Endometrial cancer recurrence after the use of a uterine manipulator during laparoscopic surgery.

Objective: Minimally invasive surgery (MIS) is the standard approach for the staging and treatment of early-stage endometrial cancer (EC) and often includes use of a uterine manipulator. Uterine perforation is a known risk in this setting, and the impact of perforation and tumor spillage on cancer recurrence is largely unknown. The aim of this study was to assess the association between uterine perforation and/or tumor spillage at the time of MIS for low-grade, early-stage EC on disease recurrence. Methods: A retrospective single-center cohort study was conducted including patients who underwent MIS for management of low-grade and early-stage EC with use of a uterine manipulator. Rates of disease recurrence were compared between patients with and without documented uterine perforation and/or tumor spillage at the time of surgery. Statistical significance was defined as p < 0.05. Results: 408 patients with low-grade and early-stage EC were identified from the tumor registry and included in the study. Uterine perforation and/or tumor spillage was documented in 5.9 % (24/408) of cases. Recurrent disease was noted in 8.1 % (33/408) of the entire cohort. Most patients had isolated local recurrence (23/33; 69.7 %), while 9.1 % (3/33) had distant recurrence and 21.2 % (7/33) had both local and distant recurrence. There was no association between uterine perforation and/or tumor spillage and recurrence rates (p = 0.67). The trend in disease free survival was shorter among patients with these complications. Conclusions: Our analysis did not demonstrate a statistically significant difference in disease recurrence rates among patients with early-stage, low-grade EC based on uterine perforation and/or tumor spillage at the time of surgery.

Qualitative results from a randomized pilot study of eHealth Mindful Movement and Breathing to improve gynecologic cancer surgery outcomes.

PURPOSE: Improved management of pain and co-morbid symptoms (sleep disturbances, psychological distress) among women undergoing surgery for suspected gynecologic malignancies may reach a population vulnerable to chronic pain. PARTICIPANTS: Women undergoing surgery for a suspected gynecologic malignancy. METHOD: We conducted a pilot randomized controlled trial of eHealth Mindful Movement and Breathing (eMMB) compared to an empathic attention control (AC). Semi-structured interviews were conducted by telephone (n = 23), recorded, transcribed, coded, and analyzed using thematic analysis. FINDINGS: Participants reported overall high acceptability such that all would recommend the study to others. Positive impacts of practicing eMMB included that it relieved tension, facilitated falling asleep, and decreased pain. Participants also reported high adherence to self-directed eMMB and AC writing practices and described facilitators and barriers to practicing. CONCLUSIONS: This qualitative feedback will inform future research to assess the efficacy of eMMB for reducing pain and use of remotely-delivered interventions more broadly. CLINICAL TRIAL REGISTRATION NUMBER: NCT03681405.

HIPEC after neoadjuvant chemotherapy is associated with acceptable toxicity and favorable quality of life in newly diagnosed advanced ovarian cancer patients.

OBJECTIVE: To evaluate toxicity, quality of life and PFS in patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by CRS and HIPEC with carboplatin. METHODS: Patients with stage IIIC or IVA epithelial ovarian cancer, who were not candidates for primary CRS, were enrolled in this phase two trial. Patients received 3-6 cycles of NAC with an IV carboplatin doublet followed by CRS with HIPEC (carboplatin 800 mg/m2 for 90 min). They were followed for at least 12 months to assess for adverse events, quality of life (QOL) and disease progression. QOL was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires prior to CRS and post-operatively at 6 weeks, 3 months, and 6 months after CRS. RESULTS: Twenty patients were enrolled. HIPEC was completed successfully in all twenty patients, and there was no peri-operative mortality. Twelve (70.6%) patients experienced a grade 3 or 4 toxicity; most commonly anemia (59%), thrombocytopenia (29%), and hypokalemia (24%). There was no significant change between the pre-operative and postoperative 6 weeks, 3 month, and 6 month FACT-O, NTX, and AD scores. Nine (45%) patients have experienced disease recurrence to date. The median progression free survival in this cohort is 11.2 months (2.5-23.7 months). CONCLUSION: The addition of HIPEC with carboplatin to interval CRS was well tolerated in patient population. Myelosuppression was the most common adverse event. CRS with HIPEC did not adversely impact these patients' QOL indices. The efficacy of this regimen should be further evaluated in a larger clinical trial.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

PURPOSE: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment. METHODS: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk. RESULTS: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI. CONCLUSIONS: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.

