A synopsis of global frontiers in fertility preservation.

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of "Oncofertility Around the Globe" to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.

Looking beyond the ovary for oncofertility care in women: uterine injury as a potential target for fertility-preserving treatments.

Treatment for cancer has the potential to significantly diminish fertility and, further, to negatively impact the obstetrical outcomes of pregnancies that do occur. Cancer survivors have decreased rates of fertility and increased rates of pregnancy complications, such as preterm birth and low birth weight, after exposure to chemotherapy. To date, research on the impact of chemotherapy and radiotherapy on fertility and pregnancy outcomes has focused largely on the gonadotoxic effect of cancer treatments on ovaries, while the uterus and endometrium have not been extensively studied. It is intuitive, however, that decreased fertility and poorer obstetrical outcomes may be substantially mediated through injury to a highly mitotic tissue like the endometrium, which is also central to embryo implantation and utero-placental exchange. Pregnancy complications in cancer survivors might be due to compromised blood supply to the endometrium and myometrium affecting placentation or altered remodeling of the pregnant uterus secondary to radiation fibrosis. Alterations in endometrial receptivity at the molecular level could affect pregnancy implantation and early pregnancy loss, but later complications also can occur. This review focuses on understanding the unintended effects of chemotherapy and radiotherapy on uterine function in female cancer survivors and the impact on pregnancy, and summarizes mechanisms to protect and treat the uterus before and after cancer chemotherapy and radiotherapy.

The role of in-depth reproductive health counseling in addressing reproductive health concerns in female survivors of nongynecologic cancers.

The purpose of this study was to characterize reproductive concerns among female cancer survivors and determine the role of targeted counseling in improving overall reproductive quality of life (QOL). A survey was administered to women from the California Cancer Registry, ages 18-40, with nongynecologic cancers diagnosed from 1993 to 2007, who received fertility-compromising treatments. In total, 356 women completed the survey, which included questions regarding their reproductive health counseling history and the reproductive concerns scale (RCS), a validated reproductive QOL tool. Factors independently associated with higher RCS scores included a desire for children at the time of diagnosis, posttreatment infertility, treatment with chemoradiation or bone marrow transplant, and income less than $100,000 per year at diagnosis. Among the highest reported reproductive concerns were those related to loss of control over one's reproductive future and concerns about the effect of illness on one's future fertility. Across our population and independent of age, in-depth reproductive health counseling prior to cancer treatment was associated with significantly lower RCS scores. Our findings highlight the importance of early counseling and targeting high-risk groups for additional counseling after completion of cancer treatment. This approach may be an effective strategy for optimizing long-term reproductive QOL in this vulnerable population.

Psychological stress and reproductive aging among pre-menopausal women.

BACKGROUND: Life history models suggest that biological preparation for current versus longer term reproduction is favored in environments of adversity. In this context, we present a model of reproductive aging in which environmental adversity is proposed to increase the number of growing follicles at the cost of hastening the depletion of the ovarian reserve over time. We evaluated this model by examining psychological stress in relation to reproductive aging indexed by antral follicle count (AFC), a marker of total ovarian reserve. We hypothesized that stress would be related to (i) higher AFC in younger women, reflecting greater reproductive readiness as well as (ii) greater AFC loss across women, reflecting more accelerated reproductive aging. METHODS: In a multi-ethnic, community sample of 979 participants [ages 25-45 (mean (standard deviation) = 35.2 (5.5)); 27.5% Caucasian] in the Ovarian Aging study, an investigation of the correlates of reproductive aging, the interaction of age-x-stress was assessed in relation to AFC to determine whether AFC and AFC loss varied across women experiencing differing levels of stress. Stress was assessed by the perceived stress scale and AFC was assessed by summing the total number of antral follicles visible by transvaginal ultrasound. RESULTS: In linear regression examining AFC as the dependent variable, covariates (race/ethnicity, socio-economic status, menarcheal age, hormone-containing medication for birth control, parity, cigarette smoking, bodymass index, waist-to-hip ratio) and age were entered on step 1, stress on step 2 and the interaction term (age-x-stress) on step 3. On step 3, significant main effects showed that older age was related to lower AFC (b = -0.882, P = 0.000) and greater stress was related to higher AFC (b = 0.545, P = 0.005). Follow-up analyses showed that the main effect of stress on AFC was present in the younger women only. A significant interaction term (b = -0.036, P = 0.031) showed the relationship between age and AFC varied as function of stress. When the sample was divided into tertiles of stress, the average follicle loss was -0.781, -0.842 and -0.994 follicles/year in the low-, mid- and high-stress groups, respectively. CONCLUSIONS: Psychological stress was related to higher AFC among younger women and greater AFC decline across women, suggesting that greater stress may enhance reproductive readiness in the short term at the cost of accelerating reproductive aging in the long term. Findings are preliminary, however, due to the cross-sectional nature of the current study.

