Surgical outcome of benign cases with pelvic adhesions undergoing robotic total hysterectomy.

BACKGROUND: Robotic total hysterectomies have been considered contraindicated for patients with intra-abdominal adherences, but the evidence for this is not strong, and we hypothesized that the procedure can be of benefit even in these cases. In our research, we analyzed how the severity of pelvic adhesions affects robotic total hysterectomy, and by comparing different types of adhesions, we can further identify the outcomes differences in between, which may aid in future surgical decision making. METHODS: Prospective cohort study (Canadian Task Force classification II-2). All 410 patients with uterine myoma or adenomyosis undergoing robotic total hysterectomies between 2011 and 2016 using the da Vinci Si system by the same surgeon in Taipei Medical University Hospital were included in the study. RESULTS: Baseline characteristics, blood loss, docking time, operation time, time to perform uterine artery ligation (UAL), pain score, hospital stay, complication rate, and laparotomy conversion rate were analyzed between benign cases with or without pelvic adhesions undergoing robotic total hysterectomy. Furthermore, in our subgroups analysis, we have divided the patients with adhesion into different groups according to the severity of adhesion. The abdomen and pelvic cavity was divided into nine sections, and the outcomes of different adhesion condition were compared. We found that patients with adhesions had increased docking time and operation time, but other differences between groups were not statistically significant. The results of the adhesion group showed no significant increases in blood loss, intra- and postoperative complications, and length of hospital stay. Only significantly longer surgical time compared with the normal group was noted. CONCLUSION: Our results suggest that robotic total hysterectomies with UAL are effective and safe for patients with benign gynecologic conditions, and the surgical method should be considered even for patients with adhesion risks.

Poziotinib Inhibits HER2-Mutant-Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer.

The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2-mutant metastatic breast cancer. SIGNIFICANCE: Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.

The debated role of bariatric surgery in improving in-vitro fertilization outcomes in morbidly-obese infertile women-a case report and brief overview.

OBJECTIVE: Obesity has a negative impact on in-vitro fertilization (IVF) outcomes, and obese women who plan IVF treatments are often encouraged to pursue weight reduction. Bariatric surgery is an effective strategy for the treatment of morbidly obese women. The current case report is to investigate the impact of bariatric surgery on IVF outcome in a morbidly obese woman with subfertility. CASE REPORT: A 37-year-old, morbidly obese woman with subfertility was indicated for IVF treatment. Due to her high body mass index (47.9 kg/m2), she was advised to lose weight; initial failure at conservative measures of weight loss prompted her to undergo bariatric surgery, combined with post-operative lifestyle change, prior to receiving IVF treatment. The woman successfully conceived at the second cycle and delivered twins by cesarean section smoothly at 36 + 3/7 weeks of gestation. Both twins have normal development up to two years of age. CONCLUSIONS: Weight reduction mediated by bariatric surgery in subfertile and morbidly obese women can be considered before IVF treatment.

Utilizing Odor-Adsorbed Filter Papers for Detection Canine Training and Off-Site Fire Ant Indications.

The red imported fire ant (RIFA, Solenopsis invicta) is an exotic aggressive pest that is notorious for its ability to seriously harm humans and animals, cause economic loss to agriculture, and damage ecosystems. This is the first study to validate the capability of filter paper adsorption as a feasible odor bearer of RIFAs and evaluate its use in detection dog training. Two live RIFA-experienced detection dogs achieved a mean 92% positive indication rate (PIR) on RIFA-scented papers with a relatively low false response rate (0.8%). The similar accuracies in recognizing live RIFAs (96%) and scented papers (92%) suggest that a filter paper is an effective odor reservoir. After training with live RIFA and scented filter papers, both RIFA-experienced and inexperienced detection dogs successfully indicated filter papers that were scented with at least 10 RIFAs for 4 h with a high PIR (>93%) and low false response rate (2%). Detection dogs correctly recognized the filter papers scented by 10 RIFAs for 24 h with a 97.6% PIR. Even for scented samples stored at -20 °C and 4 °C for 13 weeks, the positive indication rates (PIRs) were as high as 90%. These results suggest that filter paper is an effective RIFA odor bearer, and the scent can be maintained at least 13 weeks for dog identification. After RIFA-scented paper training, detection dogs showed high (>95%) PIRs for both RIFA-scented paper and live RIFAs and also successfully performed field studies. Using filter paper as a RIFA odor bearer is an effective and economical method for detection dog training and RIFA identification.

Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer.

Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2- patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2- breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2- patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2- breast cancer patients.

Successful live birth after repeated high-dose radiotherapy to the uterus.

RESEARCH QUESTION: It has been established that radiotherapy can increase the risk of adverse pregnancy outcomes. However, there is currently no consensus on the effective sterilizing dose of adulthood uterine radiotherapy. DESIGN: This is a case report of a 36-year-old women with three different cancer types who received repeated high-dose radiotherapy of 66 Gy and 50 Gy to the pelvis. The study used a dose-volume histogram, the most widely used tool to calculate the radiation distribution within a volume of interest in a patient during radiotherapy. It was determined that the current patient's uterus might have received the highest uterine radiation dosage for full-term live birth that has been reported in the current literature. RESULTS: Due to iatrogenic ovarian failure, the woman was only able to use donor eggs. After preparation of the endometrium for 18 days, it had reached 8.7 mm in thickness with a triple-line appearance. Two cleavage-stage embryos were transferred, one of which implanted successfully. The course of the pregnancy was uneventful. Finally, the patient gave birth to a healthy baby via Caesarean section at 38+5 weeks of gestation. CONCLUSIONS: The uterus may be more resistant to radiotherapy than previously understood. Uterine fertility preservation methods should be guided by the age of the patient receiving radiotherapy and the actual dose of radiation exposure of the uterus. Future studies should implement a dose-volume histogram to calculate the radiation exposure of the reproductive organs.

Development of ratiometric electrochemical molecular switches to assay endogenous formaldehyde in live cells, whole blood and creatinine in saliva.

Formaldehyde is a reactive carbonyl species (RCS) that is produced naturally in the human body via metabolic and epigenetic biochemical processes, yet in high concentrations is highly toxic to the environment as well as to living organisms. Therefore, we designed two ratiometric electrochemical molecular redox probes, Formaldehyde oxidative latent probe (FOLP) and dihydroxy-formaldehyde oxidative latent probe (HFOLP), for the selective profiling of endogenous formaldehyde. FOLP and HFOLP each underwent the aza-Cope reaction with formaldehyde followed by hydrolysis to eliminate unmask redox reporter N-alkylated aminoferrocene (AAF) to monitor their response current. The FOLP and HFOLP sensors showed broad dynamic ranges of 0.12-1000 µM and 0.09-3 mM for formaldehyde with detection limits of 48.2 nM and 31.6 µM, respectively. Also, since formaldehyde is the byproduct of biochemical reactions for detecting creatinine and creatinine is an important biomarker for chronic kidney disease (CKD), we tested the FOLP probe for its ability to monitor creatinine. It successfully did so, and this ability was used to develop an electrochemical platform for the quantification of creatinine; it showed a dynamic range of 3.25-200 µM and a limit of detection (1.3 µM). In addition, the FOLP-based assay platform delivered a reliable analytical performance for the quantification of formaldehyde in human whole blood and of creatinine in saliva, and also for the real-time monitoring of endogenous formaldehyde secretion in HeLa cells. Moreover, the concentrations determined using our method were found to be consistent with those determined using formaldehyde and creatinine fluorometric assay kits.

Could PGT-A pick up true abnormalities that have clinical relevance? Retrospective analysis of 1043 embryos.

OBJECTIVE: To determine whether preimplantation genetic testing for aneuploidy (PGT-A) could pick up true abnormalities that have clinical relevance. MATERIALS AND METHODS: This was a retrospective cohort study of patients who underwent in vitro fertilization with PGT-A from 2015 to 2017. We evaluated the associations of aneuploidy and mosaicism with maternal age, the chromosome abnormalities present in individual chromosomes, and the effect of embryo sex on the proportion of each type of error in the four chromosomes most frequently affected. RESULT(S): A total of 1043 embryos from 255 patients (mean maternal age = 39 ± 4 years) were included in the initial analysis. Of these, 36% (377/1043) were euploid, 47% (487/1043) were aneuploid, 13% (140/1043) contained mosaicism, and 4% (39/1043) gave no result. We excluded the 39 embryos with no result; thus, 1004 embryos were included in the analysis. Increased aneuploidy was associated with increased maternal age, but the rate of embryo mosaicism was not. A combined analysis of aneuploidy with noncomplex abnormalities and mosaicism showed that chromosomes 22, 21, 16, and 15 were the most frequently involved. Chromosome 22 showed the highest proportion of mosaicism and chromosome 15 showed the highest proportion of aneuploidy. When we included embryo sex in the analysis, embryo sex was associated with these chromosome errors in the most susceptible chromosome, 22. CONCLUSION(S): PGT-A showed that chromosomes 22, 21, 16, and 15 were the most frequently involved among common chromosome abnormalities, comparable with those of published data analyzed from spontaneous abortion. This result suggested that PGT-A could pick up abnormalities that have clinical relevance to spontaneous abortion. Moreover, we identified a role of embryo sex in these chromosomal errors on chromosome 22.