Preoperative Circulating Lymphocyte and Monocyte Counts Correlate with Patient Outcomes in Type I and Type II Endometrial Cancer.

Tumor-associated macrophages and tumor-infiltrating lymphocytes are associated with survival in solid malignancies. Given the physiological link to peripheral immune cell counts, we evaluated if peripheral immune cell counts were predictors of outcomes in endometrial cancer. A retrospective study was completed for endometrial cancer cases between 2000 and 2010. Kaplan-Meier, bivariate, and multivariable Cox proportion hazard analyses were performed examining the relations between survival and peripheral immune cell counts. Three hundred ten patients were identified. In bivariate analyses, high monocyte counts (> 0.7 × 109 cells/L) trended with decreased progression free survival (PFS) (p = 0.10) and poorer overall survival (OS) (p = 0.16). By contrast, high lymphocyte level (> 1.5 × 109 cells/L) was associated with improved PFS (p = 0.008) and OS (p = 0.006). These findings were consistent for type I and type II endometrial cancers. In a multivariable Cox model, high monocyte level was associated with a greater risk of disease recurrence (hazard ratio (HR) = 1.63, p < 0.035). Other significant predictors of recurrence were age, non-endometrioid histology, and the presence of lymph vascular space invasion (LVSI). In a multivariable Cox model, high lymphocyte count trended with a lower risk of death (HR = 0.66, p = 0.07). Age, surgical stage, non-endometrioid histology, and LVSI were also associated with death in this model. In this sample of endometrial cancer patients, we found that high preoperative lymphocyte counts were associated with improved overall improved survival. High monocyte counts were associated with poorer disease-free survival outcomes. Further studies that focused on understanding tumor-antagonizing and pro-tumoral effects of lymphocytes and monocytes, respectively, in endometrial cancer are recommended.

Identification of orally-bioavailable antagonists of the TRPV4 ion-channel.

Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-1665 23 and RN-9893 26, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-9893 26, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications.

Serum Calcium and Serum Albumin Are Biomarkers That Can Discriminate Malignant from Benign Pelvic Masses.

BACKGROUND: Biomarkers that aid in the differential diagnosis of malignant pelvic masses from benign ones prior to surgery are needed in order to triage women with malignant masses to appropriate specialist care. Because high albumin-adjusted serum calcium predicted ovarian cancer among women without evidence of disease, we hypothesized that it might predict cancer among women with pelvic masses that were evident radiographically. METHODS: We studied a cohort of 514 women with pelvic masses who underwent resection at Wake Forest University Baptist Medical Center from July 2009 through June 2013. We divided patients into a "training" set, to identify associations in the data, and a "testing" set, to confirm them. Data were obtained from medical records. A best fit model was selected using the Akaike Information Criterion. RESULTS: Albumin-adjusted serum calcium was significantly higher in women with malignant versus benign masses (P = 0.0004). High normocalcemia, i.e., an albumin-adjusted serum calcium ≥ 10 mg/dL, occurred in 53% of women with malignant tumors versus 12% of benign tumors. High normocalcemia was associated with an approximately 14-fold increased risk of malignancy. The best fit model (Overa) included albumin, calcium, and nonlinear terms. Overa achieved an area under the curve of 0.83 with a sensitivity of 72% and specificity of 83%, a positive predictive value of 71% and a negative predictive value of 85%. CONCLUSIONS: A model using serum calcium and serum albumin to predict malignancy in women with pelvic masses has high sensitivity and is economical. IMPACT: Our model can help triage women with ovarian cancer to appropriate surgical care.

Xanthogranulomatous Oophoritis Presenting as an Adnexal Mass and Bowel Obstruction. A Case Report.

BACKGROUND: Xanthogranulomatous inflammation of the female genital tract is a rare entity. When the gynecological organs are affected, it is particularly unusual for xanthogranulomataus inflammation to involve only the ovary. CASE: A 45-year-old woman with an intrauterine device, long-term exposure to nicotine, and hyperlipidemia presented with an adnexal mass and bowel obstruction. She underwent 2 exploratory laparotomies, ureteral stent placement, left salpingooophorectomy, and rectosigmoid resection with end colostomy. Pathology revealed xanthogranulomatous oophoritis without involvement of the associated fallopian tube. CONCLUSION: The synergistic effects of intrauterine device use, abnormal lipid levels, and long-term nicotine exposure may have contributed to the development of this patient's condition. Knowledge of xanthogranulomatous inflammation is essential to avoid misdiagnosis of malignancy and excessive surgical intervention.

