingly applied in evaluation of cervical cancer. • Cervical cancer has distinctive perfusion and diffusion characteristics. • Intravoxel incoherent motion characteristics can differentiate cervical cancer from non-malignant uterine tissues.

Outcome after loop electrosurgical excision procedure for cervical high-grade squamous intraepithelial lesion.

OBJECTIVE: The dilemma in treating cervical high-grade squamous intraepithelial lesion (HSIL) is how to achieve complete excision to minimize the risk of cervical cancer while sparing the anatomy of the cervix and its ability to function during pregnancy. The optimal management for positive margins after excisional treatment is still controversial. This study was conducted to determine the clinical and histologic predictors of residual/recurrent HSIL and assess the outcome of women with positive margin. MATERIALS AND METHODS: This retrospective cohort study included 386 women who had excisional treatment for HSIL during 1st January 2012 to 31st December 2015 in a university-affiliated hospital. RESULTS: Overall, 212 (54.9%) women had negative margins and 155 (40.2%) had positive margins. The cumulative rate of residual/recurrent HSIL at 2 and 5 years was 15.7% and 16.8% respectively in positive margins and 1.8% and 5.0% respectively in negative margins (p < 0.001). Of women who had residual/recurrent HSIL, significantly more women had positive margins compared to negative margins (74.1% vs 25.9%, p = 0.001). Positive margin was significantly associated with higher rate of subsequent abnormal cervical smear (48.2% vs 28.9%, p < 0.001), requiring further colposcopy (32.1% vs 14.4%, p < 0.001) and further treatment for SIL (7.5% vs 4.8%, p < 0.001) compared to negative margin. CONCLUSION: Most women (85%) with positive margin went without residual/recurrent HSIL, of which the option of close surveillance with cytology is reasonable. Repeat excision may be considered in selected women with positive margin, endocervical glandular involvement and those who are older or unable to comply with follow-up.

Patient-Initiated Follow-Up in Ovarian Cancer.

This study aimed to assess the feasibility of patient-initiated follow-up (PIFU) in combination with regular tumour marker monitoring as an alternative to conventional hospital follow-up for ovarian cancer survivors. Women who had recently completed treatment for ovarian cancer and had a raised pre-treatment tumour marker were recruited. Participants were allocated to PIFU (intervention group) or conventional hospital follow-up (control group) according to their own preference. Both groups had regular tumour marker monitoring. The change in fear of cancer recurrence (FCR) score as measured by the FCR inventory, and the supportive care need (SCN) scores as measured by the SCN survey at baseline and at 6 months between PIFU and hospital follow-up were compared. Out of 64 participants, 37 (58%) opted for hospital follow-up and 27 (42%) opted for PIFU. During the 6-month study period, there was no significant difference in the change of FCR between the two groups (p = 0.35). There was a significant decrease in the sexuality unmet needs score in the intervention group from baseline to 6-month FU (mean difference -8.7, 95% confidence interval -16.1 to -1.4, p = 0.02). PIFU with tumour marker monitoring is a feasible follow-up approach in ovarian cancer survivorship care. FCR and SCN were comparable between PIFU and conventional hospital follow-up.