Children Conceived by Assisted Reproductive Technology Prone to Low Birth Weight, Preterm Birth, and Birth Defects: A Cohort Review of More Than 50,000 Live Births During 2011-2017 in Taiwan.

Objectives: The use of assisted reproductive technology (ART) has increased rapidly in Taiwan. The purpose of this study is to discuss the risks of low birth weight, preterm birth, and birth defect for children conceived by assisted reproductive technology in Taiwan. Methods: Both National ART report database and National birth reports were obtained from the Health Promotion Administration in the Ministry of Health and Welfare in Taiwan. The cohort included live births (n = 1,405,625) and children conceived by ART (n = 50,988/172,818 cycles) from 2011 to 2017. The prevalence of low birth weight, preterm birth, and birth defect were compared between the ART and natural pregnancy groups. Results: Children conceived by ART displayed a higher rate of low birth weight as compared to those in the natural pregnancy group (p < 0.001), even when analyses were restricted to singleton births (p < 0.001). A higher rate of preterm birth (p < 0.001) was also observed in children conceived by ART even when analyses were restricted to singleton births (p < 0.05). A significant increased rate of birth defects was noted from children conceived by ART (p < 0.05). Conclusions: With the increasing need for and use of ART-conceptions, the likelihood of risks induced or related to Assistant Reproductive Technology (ART) has drawn considerable attention in recent years. Taiwan, as one of the leading countries with outstanding ART performances and modern medical care, the result of the current study suggests that further consideration and tighter regulations and policy are needed with regard to the use of ART.

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

Electrochemical substrate for active profiling of cellular surface leucine aminopeptidase activity and drug resistance in cancer cells.

Leucine aminopeptidase (LAP) is an essential proteolytic enzyme and potential biomarker for liver malignancy. Overexpression of LAP is directly linked with some fatal physiological and pathological disorders. In this regard, we have designed an activity based electrochemical substrate leucine-benzyl ferrocene carbamate (Leu-FC) for selective profiling of LAP activity in live cells. In practice, LAP instantaneously hydrolyze the Leu residue of the substrate Leu-FC to eliminate the unmasked electrochemical reporter amino ferrocene via predefined self-immolative cascade. The electrochemical signal is distinctly specific for LAP and free of other electroactive biological interference. The substrate Leu-FC empowered sensor displayed broad dynamic range with admirable detection limits. On top of this, the probe Leu-FC was employed in real-time active profiling of cellular LAP activity in HepG2 cells and effect of LAP inhibitor. In extent, the substrate Leu-FC can effectively monitor cisplatin induced overexpression of LAP activity in HepG2 cells in presence and absence of bestatin. The sensor showcased an excellent reliability towards monitoring cellular LAP activity in HepG2 cells. Unlike the traditional antibody-based immunoassays, our approach is capable of monitoring in-situ activity of LAP in live cells.

Live birth in male de novo Kallmann syndrome after cross-generational genetic sequencing.

PURPOSE: To present the first case proposing the use of preimplantation genetic testing for monogeneic disorders for Kallmann syndrome, providing comprehensive care in the genomic era of precision medicine. METHODS: Gonadotropin therapy was used for spermatogenesis, followed by in vitro fertilization by intracytoplasmic sperm injection and embryo transfer. Cross-generational targeted next-generation sequencing was then done for genes known to cause Kallmann syndrome. RESULTS: A heterozygous mutation at codon 102 of the FGFR1 gene was found in the patient, but the father was found to have the same mutation yet is unaffected by Kallmann syndrome. Since no causative mutation was found, a de novo or sporadic mutation was suspected as the cause of Kallmann syndrome in this case. CONCLUSIONS: Comprehensive care must be available for male Kallmann syndrome patients, as treatment should not stop at spermatogenesis, but continue with genetic counseling due to possible inheritance.

Healthy live births after mosaic blastocyst transfers with the use of next-generation sequencing.

