Detection rates and factors affecting thereof in endometrial hyperplasia, endometrial carcinoma, and cervical glandular lesions on cervical smear.

INTRODUCTION: Endometrial lesions are morphologically diverse and uncommon on cervical smears, with its detection rate and associated diagnostic categories uncharacterized. In this study, cervical smears matched to histologically proven endometrial hyperplasias and carcinomas were reviewed and compared with cervical in-situ-carcinomas/carcinomas, aiming to detail the diagnostic performance of cervical smears for upper tract and glandular lesions. METHODS: Pathology reports of cervical smears, hysterectomies, endometrial and cervical biopsies from 1995 to 2021 were retrieved. Diagnoses of cervical smears were matched to endometrial hyperplasias and carcinomas, or cervical carcinomas and reviewed. RESULTS: Totally 832 cervical smears (272 cervical carcinomas, 312 endometrial carcinomas, and 248 hyperplasias) were included. Considering all cytologic glandular diagnosis as positive, the detection rate of cervical adenocarcinoma-in-situ was the highest (64.3%), followed by cervical adenocarcinoma (63.8%), endometrial carcinoma (31.7%), and hyperplasia (with atypia-8.5%; without atypia-2.3%) (p < 0.001). Endometrial hyperplasia was most often diagnosed as atypical squamous cells of undetermined significance (ASCUS) (5.0%) or atypical glandular cells, not otherwise specified (3.6%) without indication of endometrial origin. For endometrial carcinomas, higher FIGO grading and endocervical involvement were associated with higher detection rates across all diagnostic categories (p = 0.002-0.028). High FIGO grade was associated with suspicious/favor neoplastic (C4) (31.1%vs10.3%, p < 0.001) and carcinoma (C5) (17.8% vs. 5.6%, p = 0.005) categories, but not for all glandular diagnoses combined (33.3% vs. 31.0%, p = 0.761). CONCLUSION: Detection rates for endometrial lesions are lower than cervical lesions but not insignificant. Endometrial hyperplasia should be recognized as a differential of human papilloma virus-negative ASCUS and prompt consideration of investigation of the upper genital tract.

Number Needed to Diagnose in Malignant Ascites: Effects of Volume, Repeating Collection, and Primary Malignancy on Diagnostic Performance in Peritoneal Fluid Cytology.

INTRODUCTION: Volume recommendations of 80-200 mL have been proposed for peritoneal fluid cytology. While cutoffs are impractical when volume is limited by the amount present and disease factors, collections, however, can be repeated. This study addresses adequacy and number needed to diagnose by comparing diagnostic agreement to volumes in single specimens, total volumes collected daily, and within admissions. The diagnostic yield of repeating collection within a single day, admission, and throughout admissions of a patient's lifetime was also investigated. METHODS: Peritoneal fluid cytology specimens over a 27-year period were retrieved and matched by collection date, admission number, and patient number. Case notes were reviewed to establish all cases of malignant ascites. RESULTS: In total, 19,392 specimens from 14,327 admissions and 11,089 patients were retrieved, with 1,531 patients confirmed with malignant ascites. Agreements between cytologic diagnoses within the same day and admission were high (κ > 0.8). Fluid volume increased with grade of cytologic diagnosis (p < 0.001), and greater volume was associated with higher discordance (p < 0.05). Specimens of 60-100 mL showed the best diagnostic concordance. To achieve a 99.5% diagnostic rate, three sequential aliquots, collections from two different days in an admission, or three admissions within a lifetime are required. The diagnostic yield of one aliquot within batches from the same day was only 88.9%. Gastrointestinal (p = 0.040), gynecologic (p = 0.005), and lung (p < 0.001) malignancies required the least repeats for diagnosis. CONCLUSIONS: Omission of any fluid from laboratory submission is strongly discouraged. As a simple rule, three repeats are necessary for excluding malignant ascites.

Dissection of PIK3CA Aberration for Cervical Adenocarcinoma Outcomes.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in PIK3CA E542K, E545K, or H1047R were detected in 41.7% of tumors. PIK3CA mutation detected in the patient's circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. PIK3CA mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of PIK3CA mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women's cancer.

A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis.

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).

Uterine Carcinosarcoma with Alpha-Fetoprotein-Producing Hepatoid Component: A Case Report and Literature Review.

