Traits of patients seen via telemedicine versus in person for new-patient visits in a fertility practice.

OBJECTIVE: To assess the differences in demographics, the likelihood of receiving treatment, and the clinical outcomes between new patients seen via telemedicine and those seen in person in an academic fertility practice. DESIGN: Retrospective cohort study. SETTING: University-based fertility clinic. PATIENTS: All new patients seen via telemedicine between June 1, 2017, and February 29, 2020, were compared with an equal number of all new patients seen in person between May 1, 2019, and June 30, 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was receiving treatment after a new-patient visit. Binary logistic regression analyses were performed to estimate the odds ratio for not receiving treatment according to distance to the clinic and duration of infertility. The secondary outcomes included treatment recommendation, time to treatment initiation, and time to positive pregnancy test (if achieved). In addition we assessed patient demographics and visit traits per patient encounter. RESULTS: The telemedicine and in-person groups each contained 70 patients. The following were similar between the groups: age, body mass index, Area Deprivation Index, diagnosis made at the new-patient visit, and the number of clinic contacts before starting treatment. Compared with patients who had in-person new-patient visits, those who had telemedicine new-patient visits lived farther from the clinic (mean, 223.6 vs. 69.28 miles) and had a longer duration of infertility (mean, 41.9 vs. 19.49 months). No differences were noted between the groups in the following outcomes: percent that received treatment, time to treatment initiation, or time to pregnancy. Telemedicine new-patient visits were shorter than in-person new-patient visits (mean, 56.3 ± 9.1 vs. 59.3 ± 4.6 minutes) and less likely to contain documentation of height or weight. CONCLUSIONS: Telemedicine appears to be of particular interest to patients who live farther from clinics and have longer durations of infertility, and it could reduce visit times. New patients seen in person and those seen via telemedicine are equally likely to pursue treatment. Telemedicine consultation for new-patient visits is feasible in an academic fertility practice and may be especially useful during a pandemic and in non-pandemic times in areas with limited access to fertility specialists.

Association between arthritis treatments and ovarian reserve: a prospective study.

RESEARCH QUESTION: How do anti-Müllerian hormone (AMH) concentrations in women with and without arthritis compare? Is there an association between AMH and arthritis drug regimen? DESIGN: In this prospective cohort study, AMH was measured at two time points (T0 and T1) in 129 premenopausal women with arthritis. AMH at T0 was compared with that from a bank of serum samples from 198 premenopausal women without arthritis. Primary outcomes were: (i) diminished ovarian reserve (DOR) (AMH <1.1 ng/ml) and (ii) annual rate of AMH decrease. Univariate, multivariable and Firth logistic regression identified variables associated with annual AMH decrease in excess of the 75th percentile. RESULTS: Median time between T0 and T1 was 1.72 years. At time T0, median age-adjusted AMH in women with arthritis was significantly lower than that of women without arthritis (median 2.21 ng/ml versus 2.78 ng/ml; P = 0.009). Women with arthritis at highest risk for DOR had a history of tubal sterilization or were over the age of 35. Those with highest odds of having an annual AMH decrease in excess of the 75th percentile (over 28% decrease per year) were those: over the age of 35 or who sought care for infertility. Women with arthritis taking methotrexate alone (OR 0.08, 95% CI 0.01-0.67) or methotrexate plus tumour necrosis factor-alpha antagonists (OR 0.13, 95% CI 0.02-0.89) were less likely to be in the highest quartile of annual AMH decrease than women with arthritis not taking medication. CONCLUSIONS: Women with arthritis had lower AMH than healthy controls. Long-term methotrexate use was not associated with an annual AMH decrease.

Ovarian stimulation for fertility preservation in women with cancer: A systematic review and meta-analysis comparing random and conventional starts.

