The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

Conservative surgery for ovarian torsion in young women: perioperative complications and national trends.

OBJECTIVE: To analyse populational trends and perioperative complications following conservative surgery versus oophorectomy in women <50 years of age with ovarian torsion. DESIGN: Population-based retrospective observational study. SETTING: Nationwide Inpatient Sample in the USA (2001-2015). POPULATION: In all, 89 177 ovarian torsions including 20 597 (23.1%) conservative surgeries and 68 580 (76.9%) oophorectomies. METHODS: (1) Trend analysis to assess utilisation of conservative surgery over time, (2) multivariable binary logistic regression to identify independent factors associated with conservative surgery and (3) inverse probability of treatment weighting with a generalised estimating equation to analyze perioperative complications. MAIN OUTCOME MEASURES: Trends, characteristics and complications related to conservative surgery. RESULTS: Performance of conservative surgery increased from 18.9 to 25.1% between 2001 and 2015 (32.8% relative increase, P = 0.001) but decreased steadily after age 15, and sharply declined after age 35 (P < 0.001). On multivariable analysis, younger age exhibited the largest effect size for conservative surgery among the independent factors (adjusted odds ratios 3.39-7.96, P < 0.001). In the weighted model, conservative surgery was associated with an approximately 30% decreased risk of perioperative complications overall (10.0% versus 13.6%, odds ratio 0.73, 95% confidence interval 0.62-0.85, P < 0.001) and was not associated with venous thromboembolism (0.2 versus 0.3%, P = 0.457) or sepsis (0.4 versus 0.3%, P = 0.638). CONCLUSION: There has been an increasing utilisation of conservative surgery for ovarian torsion in the USA in recent years. Our study suggests that conservative surgery for ovarian torsion may not be associated with increased perioperative complications. TWEETABLE ABSTRACT: Conservative surgery for ovarian torsion may not be associated with increased perioperative complications.

Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shp1.

Protein tyrosine phosphorylation plays a key role in regulating eukaryotic cell proliferation and differentiation. Genetic analysis in invertebrates has been invaluable for dissecting the signalling events downstream of receptor tyrosine kinases (RTKs). We have used this approach in mammals to analyse the interactions between the Kit RTK encoded by the murine Dominant white spotting (W) locus and the Shp1 protein tyrosine phosphatase, the product of the murine motheaten (me) gene. Homozygosity for mutations in both W and me ameliorates aspects of both the me and W phenotypes, including the lethal lung disease associated with me and the embryonic lethality and mast cell deficiency associated with W, demonstrating that the Kit receptor plays a role in the pathology of the me phenotype and conversely that Shp1 negatively regulates Kit signalling in vivo.

Fv2 encodes a truncated form of the Stk receptor tyrosine kinase.

The Friend virus susceptibility 2 (Fv2) locus encodes a dominant host factor that confers susceptibility to Friend virus-induced erythroleukaemia in mice. We mapped Fv2 to a 1.0-Mb interval that also contained the gene (Ron) encoding the stem cell kinase receptor (Stk). A truncated form of Stk (Sf-stk), which was the most abundant form of Stk in Fv2-sensitive (Fv2ss) erythroid cells, was not expressed in Fv2 resistant (Fv2rr) cells. Enforced expression of Sf-stk conferred susceptibility to Friend disease, whereas targeted disruption of Ron caused resistance. We conclude that the Fv2 locus encodes Ron, and that a naturally expressed, truncated form of Stk confers susceptibility to Friend virus-induced erythroleukaemia.

Characterizing the influence of vitamin D levels on IVF outcomes.