Qualifying Certainty in Radiology Reports through Deep Learning-Based Natural Language Processing.

BACKGROUND AND PURPOSE: Communication gaps exist between radiologists and referring physicians in conveying diagnostic certainty. We aimed to explore deep learning-based bidirectional contextual language models for automatically assessing diagnostic certainty expressed in the radiology reports to facilitate the precision of communication. MATERIALS AND METHODS: We randomly sampled 594 head MR imaging reports from an academic medical center. We asked 3 board-certified radiologists to read sentences from the Impression section and assign each sentence 1 of the 4 certainty categories: "Non-Definitive," "Definitive-Mild," "Definitive-Strong," "Other." Using the annotated 2352 sentences, we developed and validated a natural language-processing system based on the start-of-the-art bidirectional encoder representations from transformers (BERT), which can capture contextual uncertainty semantics beyond the lexicon level. Finally, we evaluated 3 BERT variant models and reported standard metrics including sensitivity, specificity, and area under the curve. RESULTS: A κ score of 0.74 was achieved for interannotator agreement on uncertainty interpretations among 3 radiologists. For the 3 BERT variant models, the biomedical variant (BioBERT) achieved the best macro-average area under the curve of 0.931 (compared with 0.928 for the BERT-base and 0.925 for the clinical variant [ClinicalBERT]) on the validation data. All 3 models yielded high macro-average specificity (93.13%-93.65%), while the BERT-base obtained the highest macro-average sensitivity of 79.46% (compared with 79.08% for BioBERT and 78.52% for ClinicalBERT). The BioBERT model showed great generalizability on the heldout test data with a macro-average sensitivity of 77.29%, specificity of 92.89%, and area under the curve of 0.93. CONCLUSIONS: A deep transfer learning model can be developed to reliably assess the level of uncertainty communicated in a radiology report.

Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin.

BACKGROUND: The LH surge promotes ovulation via activation of multiple signaling networks in the ovarian follicle. Studies in animal models have shown the importance of LH-induced activation of the epidermal growth factor (EGF)signaling network in critical peri-ovulatory events. We investigated the biological significance of regulatory mechanisms mediated by EGF-like growth factors during LH stimulation in humans. METHODS: We characterized the EGF signaling network in mature human ovarian follicles using in vivo and in vitro approaches. Amphiregulin (AREG) levels were measured in 119 follicular fluid (FF) samples from IVF/ICSI patients. Biological activity of human FF was assessed using in vitro oocyte maturation, cumulus expansion and cell mitogenic assays. RESULTS: AREG is the most abundant EGF-like growth factor accumulating in the FF of mature follicles of hCG-stimulated patients. No AREG was detected before the LH surge or before hCG stimulation of granulosa cells in vitro, demonstrating that the accumulation of AREG requires gonadotrophin stimulation. Epiregulin and betacellulin mRNA were detected in both human mural and cumulus granulosa cells, although at significantly lower levels than AREG. FF from stimulated follicles causes cumulus expansion and oocyte maturation in a reconstitution assay. Immunodepletion of AREG abolishes the ability of FF to stimulate expansion (P < 0.0001) and oocyte maturation (P < 0.05), confirming the biological activity of AREG. Conversely, mitogenic activity of FF remained after depletion of AREG, indicating that other mitogens accumulate in FF. FF from follicles yielding an immature germinal vesicle oocyte or from an oocyte that develops into an aberrant embryo contains lower AREG levels than that from follicles yielding a healthy oocyte (P = 0.008). CONCLUSIONS: EGF-like growth factors play a role in critical peri-ovulatory events in humans, and AREG accumulation is a useful marker of gonadotrophin stimulation and oocyte competence.

Does a physician's ability to accurately assess the likelihood of pulmonary embolism increase with training?