OBJECTIVE: To determine whether transfer of high-mosaicism (≥50%) embryos can result in healthy newborns. CASE REPORT: Two embryos resulting from controlled ovarian stimulation (COS) in Patient one, 41 years of age (y/o), underwent preimplantation genetic testing for aneuploidy (PGT-A), which demonstrated that one was mosaic (68%) and the other aneuploid; the mosaic embryo was transferred. Amniocentesis at 18 weeks of gestational age (GA) revealed a normal 46, XY karyotype. A phenotypically normal boy was delivered at 39 and 5/7 weeks of GA. For Patient two, 39 (y/o), nine embryos obtained after COS underwent PGT-A, indicating one euploid, four mosaic, and four aneuploid embryos. One euploid and one mosaic (50%) embryo were transferred, resulting in a twin pregnancy. Amniocentesis at 18 weeks of GA showed both fetuses had normal 46, XY karyotypes. Two phenotypically normal boys were delivered at 37 2/7 weeks of GA. CONCLUSION: Transfer of high-mosaicism embryos selected using current techniques can result in healthy euploid newborns. Amniocentesis suggested that mosaic embryos can be self-corrected before 18 weeks of GA.

Hyperreactio luteinalis mimicking malignancy during pregnancy with elevated CA-125.

OBJECTIVE: To report a case with benign bilateral ovarian tumor during pregnancy mimicking malignancy. CASE REPORT: A 32-year-old women at 20 weeks gestation with large bilateral adnexal masses found on prenatal ultrasound. The cysts had been growing gradually over the course of the pregnancy. MRI show huge multiple cysts in both ovaries. CA-125 was elevated at 260 U/mL. Due to initial impression was malignancy, an excisional surgery was done. Pathology revealed multiple luteinized granulosa cells with benign nature. CONCLUSION: Hyperreactio luteinalis (HL) is often asymptomatic and discovered incidentally on ultrasound or at the time of cesarean section. As the lesions are self-resolving, management is conservative and surgical intervention is required only in cases with severe complications. HL can be mistaken for malignancy, especially in cases in which the tumor marker CA-125 is elevated, leading to inadvertent surgery.

A novel strategy of using corifollitropin alfa in the ultrashort gonadotropin-releasing hormone agonist (GnRHa) protocol in unselected patients: A patient-friendly alternative.

OBJECTIVE: To compare the outcomes of in vitro fertilization (IVF) and fresh embryo transfer (ET) using corifollitropin alfa in ultrashort gonadotropin-releasing hormone agonist (GnRHa) protocol and GnRH antagonist protocol. MATERIALS AND METHODS: A total of 245 unselected patients undergoing IVF/fresh ET were enrolled between January 1 and December 31, 2017, including 135 treated with ultrashort GnRHa protocol and 110 treated with antagonist protocol. The primary outcomes were number of total injections and outpatient department (OPD) visits before ovulation triggering. The secondary outcomes were the duration of stimulation, dosage of additional gonadotropin for ovarian hyperstimulation, rates of pregnancy, clinical pregnancy, live birth, ovarian response, and ovarian hyperstimulation syndrome (OHSS) rate. RESULTS: Patients treated with ultrashort GnRHa required less additional gonadotropin, fewer total injections, but had better ovarian responses, including more oocytes retrieved, more metaphase II oocytes, and more blastocysts than those treated with antagonist did. A premature LH surge occurred only in six patients treated with antagonist protocol. The rates of pregnancy (37.0% vs. 43.6%), clinical pregnancy (25.2% vs. 34.6%), and live birth (19.3% vs. 30.0%) did not differ significantly between the two groups. The OHSS rate was similar in the two groups. CONCLUSION: In unselected patients using corifollitropin alfa, the ultrashort GnRHa protocol needed lower dose of additional gonadotropin and fewer injections but produced similar pregnancy outcomes than antagonist protocol did, suggesting that the ultrashort GnRHa protocol could be an alternative.

Primary peritoneal carcinosarcoma: A report of two cases.

OBJECTIVE: Carcinosarcomas also known as malignant mixed mullerian tumors (MMMTs) contain both carcinomatous and sarcomatous elements. Most MMMTs are arising from female genital tract, including ovaries, uterus and fallopian tubes. Extragenital carcinosarcomas are extremely rare, with an estimation less than 40 cases so far. CASE REPORT: We report two cases of primary peritoneal carcinosarcomas. An 81-year-old woman with pelvic peritoneal carcinosarcoma, heterologous type, was treated with incomplete surgery without further chemotherapy, and died of disease soon. The other one was a 76 year-old woman with abdominal peritoneal carcinosarcoma, homologous type. After optimal debulking surgery and subsequent 6 cycles of combination of paclitaxel and carboplatin chemotherapy, the patient is free of tumor half of year. CONCLUSION: Active therapy, including complete cytoreduction surgery and carboplatin-paclitaxel chemotherapy might offer a chance of disease control for these unusual primary peritoneal carcinosarcomas.