BACKGROUND: Vitamin D plays a role in reproductive capacity. Recently, several investigators have demonstrated higher IVF pregnancy rates in vitamin D replete women. The objective of this study was to validate these findings and to further elucidate the role of vitamin D in reproduction among a diverse group of women. METHODS: This was a retrospective cohort study in an academic tertiary care center of 188 infertile women undergoing IVF. Serum levels of vitamin D (25OH-D) were measured in previously frozen serum samples. The main outcome measure was clinical pregnancy, defined as sonographic presence of a heartbeat following IVF. RESULTS: The relationship between vitamin D status and pregnancy rates differed by race (P < 0.01). Among non-Hispanic whites, pregnancy rates declined with progressively lower levels of vitamin D, while in Asians, the reverse was true. Adjusting for age and number and quality of embryos transferred among non-Hispanic whites, the odds of pregnancy were four times higher in vitamin D replete versus deficient patients. Live birth rates mirrored pregnancy rates. Vitamin D status was not associated with ovarian stimulation parameters or with markers of embryo quality. CONCLUSIONS: Vitamin D deficiency is associated with lower pregnancy rates in non-Hispanic whites, but not in Asians, possibly due to their lower IVF success rates. Vitamin D deficiency was not correlated with ovarian stimulation parameters or with markers of embryo quality, suggesting its effect may be mediated through the endometrium.

Telemedicine in Community Cancer Care: How Technology Helps Patients With Cancer Navigate a Pandemic.

COVID-19 places unprecedented demands on the oncology ecosystem. The extensive pressure of managing health care during the pandemic establishes the need for rapid implementation of telemedicine. Across our large statewide practice of 640 practitioners at 221 sites of service, an aggressive multidisciplinary telemedicine strategy was implemented in March by coordinating and training many different parts of our healthcare delivery system. From March to September, telemedicine grew to serve 15%-20% of new patients and 20%-25% of established patients, permitting the practice to implement safety protocols and reduce volumes in clinic while continuing to manage the acute and chronic care needs of our patient population. We surveyed practice leaders, queried for qualitative feedback, and established 76% were satisfied with the platform. The common challenges for patients were the first-time use and technology function, and patients were, in general, grateful and happy to have the option to visit their clinicians on a telemedicine platform. In addition to conducting new and established visits remotely, telemedicine allows risk assessments, avoidance of hospitalization, family education, psychosocial care, and improved pharmacy support. The implementation has limitations including technical complexity; increased burden on patients and staff; and broadband access, particularly in rural communities. For telemedicine to improve as a solution to enhance the longitudinal care of patients with cancer, payment coverage policies need to continue after the pandemic, technologic adoption needs to be easy for patients, and broadband access in rural areas needs to be a policy priority. Further research to optimize the patient and clinician experience is required to continue to make progress.

Telemedicine for cancer care: implementation across a multicenter community oncology practice.

PURPOSE: To describe onboarding and utilization of telemedicine across a large statewide community oncology practice and to evaluate trends, barriers, and opportunities in care delivery during the coronavirus disease 2019 pandemic. METHODS: We describe telemedicine onboarding and utilization across a statewide oncology practice, covering 221 sites of service and more than 650 practitioners. We describe qualitatively the onboarding process of a diverse set of administrative, technical, and clinical partners. We describe quantitatively utilization throughout the practice. We describe a survey conducted to enlighten barriers and opportunities for optimal utilization. RESULTS: Multistakeholder education was directed to clinical teams, administrative and technical support staff, and patients through webinars and team meetings. Utilization was high from April through October 2020, representing 15% to 20% of new-patient visits and 20% to 25% of established-patient visits. In a survey offered to all clinicians, 96% of respondents indicated they are using telemedicine, with 33% using it for more than 25% of patient encounters. Among respondents, 59% reported that the use of telemedicine helps expedite diagnosis and treatment more than seeing patients in person in the clinic, 55% of respondents managed urgent issues by telemedicine, 80% believed that patients benefited From urgent assessment by telemedicine, and 57% believed an emergency department visit or a hospitalization was avoided because of a telemedicine visit. Most clinicians reported that patients enjoy benefits of telemedicine because of decreased exposure risk, decreased transportation requirements, and ease of including caregivers in the visit with the treating clinician. The most common barriers to patients accessing telemedicine were technical challenges and broadband access. Despite this, less than 5% of respondents routinely use telephone-only communication, as most typically use bimodal audio/video communication. Many clinicians have expansion ideas on how telemedicine can further expand the longitudinal care delivery for our patient population. CONCLUSIONS: Telemedicine can be implemented successfully across a large statewide oncology practice and service a high volume of patients. Clinicians utilize telemedicine for new and established patients with minimal dysfunction. Clinicians believe patients benefit From telemedicine For new, established, and urgent care visits. Broadband access functionality should be explored to optimally serve our patient population.

Ovulation rates in a stair-step protocol with Letrozole vs clomiphene citrate in patients with polycystic ovarian syndrome.

PURPOSE: To compare ovulation rates between Letrozole and Clomiphene Citrate (CC) using a stair-step protocol to achieve ovulation induction in women with Polycystic Ovarian Syndrome (PCOS). METHODS: This is a retrospective cohort of predominantly Hispanic PCOS women of reproductive age who completed ovulation induction (OI) comparing women who underwent Letrozole stair-step protocol to those who underwent OI with CC stair-step. All women had a diagnosis of PCOS based on the 2003 Rotterdam criteria. For both protocols, sequentially higher doses of Letrozole or CC were given 7 days after the last dose if no dominant follicles were seen on ultrasonography. The primary outcome was ovulation rate (determined by presence of a dominant follicle) between the two treatment groups. Secondary outcomes included time to ovulation, clinical pregnancy rates and side effects. RESULTS: 49 PCOS patients completed a Letrozole stair-step cycle and 43 completed a CC stair-step cycle for OI. Overall, demographics were comparable between both groups. Ovulation rates with the Letrozole stair-step protocol were equivalent to CC stair-step protocol (96% vs 88%, p = 0.17). Although the mean time (days) to ovulation was shorter in the Letrozole group (19.5 vs 23.1, p = 0.027), the pregnancy rates were similar for both groups. CONCLUSIONS: This is the first study to date that has compared the efficacy of the stair-step protocol in PCOS patients using Letrozole and CC. Both Letrozole and CC can be prescribed in a stair-step fashion. Letrozole stair-step was as efficacious as CC stair-step; patients achieved comparable rates of ovulation and clinical pregnancy. Time to ovulation was shorter in the Letrozole protocol.

GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells.

Friend virus induces the development of erythroleukemia in mice through the interaction of a viral glycoprotein, gp55, with a truncated form of the Stk receptor tyrosine kinase, short form-Stk (Sf-Stk), and the EpoR. We have shown previously that the ability of Sf-Stk to participate in the transformation of Friend virus-infected cells requires the kinase activity and Grb2-binding site of Sf-Stk. Here we show that Grb2 heterozygous mice exhibit decreased susceptibility to Friend erythroleukemia and that expansion of erythroid progenitors in response to infection requires the C-terminal SH3 domain of Grb2. A fusion protein in which the Grb2-binding site in Sf-Stk is replaced by Gab2, supports the growth of progenitors from mice lacking Sf-Stk, whereas a Sf-Stk/Gab1 fusion protein does not. Gab2 is expressed in spleens from Friend virus-infected mice, co-immunoprecipitates with Sf-Stk and is tyrosine phosphorylated in the presence of Sf-Stk. Mice with a targeted deletion in Gab2 are less susceptible to Friend erythroleukemia and the expansion of erythroid progenitor cells in response to infection can be rescued by expression of Gab2, but not Gab1. Taken together, these data indicate that a Sf-Stk/Grb2/Gab2 complex mediates the growth of primary erythroid progenitor cells in response to Friend virus.

A gene related to the proto-oncogene fps/fes is expressed at diverse times during the life cycle of Drosophila melanogaster.

The proto-oncogene fps/fes encodes a distinctive type of protein-tyrosine kinase. We identified a Drosophila gene (dfps85D) whose product resembles the proteins encoded by vertebrate fps/fes and the closely related gene fer. dfps85D is located at chromosomal position 85D10-13 and is unlikely to correspond to any previously defined genetic locus in Drosophila melanogaster. Expression of the gene is entirely zygotic in origin and occurs throughout the life cycle. But hybridization in situ revealed that the pattern of expression is specialized and evolves in a provocative manner. The most notable feature of expression is the diversity of developmental periods, tissues, and cells in which it occurs. In some tissues, expression is transient; in others, it is continuous. Expression occurs in both mitotic and terminally differentiated tissue and, at various times in development, is prominent in imaginal disks, gut, muscle, testes, ovaries, retina, and other neural tissues. It appears that the use of dfps85D is more diversified than that of other Drosophila protein-tyrosine kinases reported to date and contrasts sharply with the restricted expression of fps itself in vertebrates. The detailed description of expression provided here will help guide the search for mutants in dfps85D.