Type 2 Endometrial Cancer is Associated With a High Density of Tumor-Associated Macrophages in the Stromal Compartment.

INTRODUCTION: Tumor-associated macrophages (TAMs) play a pivotal role in orchestrating the microenvironment. The TAMs differentially polarize into M1 or M2 macrophages with distinct actions. The aim of our work is to characterize density, subtype, and location of TAMs in endometrial hyperplasia and cancer. METHODS: Formalin-fixed, paraffin-embedded sections of hyperplasia (n = 5), type 1 (n = 5), and type 2 (n = 5) endometrial cancer were stained with anti-CD68 and anti-CD163 monoclonal antibodies as markers for total TAMs and M2 TAMs, respectively. Macrophages were counted at 40× magnification in 10 high-power fields (HPFs) per slide by 4 observers. Repeated measures models were constructed to determine the relationships between macrophages and lesion categories. RESULTS: Most CD68+ TAMs were located in the stromal (mean = 41.0/HPF) compared to epithelial (mean = 11.0/HPF) or luminal (mean = 11.6/HPF) compartments. Similar but reduced findings were observed for CD163+ (M2 subtype) TAMs. The CD68+ stromal TAM density was highest in patients with type 2 cancers (mean = 54.0/HPF) compared to those with type 1 cancers (mean = 35.5/HPF) and hyperplasia (mean = 29.0/HPF). Women with hyperplasia had more CD163+ (M2 subtype) TAMs (26.7/HPF) than patients with either type of cancer (type 1 = 12.5/HPF and type 2 = 11.5/HPF). Based on the repeated measures models, type 2 cancers had 38.6/HPF more CD68+ TAMs than type 1 cancers (P < .0001) and type 1 and type 2 cancers had similar numbers of CD163+ TAMs (P = .27). CONCLUSIONS: Type 2 cancers have nearly twice the TAM density of type 1 cancers. This difference may be due to M1 macrophage predominance in the stroma of type 2 cancers.

Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers.

INTRODUCTION: Chemoresistance is a major limitation in the treatment of ovarian cancer. Phenoxodiol is a novel biomodulator capable of reversing chemoresistance in vitro and in vivo. In this study, we determined the safety and efficacy of intravenous phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant ovarian cancers. METHODS: Thirty-two patients were randomized to 1 of 2 treatment arms according to their previous responses: (1) platinum refractory/resistant, cisplatin (40 mg/m intravenous) weekly on day 2 + phenoxodiol (3 mg/kg) weekly on days 1 and 2 and (2) taxane refractory/resistant, paclitaxel (80 mg/m IV) weekly on day 2 and phenoxodiol (3 mg/kg) weekly on days 1 and 2. Patients continued on treatment until complete response, disease progression, unacceptable toxicity, or voluntary withdrawal. RESULTS: There were no treatment-related deaths. There was only one treatment-related hospitalization and 2 grade 4 toxicities. In the cisplatin arm, there were 3 partial responses, 9 patients (56%) achieved stable disease, 4 (25%) progressed, and the overall best response rate was 19%. In the paclitaxel arm, there was one complete response and 2 partial responses, 8 patients (53%) achieved stable disease, 4 patients (27%) progressed, and the overall best response rate was 20%. DISCUSSION: The combination of IV phenoxodiol with cisplatin or paclitaxel was well tolerated in this study. Cisplatin-phenoxodiol was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

Large cell neuroendocrine carcinoma of the cervix: prognostic factors and survival advantage with platinum chemotherapy.