PURPOSE: Pulmonary embolism (PE), an elusive diagnosis, is detected by a diagnostic work-up that is often guided by the physician's level of clinical suspicion. The ability to accurately assess PE risk on solely clinical grounds may increase with the physician's level of training. This study documented the ability of house staff practicing in an academic teaching hospital to accurately assess the clinical likelihood of PE in patients. METHOD: During a seven-month period, all 245 patients with suspected acute PE who had had lung scans ordered via a computerized order-entry system were enrolled in the study. When ordering the lung scans, all physicians (interns, residents, and attending physicians) were required to also enter their levels of clinical suspicion on a scale of 0 to 100. The physicians' levels of clinical suspicion were correlated with the final determinations of PE, and receiver operating characteristic (ROC) curves were calculated for patients' and physicians' subgroups. RESULTS: Attending physicians were most able to diagnose PE; residents were moderately able to make the diagnosis, and interns were least able to diagnose PE. The area under the ROC curve for a correct identification of patients with PE was greatest for attending physicians (0.839), intermediate for residents (0.601), and least for interns (0.594). CONCLUSION: The ability to correctly assess a patient's likelihood of PE increases with a physician's level of training, suggesting that more senior physicians should be involved in the diagnostic work-up of patients with suspected acute PE. More instruction may help medical students, interns, and residents navigate clinical scenarios in which the diagnosis is uncertain or in which sequential tests must be performed to reach the correct diagnosis.

Enzymatic synthesis of 3H-labeled Ring-A reduced metabolites of aldosterone and their separation by high pressure liquid chromatography.

Specific methods are described for the enzymatic synthesis of each of the six possible 3H-labeled Ring-A reduced metabolites of aldosterone (5 alpha- and 5 beta-DHAldo; 3 alpha,5 alpha-THAldo; 3 beta,5 alpha-THAldo; 3 alpha,5 beta-THAldo; and 3 beta,5 beta-THAldo; see footnote 1 for full names). Use of heated jacketed columns (C8-reverse phase) and two HPLC solvent systems, with isocratic aqueous methanol or acetonitrile, respectively, have been developed which resolve all six Ring-A reduced metabolites of aldosterone. The relative retention times and elution order of each reduced metabolite are different with each solvent system and hence help confirm the identities of Ring-A reduced metabolites made in vivo from physiological quantities of [3H]aldosterone. The use of an on-line beta-radioactivity detector (Berthold LB-504) enhanced the sensitivity of detection and markedly improved the resolution of these metabolites, compared with that obtained by off-line scintillation counting. Thus, the use of increased temperature with these two solvent systems, together with an on-line radioactivity detector, provide a useful and efficient analytical tool for the separation and identification of each reduced metabolite of aldosterone.

Work-up of patients with malignancy after an intermediate-probability ventilation-perfusion scan: why don't physicians pursue a definitive diagnosis?

RATIONALE AND OBJECTIVES: The authors determined whether there are specific patient characteristics associated with the clinical decision to eschew further diagnostic testing in patients in whom a ventilation-perfusion (V-P) scan indicates intermediate probability of pulmonary embolism (PE). MATERIALS AND METHODS: The authors reviewed all intermediate-probability V-P scans obtained in a 12-month period. Patients were divided into two groups. Group 1 comprised patients in whom a definitive diagnosis of PE was not obtained and who were not treated for PE (n = 57); group 2 comprised patients in whom the diagnosis of PE was confirmed or excluded and who, if PE was confirmed, received appropriate treatment (n = 14). Age, gender, frequency of malignancy, and survival of patients in groups 1 and 2 were compared. RESULTS: The frequency of malignancy was significantly greater in group 1 than in group 2 (P = .012). Although the estimated 2-year survival of group 1 patients was significantly less than that of group 2 patients (P = .039), this difference is likely due to confounding by age and malignancy. CONCLUSION: When an intermediate-probability V-P scan is obtained, physicians are significantly less likely to pursue a definitive diagnosis of PE in patients with malignancy.

Physicians' attitudes toward misdiagnosis of pulmonary embolism: a utility analysis.