The DFer gene of Drosophila melanogaster encodes two membrane-associated proteins that can both transform vertebrate cells.

The vertebrate gene FER encodes two protein-tyrosine kinases with molecular weights of 51,000 and 94,000 and distinctive aminotermini. The larger kinase is expressed ubiquitously among vertebrate tissues, whereas expression of the smaller kinase appears to be limited to spermatogenic cells in the testes. Here we show that Drosophila melanogaster contains an apparent ortholog of FER (DFer) that also produces two mRNAs by separate initiation of transcription, and two proteins with molecular weights of 45,000 and 92,000. Both proteins are in part loosely associated with cytoplasmic membranes. Both can transform avian and rodent cells with roughly equal potency, when expressed from retroviral vectors. Fusing the myristoylation signal from the SRC protein-tyrosine kinase to the aminoterminus of the DFer protein increased the strength of attachment to membranes but augmented transformation only marginally. The results provide the first demonstration of neoplastic transformation by a protein-tyrosine kinase of Drosophila and by FER from any species. The products of Drosophila and vertebrate FER may be part of similar signaling pathways in the two species.

Phase II study of mitoxantrone, leucovorin, and infusional fluorouracil for treatment of metastatic breast cancer.

A new combination of mitoxantrone, folinic acid (leucovorin), and infusional fluorouracil (5-FU) was administered to 57 previously treated patients with metastatic breast cancer to evaluate the response rate, response duration, and toxicity of this regimen. Fifty-three patients who received 313 courses of therapy were assessable for response and toxicity. Median age was 48 years (range, 33 to 80 years), and the patients had received an average of 1.5 chemotherapy regimens before this study. Of 53 assessable patients, 24 (45%, or 42% of all entered patients) experienced partial responses (PRs) with a median duration of 6 months (range, 2 to 13 months). Nine (69%) of 13 assessable patients without prior doxorubicin treatment responded, compared with 15 (38%) of 40 with prior doxorubicin (P less than .05). Toxicity was generally mild with dose reductions necessitated more often by mucositis and/or diarrhea than by myelosuppression. One patient with prior high-dose doxorubicin treatment developed congestive heart failure. The combination of mitoxantrone, leucovorin, and infusional 5-FU is an active and well-tolerated regimen for metastatic breast cancer and deserves further evaluation in patients without prior doxorubicin therapy.

Splenomegaly in Hmong refugees.

We review asymptomatic splenomegaly in Indochinese refugees and provide recommendations for evaluation of the problem. Prevalence of splenomegaly in newly arrived Indochinese refugees was 2.5%, three times more prevalent in the Hmong than in the non-Hmong refugees. Male Hmong refugees aged 15 to 29 years had the highest prevalence (10%). For the 50 Hmong refugees studied, there was no evidence that their splenomegaly was caused by clonorchiasis, schistosomiasis, tuberculosis, syphillis, lymphoma, tropical splenomegaly syndrome, or clinical malaria. Cases were more likely to have hepatomegaly, hepatitis B surface antigen positivity, and a low mean corpuscular volume than a reference population of Hmong refugees. Malaria antibody titers were elevated in all but one of the 41 cases (98%) tested.

The ovarian contribution to peripherally derived serum C19 conjugates.