OBJECTIVE: In female cancer patients anticipating chemotherapy or radiation, oocyte retrieval for fertility should be performed as efficiently as possible to avoid postponing cancer treatments. Our objective was to compare clinical outcomes among female cancer patients who underwent a conventional early follicular phase-start ovarian stimulation cycle and those who underwent a random-start ovarian stimulation cycle. EVIDENCE REVIEW: A systematic review of the literature was performed in accordance with PRISMA guidelines. Medline, Embase.com, Scopus, Cochrane Library, and Clinicaltrials.gov databases were searched to identify all original research published in English through July 2020 on the topic of female cancer patients undergoing ovarian stimulation with a random or conventional start. Studies lacking a comparison group or including women who had already undergone chemotherapy at the time of ovarian stimulation were excluded. The primary author assessed all identified article titles and abstracts, and two independent reviewers assessed full-text articles and extracted data. A meta-analysis with a random-effects model was used to calculate weighted mean differences (WMDs) for outcomes of interest. The primary outcome was the number of mature (meiosis II) oocytes retrieved. Secondary outcomes included duration of stimulation, total dose of gonadotropins, total number of oocytes retrieved, fertilization rate, and number of embryos or zygotes cryopreserved. RESULTS: A total of 446 articles were screened, and 9 full-text articles (all retrospective cohort or prospective observational) were included for review. Additionally, pooled primary retrospective data from two institutions were included. In total, data from 10 studies including 1653 women were reviewed. Five studies reported the number of embryos cryopreserved, and four reported fertilization rates. Random-start cycles were slightly longer (WMD 0.57 days, 95 % confidence interval [CI] 0.0-1.14 days) and used more total gonadotropins (WMD 248.8 international units, 95 % CI 57.24-440.40) than conventional-start cycles. However, there were no differences in number of mature oocytes retrieved (WMD 0.41 oocytes, 95 % CI -0.84-1.66), number of total oocytes retrieved (WMD 0.90 oocytes, 95 % CI -0.21-2.02), fertilization rates (WMD -0.12, 95 % CI -1.22-0.98), or number of embryos cryopreserved (WMD 0.12 embryos, 95 %CI -0.98-1.22) between random-start and conventional-start cycles. All outcomes except for the parameter "total oocytes retrieved" yielded an I2 of over 50 %, indicating substantial heterogeneity between studies. CONCLUSION(S): Although random-start cycles may entail a longer duration of stimulation and use more total gonadotropins than conventional-start cycles, the absolute differences are small and likely do not significantly affect treatment costs. The similar numbers of mature oocytes retrieved, fertilization rates, and number of embryos cryopreserved in the two start-types suggest that they do not differ in any clinically important ways. Given that random-start cycles can be initiated quickly, they may help facilitate fertility preservation for cancer patients.

Recent trends in embryo disposition choices made by patients following in vitro fertilization.

PURPOSE: To assess longitudinal trends in in vitro fertilization (IVF) patients' choices for disposing of cryopreserved embryos. METHODS: This is a retrospective cohort study of embryo disposition forms submitted between January 2000 and February 2020 at a university-based fertility clinic. Primary outcome was disposition decision. Binary and multivariable logistic regression were performed to determine odds ratios (OR) for decisions according to female age, education, race, religion, state of residence, area deprivation index based on zip code, and IVF pregnancy history. We also assessed disposition year, storage duration, and number of stored embryos. RESULTS: Forms were reviewed from 615 patients; 50.6% chose to discard embryos, 45.4% donated to research, and 4.1% chose reproductive donation. In the regression model, two factors were significantly associated with donation to research: female listing "no preference" or declining to list religious preference (OR 2.56, 95%CI 1.44-4.54) and live birth of multiples after IVF (OR 1.58, 95%CI 1.05-2.36). Before 2012, females younger than age 30 at storage were equally likely to choose to donate embryos to research as discard them. However, between 2013 and 2020, females younger than 30 were significantly more likely to discard than donate embryos for research (OR 2.87, 95%CI 1.13-7.28). CONCLUSION: Since 2013, the majority of patients younger than 30 at storage have chosen to discard cryopreserved embryos. Before then, patients were more likely to donate embryos for research. To ensure sufficient embryos are available for research, young patients, who are most likely to have cryopreserved embryos, should be counseled about options for donation.