A 67-year-old woman presented with postmenopausal vaginal bleeding. Full body imaging demonstrated an intrauterine mass with deep myometrial invasion but no nodal or other metastatic disease. Uterine curettage was performed. Histologically, the tumor was an endometrioid adenocarcinoma with sarcomatous element and a hepatoid component, the latter was immunohistochemically positive for alpha-fetoprotein, HepPar-1, and arginase-1. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Serum alpha-fetoprotein level decreased from 31896 ug/l preoperatively to 2063 ug/l postoperatively. Eight weeks later, a rise in serum alpha-fetoprotein was detected, and a biopsy-proven vaginal recurrence was diagnosed. Palliative chemotherapy led to tumor shrinkage and a concurrent decrease in the serum alpha-fetoprotein level. A rise in serum alpha-fetoprotein, refractory to second-line chemotherapy, was accompanied by subsequent development of ureteric obstruction, ascites, and radiological evidence of peritoneal metastases. This is an unusual case of uterine carcinosarcoma with an alpha-fetoprotein-producing hepatoid adenocarcinoma component. Serum alpha-fetoprotein level corresponds to disease recurrence and progression.

Vaginal Pessary in Women With Symptomatic Pelvic Organ Prolapse: A Randomized Controlled Trial.

OBJECTIVE: To compare pelvic floor symptoms, quality of life, and complications in women with symptomatic pelvic organ prolapse (POP) with or without vaginal pessaries in addition to those who do pelvic floor exercises for 12 months. METHODS: This was a parallel-group, single-blind, randomized controlled trial with 12 months of follow-up. Women with symptomatic stage I to stage III POP were randomized to either pelvic floor exercises training (control group) or pelvic floor exercises training and insertion of a vaginal pessary (pessary group). The primary outcome was the change of prolapse symptoms and quality of life by using the Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaires. Secondary outcomes included bothersome of prolapse symptoms, desired treatment, and any complications. RESULTS: From December 2011 through November 2014, 311 women were screened and 276 were randomized as follows: 137 to the control and 139 to the pessary group. One hundred thirty-two (95.0%) women in the pessary group and 128 (93.4%) in the control group completed the study. The Pelvic Organ Prolapse Distress Inventory of Pelvic Floor Distress Inventory and the Pelvic Organ Prolapse Impact Questionnaire of Pelvic Floor Impact Questionnaire scores decreased in both groups after 12 months, but the mean score differences were higher in the pessary group (Pelvic Organ Prolapse Distress Inventory: -29.7 compared with -4.7, P<.01; Pelvic Organ Prolapse Impact Questionnaire: -29.0 compared with 3.5, P<.01). Complication rates were low and similar in both groups. CONCLUSION: We provided further evidence in nonsurgical treatment for POP. Prolapse symptoms and quality of life were improved in women using a vaginal pessary in addition to pelvic floor exercises. CLINICAL TRIAL REGISTRATION: Centre for Clinical Research and Biostatistics-Clinical Trials Registry, https://www2.ccrb.cuhk.edu.hk/web/?page_id=746, ChiCTR-TRC-11001796.

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

OBJECTIVES: The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. BACKGROUND: Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. METHODS: In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). RESULTS: The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. CONCLUSIONS: Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565).

A pilot study of urine cytokines in ketamine-associated lower urinary tract symptoms.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate urine cytokine and chemokine levels in symptomatic ketamine abusers compared with age-matched controls. METHODS: Midstream urine specimens were collected in a prospective study of 23 ketamine abusers and 27 controls who had never used ketamine. Their basic demographic and urinary symptoms were compared. The urine was analyzed by a multiplex panel screen for 19 cytokines/chemokines: EGF, GM-CSF, GRO, IL-1Ra, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IP-10, MCP-1, MIP-1b, sCD40L, sIL-2Ra, VEGF, MCP-4, and TARC using Luminex™ xMAP® technology. Protein concentration values were normalized to urine creatinine concentrations. RESULTS: Mean age of the control group was 21.1 ± 4.3 years (n = 27) and of the ketamine group was 20.6 ± 3.7 years (n = 23). All participants were women. The urine cytokine analysis showed a significant elevation in EGF levels in the ketamine group with lower urinary tract symptoms (LUTS) compared with the control group (p < 0.005). Levels of the remaining 18 proteins tested were not different from control values. CONCLUSIONS: Urinary EGF levels were increased among symptomatic ketamine abusers. This suggests inflammation and epithelial repair may play a role in ketamine-associated LUTS, and this may in turn help in understanding the pathophysiology of this disease entity, leading to better treatment options.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.

BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. FUNDING: Cytokinetics Inc.

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc.