Marcia A. Ciccone

Time interval between endometrial biopsy and surgical staging for type I endometrial cancer: association between tumor characteristics and survival outcome.

OBJECTIVE: To examine whether wait time between endometrial biopsy and surgical staging correlates with tumor characteristics and affects survival outcomes in patients with type I endometrial cancer. METHODS: A retrospective study was conducted to examine patients with grade 1 and 2 endometrioid adenocarcinoma diagnosed by preoperative endometrial biopsy who subsequently underwent hysterectomy-based surgical staging between 2000 and 2013. Patients who received neoadjuvant chemotherapy or hormonal treatment were excluded. Time interval and grade change between endometrial biopsy and hysterectomy were correlated to demographics and survival outcomes. RESULTS: Median wait time was 57 days (range 1–177 days) among 435 patients. Upgrading of the tumor to grade 3 in the hysterectomy specimen was seen in 4.7% of 321 tumors classified as grade 1 and 18.4% of 114 tumors classified as grade 2 on the endometrial biopsy, respectively. Wait time was not associated with grade change (P>.05). Controlling for age, ethnicity, body habitus, medical comorbidities, CA 125 level, and stage, multivariable analysis revealed that wait time was not associated with survival outcomes (5-year overall survival rates, wait time 1–14, 15–42, 43–84, and 85 days or more; 62.5%, 93.6%, 95.2%, and 100%, respectively, P>.05); however, grade 1 to 3 on the hysterectomy specimen remained as an independent prognosticator associated with decreased survival (5-year overall survival rates, grade 1 to 3 compared with grade change 1 to 1, 82.1% compared with 98.5%, P=.01). Among grade 1 preoperative biopsies, grade 1 to 3 was significantly associated with nonobesity (P=.039) and advanced stage (P=.019). CONCLUSION: Wait time for surgical staging was not associated with decreased survival outcome in patients with type I endometrial cancer. LEVEL OF EVIDENCE: II

Calcium/calmodulin-dependent kinase II regulates the interaction between the serotonin transporter and syntaxin 1A.

Plasma membrane serotonin transporters (SERTs) regulate serotonin (5HT) levels in brain and are a site of action of antidepressants and psychostimulant drugs of abuse. Syntaxin 1A is a component of the synaptic vesicle docking and fusion apparatus and has been shown to interact with multiple plasma membrane neurotransmitter transporters including SERT. Previously, we showed that syntaxin 1A regulates the transport stoichiometry of SERT. When not bound to syntaxin 1A, SERT shows both substrate-independent Na(+) fluxes and substrate-dependent Na(+) fluxes of variable stoichiometry; these fluxes are eliminated in the presence of syntaxin 1A as Na(+) flux becomes strictly coupled to 5HT uptake. However, not known are the endogenous signaling molecules that determine the conducting states that SERT exhibits. In the present experiments, we show that inhibitors of calcium/calmodulin-dependent kinase II (CaM kinase II) modulate the stoichiometry of 5HT flux and that this effect requires syntaxin 1A. The modulation correlates with a shift in the affinity of SERT for syntaxin 1A binding. The regulation by CaM kinase II is eliminated by a mutation in the N-terminal domain of SERT. In neonatal thalomocortical neurons that endogenously express SERT and syntaxin 1A, inhibition of CaM kinase II reveals SERT-mediated currents. These data suggest that calcium-mediated signals can serve as a trigger for regulating protein-protein interactions that control SERT conducting states.

Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature

ABSTRACT Introduction: While serine-threonine kinases (STK) are attractive therapeutic targets in epithelial ovarian cancer, clinical outcomes of STK inhibitors in the management of recurrent disease have not been completely described. Areas covered: A systematic literature review of published clinical studies on STK inhibitors targeting mTOR, MAPK, and aurora kinase pathways in recurrent epithelial ovarian cancer was conducted, revealing 18 clinical trials (497 patients). Pooled analyses were performed to assess treatment response, survival time, and adverse events. Median progression-free survival was 3.4 months in STK inhibitor-based therapy, and the average response rate and clinical benefit rate were 13% and 67%, respectively. Among regimens comprised of only STK inhibitors (11 trials, 299 patients), median progression-free time was 2.7 months, response rate was 10%, and clinical benefit rate was 64%. Compared to single STK inhibitor monotherapy (52.5%), clinical benefit rates significantly improved when STK inhibitors were combined with a cytotoxic agent (71.4%), other class biological agent (74.2%), or an additional STK inhibitor (95.0%) (all, P ≤ 0.002). Expert opinion: STK inhibitor-based therapy showed modest activity for recurrent epithelial ovarian cancer with reasonable clinical benefit rates, suggesting its potential utility for maintaining disease stability if supported by future studies. Efficacy appears greatly improved in appropriately selected patient populations, especially those with low-grade serous ovarian carcinoma, platinum-sensitive disease, cancers with somatic RAS or BRAF mutations, and when used in a combination regimen with a cytotoxic or biological agent.

Toe metastasis: A rare pattern of cervical cancer spread☆

Highlights • Toe metastasis is a rare pattern of cervical cancer spread.• Enlarged erythematous toe is an important sign suggesting bone metastasis.• Toe metastasis represents a grave prognostic indicator of cervical cancer.

Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series

Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent müllerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51–64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers.

Successful resuscitation after cardiac arrest secondary to carboplatin infusion: A case report

Highlights • Sudden cardiac arrest can be a form of carboplatin hypersensitivity reaction.• Platinum retreatment and cumulative cycles of ≥ 8 are risk factors.• Awareness of the reaction related to carboplatin infusion is necessary.• Successful resuscitation with high quality CPR is achievable with trained staffs.

Prolonged intubation after robotic-assisted hysterectomy for endometrial cancer: Case reports

Highlights • Experienced prolonged intubation after robotic hysterectomy for endometrial cancer• Risk triad: Trendelenburg position, high pneumo-pressure, and excess hydration• Recognition of the risk triad is key to avoiding airway complications in robotic surgery.• Introduction of a 5-step method to prevent airway complications in robotic surgery

Outcomes of Treatment for Endometrial Hyperplasia in Women Younger Than Age 35 Years

INTRODUCTION: The objective of this study was to describe treatment outcomes in young women with endometrial hyperplasia. METHODS: A retrospective cohort study of women younger than 35 years with a biopsy diagnosis of endometrial hyperplasia was performed. Demographics, treatment, and histopathology were compared. The institutional review board at the University of Southern California approved this protocol. RESULTS: Two hundred twenty-three patients were identified: 70 atypical and 153 nonatypical endometrial hyperplasia. Mean age was 29.9±4.1 years, and mean body mass index was 40.1±10.5 kg/m2. There was no difference between groups in age, body mass index, gravidity, or parity. Women with atypical endometrial hyperplasia were more likely to have diabetes (25.7% compared with 13.7%, P=.037) and to have a thicker endometrium on ultrasound examination (15.2 mm compared with 12.1 mm, P=.03). Forty-six (20.6%) women had one biopsy and were lost to follow-up. For women managed nonsurgically, the median number of biopsies was four (range one to 22) and the mean follow-up was 24.1±23.3 months. The most common treatment was systemic progestin therapy (75.6%). Among women treated for nonatypical endometrial hyperplasia, the most recent biopsy was benign in 64 of 102 (62.7%), nonatypical in 24.5%, atypical in 11.8%, and cancer in 1.0%. Among women treated for atypical endometrial hyperplasia, the most recent biopsy was benign in 30 of 56 (53.6%), nonatypical in 19.6%, atypical in 17.9%, and cancer in 8.9%. CONCLUSIONS: After 2 years of treatment, nonatypical endometrial hyperplasia rarely progresses to cancer, but 11.8% progress to atypical endometrial hyperplasia. Atypical endometrial hyperplasia progresses to cancer in 8.9% of patients despite treatment. A high lost-to-follow-up rate highlights the need for aggressive counseling and outreach in this high-risk population.