OBJECTIVE: Large cell neuroendocrine carcinoma of the cervix (LCNEC) is a rare cervical neoplasm associated with poor survival. Our objective was to identify treatments associated with improved survival. METHODS: Relevant data were abstracted from an English literature MEDLINE search, SEER database, and a patient treated at our institution. Multivariate analysis was performed by generating Cox proportional hazard ratios. RESULTS: We identified 62 patients with LCNEC: 49 cases from the English literature, 12 patients in the SEER database and our patient. Out of the 62 women, median age was 37 (range, 21-75). FIGO stage was as follows: 58% had stage I disease, 16% had stage II, 2% had stage III, 8% had stage IV disease and 16% had no stage documented. Of all patients, 73% underwent primary surgery, 4.7% underwent primary radiation, 4.7% underwent chemotherapy, 8% had chemoradiation, and 9.6% had no primary treatment. Of all patients, 58% died of disease, 26% had no evidence of disease, 3% were alive with disease, and 13% had no survival data. The overall median survival was 16.5 months (0.5-151 months). Median overall survival for stage I, II, III, and IV cancers was 19, 17, 3, and 1.5 months, respectively. In a multivariate analysis, earlier stage (p<0.00001) and the addition of chemotherapy (p=0.04) were associated with improved survival. Both platinum agents (p=0.034) and platinum and etoposide together (p=0.027) were associated with improved survival. CONCLUSIONS: Perioperative chemotherapy, in particular platinum with or without etoposide, improves survival in the rare LCNEC.

The discovery of an orally efficacious positive allosteric modulator of the calcium sensing receptor containing a dibenzylamine core.

The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.

Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor.

AP18 1 was recently disclosed as an antagonist of the TRPA1 receptor by the research group of Patapoutian. However, no detailed structure-activity relationships around 1 have been disclosed. Thus, a small number of oximes related to AP18 were examined in order to characterize the determinants of TRPA1 activity. Congeners of AP18 were found to possess both agonist and antagonist activity, suggesting that AP18 may behave as a covalent antagonist of the TRPA1 ion-channel.

Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.

The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.

Identification and characterization of novel TRPV4 modulators.

TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies.

Preparation of heteroaryloxetanes and heteroarylazetidines by use of a Minisci reaction.

Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroaromatic bases was achieved by using a radical addition method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetidine into heteroaromatic systems that have found important uses in the drug discovery industry, such as the marketed EGFR inhibitor gefitinib, a quinolinecarbonitrile Src tyrosine kinase inhibitor, and the antimalarial hydroquinine.

Preparation of aryloxetanes and arylazetidines by use of an alkyl-aryl suzuki coupling.

The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.

Correlating efficacy in rodent cognition models with in vivo 5-hydroxytryptamine1a receptor occupancy by a novel antagonist, (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405).

5-Hydroxytryptamine (5-HT)(1A) receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT(1A) antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (K(i) = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT(1A) receptor antagonist (K(B) = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [(3)H]WAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT(1A) receptors in the rat cortex, with an ED(50) value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT(1A) receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT(1A) receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.

Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease.

OBJECTIVES: To compare the survival and peri-operative morbidities of patients with advanced epithelial ovarian cancer (EOC, stage IIIC and IV) who were treated with primary debulking surgery (PDS) followed by adjuvant platinum-based chemotherapy, or neoadjuvant chemotherapy followed by cytoreductive surgery (NAC). METHODS: 172 patients with advanced EOC diagnosed at YNHH (1998-2005) were retrospectively reviewed. 109 patients were treated with PDS and 63 patients were treated with NAC [37 received carboplatin/paclitaxel (CP), 26 received carboplatin/cyclophosphamide (CC)]. RESULTS: NAC patients had significantly less intra-operative blood loss, operating time, units of transfusion, and shorter hospital stay (p<0.05). Optimal cytoreduction was achieved in 95% NAC patients, versus 71% of PDS group (p<0.001). Three patients in the NAC group (5%) versus 27 patients (25%) in the PDS group required aggressive surgery in addition to standard cytoreduction. Within the NAC group, overall survival (OS) is improved in patients who received CP compared to CC (83 vs. 26 months, p=0.008). Patients with extra-abdominal disease who received CP as NAC had improved progression-free survival (PFS) and OS when compared to the PDS group with stage IV disease (15 vs. 9 months, p=0.015; 31 vs. 20 months, p=0.032, respectively). CONCLUSION: This study demonstrates that NAC is associated with less peri-operative morbidity, less need for further aggressive surgery, and similar survival. Additionally, in patients with extra-abdominal disease, NAC is associated with an improved PFS and OS. Therapy with platinum and taxane should be the treatment of choice in NAC.