RATIONALE AND OBJECTIVES: The purpose of this study was to measure physicians' utilities for outcomes after ventilation-perfusion lung scanning and to explore physicians' attitudes toward misdiagnosis and the treatment of patients suspected of having pulmonary embolism (PE) in a quantitative manner by using a utility analysis. MATERIALS AND METHODS: Before ordering lung scanning for suspected PE, physicians rated five possible outcomes on a scale of 0-100 by using a computer order-entry system. These responses were rescaled and transformed to a utility measure by using the Torrance transformation. RESULTS: The mean utility for the potential outcomes after 341 lung scans were (a) no PE and no treatment (true-negative, 93 +/- 22 [mean +/- standard deviation]), (b) PE with appropriate treatment (true-positive, 84 +/- 24), (c) no PE but patient received treatment (false-positive, 54 +/- 32), (d) PE but patient did not receive treatment (false-negative, 14 +/- 23), and (e) death during pulmonary angiography (2 +/- 11). After lung scanning for acute PE, physicians placed greatest value on excluding the diagnosis (true-negative). Providing unnecessary treatment (false-positive) was valued in the midrange of utilities. The value of missing PE (false-negative) was rated almost equal to that of dying during pulmonary angiography. CONCLUSION: Physicians consider providing treatment for PE without objective confirmation of an embolus to be preferable to missing a case of PE.

Controversies in the use of lower extremity sonography in the diagnosis of acute deep vein thrombosis and a proposal for a unified approach.

During the past 10 years, lower extremity venous ultrasonography (LEUS) has essentially replaced contrast venography for the evaluation of patients suspected of acute thromboembolic disease. Along with this change in technology, the number of studies performed to rule out DVT has increased dramatically, and there has been controversy in the literature regarding the most appropriate role of LEUS. Specifically, four questions have been raised: (1) What is the appropriate role of LEUS in patients with a nondiagnostic V/Q scan?; (2) Is there a need to examine the contralateral (asymptomatic) leg of patients presenting with unilateral DVT symptomatology?; (3) What role, if any, does LEUS play in the evaluation of patients with bilateral leg symptoms?; and (4) When can a limited examination of the leg be performed? The purpose of this article is to provide a balanced review of these issues and to present an algorithm for a reasonable, integrated approach to the use of LEUS among patients suspected of having acute thromboembolic disease.

Newer diagnostic modalities for pulmonary embolism. Pulmonary angiography using CT and MR imaging compared with conventional angiography.

CTPA is a highly sensitive and excellent primary method for evaluating patients with symptoms of PE. Ongoing studies will demonstrate the good clinical outcome of patients with negative CTPA results. The ability to visualize the lung parenchyma in addition to the pulmonary vasculature, and the smaller number of nondiagnostic scans, make CT more cost effective than V/Q scans, and CT therefore should be used as a first-line evaluation. MR imaging is a continually developing modality with more imaging options that could make it an invaluable or adjunctive test in the near future.

Barriers and opportunities for early detection of breast cancer in Gaza women.

A survey of 100 women living inside Gaza (WIG) and 55 Gaza women residing outside Gaza (WOG) was conducted to investigate barriers and opportunities for breast cancer screening, and to better understand possible differences based on residency. The survey found that over 90% of both groups were willing to undergo a diagnostic mammogram for a breast complaint and 86% of WIG and 85% of WOG believed survival was increased with early detection. However, only 27% of WIG and 50% WOG were willing to undergo screening mammography. Religion and culture were not barriers to mammography for over 94% of WIG and 98% of WOG. Limited resources and lack of access to medical facilities were identified as barriers in up to 55% of WIG compared to 15% of WOG. Misconceptions about breast cancer were reported more frequently by WIG, including beliefs that breast cancer is not very common and that breast cancer can be contagious.

Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF.

BACKGROUND: There is concern that IVF could compromise normal imprinting and methylation of DNA. Methylenetetrahydrofolate reductase (MTHFR) regulates the flow of folic acid-derived, one-carbon moieties for methylation and is critical to early embryonic development. Therefore, we hypothesized that common polymorphisms in MTHFR could associate with IVF outcome. METHODS: MTHFR C677T and A1298C polymorphism genotyping was performed on 374 subjects for this study, representing 197 couples undergoing IVF in a university setting from July 2005 to January 2006. Analysis of variance (ANOVA), chi-square and/or multivariate analyses were used to assess whether these polymorphisms are associated with embryo quality or with ongoing pregnancy or spontaneous abortion rates. RESULTS: Allele frequencies for C677T ( p=0.67, q=0.33) and A1298C ( p=0.71, q=0.29) were in Hardy-Weinberg equilibrium. The C677T and A1298C variants, either alone or in combination, did not associate with embryo quality or short-term pregnancy outcome. CONCLUSIONS: The common polymorphisms in MTHFR are not associated with embryo quality, as defined by cell number or fragmentation score, or with short-term pregnancy outcomes. Therefore, in our population in which women receive adequate folic acid, MTHFR genotypes are not informative in explaining IVF failure. Further studies, however, examining birth outcomes and the other enzymes in the folic acid pathway are warranted.