A digital media attention diversion improves mood and fear in patients receiving chemotherapy for recurrent gynecologic malignancies: results of a randomized trial.

BACKGROUND: Recurrent gynecologic cancer patients experience symptoms that affect psychologic, emotional, social, and physical well-being. Chemotherapy can further exacerbate these symptoms. Poor mood, pain, and fatigue are linked and are detrimental to quality of life. Interventions targeting these symptoms may improve patient-reported outcomes and performance status. OBJECTIVES: To determine the ability of a humorous digital media attention diversion to improve symptom domains of positive and negative mood during chemotherapy for patients with recurrent gynecologic cancers. STUDY DESIGN: This randomized, crossover clinical trial enrolled women with recurrent gynecologic cancers. Subjects participated over three cycles of chemotherapy. The primary outcome was the change in mood on the validated Positive and Negative Affect Scale-Extended (PANAS-X) instrument, which measures positive and negative affect domains. All subjects completed the PANAS-X after receiving chemotherapy during cycle 1 on study. In atudy arm 1, subjects watched their choice of humorous movies on a digital media device while receiving chemotherapy during cycle 2 on study. They selected from non-humorous movies during cycle 3 on study. In arm 2, the order of movies was reversed. After each cycle, mood, fatigue, and other patient-reported outcomes were assessed for comparison with baseline measurements. RESULTS: The target enrollment of 66 subjects was achieved. Subjects watched humorous content for an average of 96.0 min and non-humorous content for an average of 62.5 min. Negative mood improved after exposure to humorous (p=0.017) and non-humorous content (p=0.001). Patient-reported fear also improved after exposure to both humorous (p=0.038) and non-humorous content (p=0.002). Subjects reported higher use of affiliating and self-effacing humor types. CONCLUSIONS: Offering patients a choice of digital media during chemotherapy significantly improved negative mood and fear. This was seen with both humorous and non-humorous content. This low-cost and low-risk intervention should be implemented as an attention diversion to improve negative mood and fear for patients receiving chemotherapy.

Outcomes and Cost Analysis of Surveillance Strategies After Initial Treatment for Women With Recurrent Ovarian Cancer.

OBJECTIVE: The aim of this study was to determine whether there is a survival or cost benefit dependent on detection strategy of recurrent ovarian cancer (ie, imaging, physical examination findings, report of symptoms, or rising cancer antigen 125 [CA-125] levels). METHODS/MATERIALS: A retrospective chart review of 112 ovarian cancer patients was conducted, and method of detection of recurrent disease was determined from medical records. The following primary outcomes were determined using Cox proportional hazards regression model: progression-free survival (PFS) after diagnosis of recurrence and time to death after diagnosis of recurrence (overall survival [OS]). Several approaches to disease surveillance were proposed, and a cost model was applied. RESULTS: Median time to recurrence was 13.5 months. Overall, 6.3% presented with only physical examination findings; 24.1%, with elevating CA-125 levels; 34.8%, with imaging; and 32.1%, with symptoms. Most patients presenting with recurrent disease diagnosed by rising CA-125 were white (62.9%); those with imaging and symptomatic recurrences were blacks (56.4% and 57.1%, respectively). There was a small but not statistically significant OS benefit for recurrence detected via CA-125 (P = 0.85; OS per detection method: PE, 20.7 months; CA-125, 26.8 months; imaging, 17.8 months; and symptoms, 6.6 months). We modeled costs of surveillance in our patient cohort; up to 40.8% of cases of ovarian cancer recurrences would have been missed if no imaging were obtained during surveillance. CONCLUSIONS: Results indicate minimal differences in PFS and statistically insignificant differences in OS, depending on detection method. Notably, black patients with Medicaid presented most often with symptomatic recurrences, which surprisingly did not affect patient OS and PFS; and interestingly, pr\ivate or self-pay insurance was associated with decreased OS among black patients. From our cost analysis, we estimate that the most cost-effective surveillance strategy for the first year costs $9.2 million annually and includes office visit biannually, biannual CA-125 levels, and annual asymptomatic imaging.