While serum markers of peripheral androgen metabolism, such as 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-diolG) and androsterone glucuronide (AoG), have been highly correlated with adrenal androgen production, the relative ovarian contribution to the pool of various C19 conjugates has not been fully investigated. Our hypothesis was that whereas the ovary may not produce C19 conjugates directly, ovarian androgens, such as testosterone (T) and androstenedione (A), may be used as substrate for peripheral production of these conjugates. To determine whether the ovary contributes directly to the pool of C19 conjugates, blood was obtained from the ovarian and peripheral veins of eight normal women (NW) at hysterectomy. To assess the indirect ovarian contribution to C19 conjugate production, the effect of ovarian suppression and stimulation on circulating 3 alpha-diol and Ao conjugate levels was examined in 10 NW and 10 anovulatory nonhirsute patients with PCO (NH-PCO). Ovarian suppression was carried out with leuprolide acetate (1 mg, sc) daily until the serum estradiol level was 30 pg/mL and was continued thereafter during ovarian stimulation with im human menopausal gonadotropin or FSH. Blood samples were taken before, during, and after GnRH agonist suppression and just before hCG stimulation. Both unconjugated and conjugated androgens were quantified in serum by specific RIAs. No peripheral-ovarian gradients were found for 3 alpha-diol or Ao sulfates (3 alpha-diolS or AoS) or glucuronides. In the NH-PCO group, both T and A levels were elevated, and they were suppressed significantly to levels similar those in NW. With stimulation, T and A levels rose significantly to higher levels than those observed in NW. Both AoS and 3 alpha-diolS, but not AoG and 3 alpha-diolG, decreased significantly with agonist suppression in the two groups; the decrease in levels of AoS and T correlated significantly in the NH-PCO group. With stimulation, the Ao and 3 alpha-diol conjugate levels increased significantly in NH-PCO and were most marked for Ao S and 3 alpha-diol S, which were previously suppressed; the increase in AoG and A correlated highly. Our data suggest that while there is no evidence for the direct ovarian production of C19 conjugates, these markers of peripheral androgen action are influenced by precursors from the ovary, principally A and T.

Production of 3 alpha-androstanediol glucuronide in human genital skin.

3 alpha-Androstanediol glucuronide (3 alpha diol-G) is produced extrasplanchnically and is a good clinical marker of androgen action in peripheral tissues. However, the direct formation of androgen glucuronides in peripheral sites such as skin has not been determined in man. Genital skin from 21 premenopausal women and 8 men and foreskin from 6 neonates were incubated with either [14C]testosterone [14C]dihydrotestosterone (DHT) to determine the production of DHT glucuronide and 3 alpha diol-G in skin. After hydrolysis of incubation medium with glucuronidase, followed by extraction and sequential chromatography, constant 3H to 14C ratios of 3 alpha diol confirmed the production of DHT glucuronide and 3 alpha diol-g. The conversion of DHT to 3 alpha diol-G was higher than the conversion from testosterone (P less than 0.05), and conversion was higher in men than in women. These data provide evidence for the direct formation of C19 steroid glucuronides by human skin.

Teratogenic effects of anticonvulsants.

The incidence of malformations in fetal mice exposed to phenytoin depends on drug dosage and the strain of mice. Animal research also suggests that most anticonvulsants are teratogenic in experimental animals when large doses are used, but the effect of valproate sodium on the fetus is poorly known. Cleft lip and palatal defects have been most extensively studied, but defects have also been noted in eyes, heart, and limb buds. Data from humans are less clearer than the animal data, but human maternal exposure to anticonvulsants may increase infant clefting by threefold to tenfold. If a woman at risk for childbearing is given anticonvulsants for the first time, carbamazepine may be given first. Before pregnancy, the true need for anticonvulsants should be reassessed, but abrupt discontinuation of anticonvulsants during pregnancy is not now recommended.

Phenytoin and carbamazepine in production of cleft palates in mice. Comparison of teratogenic effects.

The teratogenic activity of two anticonvulsant drugs, phenytoin sodium and carbamazepine, was studied in pregnant mice fed phenytoin and carbamazepine during days 8 to 13. Incidence of palatal defects and other abnormalities correlated with increasing dosages and blood levels of the drugs. Phenytoin produced a much higher incidence of teratogenic effects than carbamazepine.

Teratogenic effects of valproate in the CD-1 mouse fetus.

Valproate sodium has been implicated in the production of spina bifida in humans; this article reports an animal model. Teratogenicity of valproate sodium was studied by oral administration of single doses of 225, 340, and 560 mg/kg to pregnant CD-1 mice on days 7 through 12 of gestation. All fetuses were examined on day 17. Treated fetuses demonstrated external malformations and a decrease in weight. The incidence of malformations was greater at the higher dosage levels of 340 mg/kg and 560 mg/kg, with a predominance of exencephaly, open eyelids, and gross skeletal defects. There was a significant increase in the resorption rate of the fetuses in the treated groups. There was also a significant increase in the malformations observed per litter and per live fetus population when compared with controls.