Reassessment of vena caval filter use in patients with cancer.

PURPOSE: Noting a doubling in mortality soon after placement of filters in the inferior vena cava (IVC) from 1985 (7.8%) to 1992 (15.2%), the authors performed a study to define risk factors associated with death soon after IVC filter placement and to develop revised guidelines for filter placement. PATIENTS AND METHODS: During a 4-year period, 141 IVC filters were placed in 137 patients. Patients were divided into two clinical risk groups: those with possible malignancy and those with possible suprainguinal venous thrombus. Survival was monitored for up to 3 weeks after hospital discharge. RESULTS: Death occurred in 16 (26%) of 61 patients with malignancy (P = .0086, compared with patients without malignancy), seven (35%) of 20 patients with suprainguinal venous thrombus (P = .0422, compared with patients without suprainguinal venous thrombus), and six (46.2%) of 13 patients with malignancy and suprainguinal venous thrombus (P = .0091, compared with patients without malignancy or suprainguinal venous thrombus). CONCLUSION: The data indicate that for some patients with malignancy or suprainguinal venous thrombus, insertion of an IVC filter gives little or no survival benefit. A reassessment of IVC filter use in these patients is warranted.

Arteriography and radiology of impotence.

Both arterial and venous dysfunction are now recognized as significant causes of organic impotence. Numerous therapeutic modalities are currently available, including surgical bypass, venous ligation, transluminal angioplasty, and transcatheter vessel occlusion. The specific nature of this patient population requires correlation of angiographic findings with the patient's history and physical examination to determine the appropriate intervention and obtain a satisfactory outcome.

Utilization of outpatient diagnostic imaging. Does the physician's gender play a role?

OBJECTIVE: To examine physician and patient characteristics related to the ordering of imaging studies in a general medicine practice and to determine whether physician gender influences ordering patterns. DESIGN: Retrospective cohort study. SETTING: Hospital-based academic general medicine practice of 29 attending physicians. PATIENTS: All 8,203 visits by 5,011 patients during a 6-month period. METHODS: For each visit the following variables were abstracted from the electronic patient record: patient age, patient gender, visit urgency, visit type, and physician seen. All diagnostic imaging studies performed within 30 days of each outpatient visit were identified from the hospital's Radiology Information System. Screening mammography was not included in the analysis. Physician variables included gender and years since medical school graduation. Logistic regression analysis was used to evaluate the effect of various patient, physician, and visit characteristics on the probability of a diagnostic imaging study being ordered. RESULTS: Patient age, urgent visits, visit frequency, and the gender of the physician were all significantly related to the ordering of an imaging study. Correcting for all other factors, the ordering of an imaging study during an outpatient medical visit was 40% more likely if the physician was female (odds ratio = 1.40; 95% confidence interval [CI] 1.01, 1.95). Female physicians were 62% more likely (95% CI 0.99, 2.64) than male physicians to order an imaging study for a male patient and 21% more likely (95% CI 0.87, 1.69) to order an imaging study for a female patient. CONCLUSIONS: Physician gender is a predictor of whether an outpatient medical visit generates an imaging study. Reasons for this observation are unclear, but may be the result of different practice styles of male and female physicians or unmeasured patient characteristics.

Bedside placement of peripherally inserted central catheters: a cost-effectiveness analysis.

PURPOSE: To compare two strategies for placement of peripherally inserted central catheters (PICCs). In strategy A, all PICC placements were initially attempted at the patient's bedside by trained intravenous (i.v.) nurses, with failures referred to the interventional radiology (IR) service. In strategy B, all PICCs were placed by interventional radiologists under fluoroscopic and/or venographic guidance. MATERIALS AND METHODS: Decision analysis and cost-effectiveness models were constructed with commercially available software. Data used in the model were obtained from a review of the authors' experience with bedside placement of PICCs by an i.v. team and data obtained from the literature. RESULTS: The cost-effectiveness of strategy A relative to strategy B depends on (a) the ability of the i.v. team to access a vein at the patient's bedside, (b) the cost of fluoroscopy or the IR suite, and (c) the intended use of the PICC. CONCLUSION: If the cost of fluoroscopy or the IR suite exceeds $100, strategy A is more cost-effective for most intended PICC uses. If the cost is less than $75, strategy B is more cost-effective for all intended PICC uses. If the cost is between $75 and $100, the most cost-effective strategy depends on the intended use of the PICC and the need to have the tip placed at the junction of the superior vena cava and right atrium.