Wilms' tumor of the ovary.

Extrarenal Wilms' tumor of the ovary is a very rare tumor likely derived from embryonic mesonephros. We present the first reported case of a teratoid extrarenal Wilms' tumor of the ovary with a short review of the existing literature. In the case, a 26-year-old woman presented with back pain and was found to have a dermoid cyst; three years later, she presented again, now pregnant, with severe abdominal pain. She was diagnosed with an immature teratoma consisting of a Wilms' tumor (immature component) arising within a mature teratoma and treated exclusively with surgery and surveillance. The recovery from surgery was uneventful and the patient remains without evidence of disease with eleven months of follow-up.

Increased Notch1 expression is associated with poor overall survival in patients with ovarian cancer.

OBJECTIVE: Despite improvements in surgery and chemotherapy, ovarian cancer remains a deadly disease in need of improved therapies. We have previously shown that Notch1 intracellular domain (NICD) is highly expressed in ovarian cancer. We have also shown that NICD inhibition can lead to growth arrest in ovarian cancer cells. The objective of the current study was to delineate whether NICD expression correlates with prognosis of women with ovarian cancer. METHODS: After the institutional review board approval, patients with a diagnosis of primary ovarian cancer between the years 2001 and 2007 who underwent surgery at our institution were identified. Paraffin blocks from the primary ovarian tumor were analyzed, and core samples were obtained to build a tissue microarray. Cytoplasmic NICD expression was assessed by quantitative immunofluorescent morphometry using the automated quantitative analysis system. These results were correlated with clinical and pathology data retrieved from the patient records. RESULTS: We identified 328 patients with primary ovarian cancer during this period. Seventeen percent of patients had stage I, 11% had stage II, 59% had stage III, and 13% had stage IV disease. Most patients (70%) had papillary serous histology, and most (86%) underwent optimal debulking to less than 1 cm of residual disease. High NICD expression was found to correlate strongly with low overall survival (P = 0.001). This effect remained in multivariate analysis (P = 0.023). CONCLUSIONS: High expression of NICD in the primary tumor of women with ovarian cancer is an independently poor prognostic factor for overall survival. Further research into the therapeutic inhibition of the Notch1 pathway is warranted.

Glycocapture-assisted global quantitative proteomics (gagQP) reveals multiorgan responses in serum toxicoproteome.

Blood is an ideal window for viewing our health and disease status. Because blood circulates throughout the entire body and carries secreted, shed, and excreted signature proteins from every organ and tissue type, it is thus possible to use the blood proteome to achieve a comprehensive assessment of multiple-organ physiology and pathology. To date, the blood proteome has been frequently examined for diseases of individual organs; studies on compound insults impacting multiple organs are, however, elusive. We believe that a characterization of peripheral blood for organ-specific proteins affords a powerful strategy to allow early detection, staging, and monitoring of diseases and their treatments at a whole-body level. In this paper we test this hypothesis by examining a mouse model of acetaminophen (APAP)-induced hepatic and extra-hepatic toxicity. We used a glycocapture-assisted global quantitative proteomics (gagQP) approach to study serum proteins and validated our results using Western blot. We discovered in mouse sera both hepatic and extra-hepatic organ-specific proteins. From our validation, it was determined that selected organ-specific proteins had changed their blood concentration during the course of toxicity development and recovery. Interestingly, the peak responding time of proteins specific to different organs varied in a time-course study. The collected molecular information shed light on a complex, dynamic, yet interweaving, multiorgan-enrolled APAP toxicity. The developed technique as well as the identified protein markers is translational to human studies. We hope our work can broaden the utility of blood proteomics in diagnosis and research of the whole-body response to pathogenic cues.