Dual triggering with GnRH agonist plus hCG versus triggering with hCG alone for IVF/ICSI outcome in GnRH antagonist cycles: a systematic review and meta-analysis.

PURPOSE: To summarize available evidence from randomized-controlled trials which have evaluated triggering of final oocyte maturation with concomitant GnRH agonists and hCG in patients undergoing IVF, and to analyze whether dual triggering is as efficacious as hCG triggering in terms of oocyte and pregnancy outcomes. METHODS: A comprehensive literature search was performed to identify randomized-controlled trials comparing IVF outcomes between women receiving combined administration of hCG with GnRH agonists and those receiving hCG alone for triggering of final oocyte maturation. RESULTS: Four studies including 527 patients eligible for inclusion in meta-analysis were identified. No significant difference in the number of mature oocytes or fertilized oocytes retrieved was found between groups. Clinical pregnancy rate with dual triggering was significantly higher as compared with hCG-alone triggering (pooled OR = 0.48, 95% CI 0.31-0.77, P = 0.002), but there was no significant difference in the ongoing pregnancy rate between groups. CONCLUSION: Results of meta-analysis indicate comparable or significantly improved outcomes with the use of GnRH agonists plus hCG as compared with hCG alone for triggering of final oocyte maturation.

Improvement of overactive bladder symptoms: Is correction of the paravaginal defect in anterior vaginal wall prolapse necessary?

BACKGROUND: To explore the relationship between overactive bladder (OAB) symptoms and paravaginal defects (PVDs), and to identify the necessity of PVD repair by transvaginal mesh (TVM) for the treatment of OAB symptoms. METHODS: A retrospective clinical study of 30 women with advanced cystocele with limited apical and posterior vaginal wall prolapse was conducted to identify any changes in OAB symptoms following a single Perigee procedure. Prolapse was assessed using the pelvic organ prolapse quantification (POP-Q) system, and paravaginal defects were identified by sonography. Complete urodynamic examination was performed prior to and one year after operation. All patients completed the overactive bladder questionnaire pre- and postoperatively for a quantitative assessment of OAB symptoms. RESULTS: All patients showed a significant improvement at points Aa and Ba in the POP-Q system. The results of the administered questionnaire revealed statistically significant improvement postoperatively. The difference of OAB symptoms between the group with PVDs and that with central defects was not statistically significant (p = 0.67). Moreover, no statistically significant improvement of OAB symptoms in the group with repaired PVDs was observed postoperatively (p = 0.42). CONCLUSION: Statistical improvements of symptoms exist after Aa and Ba points recovery as evaluated by POP-Q system regardless of PVD existence identified by sonography. Repairing PVD did not show significantly improve the severity of OAB symptoms in objective urodynamic data or subjective questionnaire data. The superiority of TVM in PVD repair to manage OAB symptoms seems not manifest.

Learning from Ambiguously Labeled Face Images.

Learning a classifier from ambiguously labeled face images is challenging since training images are not always explicitly-labeled. For instance, face images of two persons in a news photo are not explicitly labeled by their names in the caption. We propose a Matrix Completion for Ambiguity Resolution (MCar) method for predicting the actual labels from ambiguously labeled images. This step is followed by learning a standard supervised classifier from the disambiguated labels to classify new images. To prevent the majority labels from dominating the result of MCar, we generalize MCar to a weighted MCar (WMCar) that handles label imbalance. Since WMCar outputs a soft labeling vector of reduced ambiguity for each instance, we can iteratively refine it by feeding it as the input to WMCar. Nevertheless, such an iterative implementation can be affected by the noisy soft labeling vectors, and thus the performance may degrade. Our proposed Iterative Candidate Elimination (ICE) procedure makes the iterative ambiguity resolution possible by gradually eliminating a portion of least likely candidates in ambiguously labeled faces. We further extend MCar to incorporate the labeling constraints among instances when such prior knowledge is available. Compared to existing methods, our approach demonstrates improvements on several ambiguously labeled datasets.