N-glycoproteome of E14.Tg2a mouse embryonic stem cells.

E14.Tg2a mouse embryonic stem (mES) cells are a widely used host in gene trap and gene targeting techniques. Molecular characterization of host cells will provide background information for a better understanding of functions of the knockout genes. Using a highly selective glycopeptide-capture approach but ordinary liquid chromatography coupled mass spectrometry (LC-MS), we characterized the N-glycoproteins of E14.Tg2a cells and analyzed the close relationship between the obtained N-glycoproteome and cell-surface proteomes. Our results provide a global view of cell surface protein molecular properties, in which receptors seem to be much more diverse but lower in abundance than transporters on average. In addition, our results provide a systematic view of the E14.Tg2a N-glycosylation, from which we discovered some striking patterns, including an evolutionarily preserved and maybe functionally selected complementarity between N-glycosylation and the transmembrane structure in protein sequences. We also observed an environmentally influenced N-glycosylation pattern among glycoenzymes and extracellular matrix proteins. We hope that the acquired information enhances our molecular understanding of mES E14.Tg2a as well as the biological roles played by N-glycosylation in cell biology in general.

Galactosyl human serum albumin-NMP1 conjugate: a near infrared (NIR)-activatable fluorescence imaging agent to detect peritoneal ovarian cancer metastases.

Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM), and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)-fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and result in lower background autofluorescence than those emitting in the visible range. A NIR-activatable hGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it. hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMP1). The activation ratio of hGSA-NMP1 was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMP1 was ~100-fold in vitro. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare hGSA-NMP1 with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMP1 for POCM implant detection were determined by colocalizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 h of incubation with hGSA-NMP1. In vivo submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMP1. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ~0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMP1. We conclude that hGSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.

Azacytidine induces cell cycle arrest and suppression of neuroendocrine markers in carcinoids.

Neuroendocrine tumors (NETs) hypersecrete neuropeptides that cause debilitating symptoms of carcinoid syndrome, including cardiac abnormalities. Surgical resection is the only potentially curative treatment for NETs; however, 90% of NE cancer patients are not candidates for surgery due to extensive hepatic sites involved with NETs. Recently, DNA methyltransferase inhibitors (DNMTI) such as azacytidine (AzaC) have shown efficacy in clinical treatments of hematological malignancies, but effects on NETs are not well-studied. We hypothesized that this novel class of drugs inhibits NET cell growth and decreases NE markers. Three carcinoid types-human midgut (CDNT2.5), pulmonary (H727), and gastrointestinal (BON)- were treated with AzaC (0-100uM) over 6 days. MTT Assays were used to measure cellular proliferation. Western blots were performed with antibodies against chromogranin A (CgA), Neuron-Specific Enolase (NSE), and Cyclin B1. Flow cytometric data was collected from AzaC-treated CNDT2.5 cells for DNA cell cycle analysis. Results showed that treatment of CDNT2.5, H727, and BON carcinoid cells with AzaC resulted in a dose-dependent reduction in tumor cell proliferation. Flow cytometric analysis showed that AzaC-treated cells accumulate in the G2 Phase of cell cycle. AzaC treatment led to: significant decreases in CgA and NSE, indicating that AzaC inhibits neuroendocrine markers; and significant increases in the levels of Cyclin B1, further supporting the flow cytometric data and conclusion that AzaC induces G2/M arrest. The data indicate that AzaC suppresses cell growth in three different carcinoid types, reduces neuroendocrine markers in CNDT2.5 cells, and inhibits cell proliferation by inducing G2/M phase arrest. The results suggest that DNMTIs may be a novel class of therapeutic agents that can effectively control tumor growth and the release of bioactive peptides in patients with NETs.