Zika virus and assisted reproduction.

PURPOSE OF REVIEW: Due to the fact that the Zika virus can be sexually transmitted, there is a potential risk for disease transmission at several stages of assisted reproduction. Such a possibility poses a serious challenge to couples pursing fertility with reproductive technologies. Here, we discuss what is known regarding Zika virus infection with respect to sexual transmission and correlate this knowledge with recent recommendations in the realm of infertility treatment. RECENT FINDINGS: Zika virus can be transmitted from infected men and women through vaginal, oral or anal intercourse. Zika virus RNA has been detected in blood, semen, cervical mucus and vaginal fluid. Currently, the Centers for Disease Control recommends that infected men wait 6 months, and infected women 8 weeks, prior to attempting pregnancy. Reproductive tissue donors should wait 6 months before giving a specimen. SUMMARY: Further study of Zika virus transmission in different reproductive tissues and establishment of validated testing methods for viral disease transmissibility are urgently needed. Reproductive technologists need to establish screening, testing and laboratory protocols aimed to reduce the risk of Zika virus transmission during assisted reproduction.

Gynecologic Malignancies in Pregnancy: Balancing Fetal Risks With Oncologic Safety.

IMPORTANCE: Cancer occurs in 0.05% to 0.1% of all pregnancies. Despite literature reporting good oncologic and fetal outcomes in women treated for cancer during pregnancy, as many as 44% of gynecologists would offer termination, and 37% would not administer chemotherapy or radiotherapy in pregnancy. OBJECTIVES: The aims of this study were to summarize current recommendations for the treatment of cervical and ovarian cancers in pregnancy and to review updates on existing knowledge regarding the safety of surgical and chemotherapeutic treatments in pregnancy, including both oncologic and fetal outcomes. EVIDENCE ACQUISITION: A detailed literature review was performed on PubMed. RESULTS: The treatment of gynecologic malignancies during pregnancy mirrors that outside pregnancy, with a balance between maternal versus fetal health. Fertility-sparing surgery can be offered to stage IA2 and low-risk IB1 cervical, stage I epithelial ovarian, germ cell ovarian, or sex-cord stromal ovarian tumors. Delayed treatment can be offered for stage IB1 cervical cancer. Neoadjuvant and/or adjuvant chemotherapy can be given for advanced gynecologic cancers with good disease-free survival without significant adverse neonatal outcomes. CONCLUSIONS: A multidisciplinary approach and improved education of providers regarding the surgical and chemotherapeutic treatments in pregnancy are needed in order to fully inform patients regarding treatment options. Further research in women who are pregnant is needed to determine the safety of diagnostic and therapeutic procedures used in the nonpregnant woman. RELEVANCE: This article reviews and supports treatment of gynecologic cancer during pregnancy, calls for additional study and long-term follow-up, and justifies improved education of patients and providers regarding treatment options. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians. LEARNING OBJECTIVES: After completing this activity, the learner should be better able to (1) review general principles in the management and treatment of gynecologic cancers in pregnancy, (2) review the diagnosis and treatment of cervical cancer in pregnancy, and (3) review the diagnosis and treatment of ovarian cancer in pregnancy.

Breast Cancer in Pregnancy: Avoiding Fetal Harm When Maternal Treatment Is Necessary.

The management of breast cancer during pregnancy poses unique challenges and requires a multi-disciplinary approach. In this review, we discuss the treatment of breast cancer in pregnancy and recent updates regarding the safety of surgical and chemotherapeutic treatments, including both oncologic and fetal outcomes. The treatment of breast cancer during pregnancy mirrors that outside of pregnancy, with a few important differences dictated by the balance of maternal versus fetal health. Overall, surgical treatment, neo-adjuvant chemotherapy, and/or adjuvant chemotherapy are feasible in most women during pregnancy. Further research to determine the safety of these therapies in pregnancy-associated breast cancer is warranted.

Comparison of ovarian stimulation response in patients with breast cancer undergoing ovarian stimulation with letrozole and gonadotropins to patients undergoing ovarian stimulation with gonadotropins alone for elective cryopreservation of oocytes†.

The primary objective of this study is to compare the oocyte yield in breast cancer patients undergoing controlled ovarian stimulation (COS) using letrozole and gonadotropins with patients undergoing COS with standard gonadotropins for elective cryopreservation of oocytes. Odds ratios (OR) for the number of mature oocytes were estimated. Pregnancy outcomes for breast cancer patients undergoing frozen-thawed 2-PN embryo transfers (FETs) after oncologic treatment were also noted. 220 and 451 cycles were identified in the breast cancer and the elective cryopreservation groups, respectively. Patients in the former group had lower peak estradiol levels [464.5 (315.5-673.8) pg/mL] compared to the latter [1696 (1058-2393) pg/mL; p < 0.01]. More oocytes were retrieved in the breast cancer group (12.3 ± 3.99) compared to the elective cryopreservation group (10.9 ± 3.86; p < 0.01). The odds for mature oocytes with letrozole and gonadotropins was 2.71 (95% CI 1.29-5.72; p = 0.01). Fifty-six FETs occurred in the breast cancer group. The clinical pregnancy and live birth rates per FET cycle were 39.7%, and 32.3%, respectively. Our findings suggest that COS with letrozole and gonadotropins yield more mature oocytes at lower estradiol levels compared to COS with gonadotropins alone. Breast cancer patients undergoing FET after oncologic treatment have live birth rates comparable to age-matched counterparts.

Mathematical Modeling of the Biomarker Milieu to Characterize Preterm Birth and Predict Adverse Neonatal Outcomes.

PROBLEM: To identify preterm neonates at risk for adverse neonatal outcomes. METHOD OF STUDY: A nested case-control study from the prospectively followed Boston Birth Cohort of mother-neonate pairs was performed. A classification model for preterm-born neonates was derived from 27 cord blood biomarkers using orthogonal projections to latent structures discriminant analysis. Predictive relationships were made between biomarkers and adverse outcomes using logistic regression. RESULTS: From 926 births (53% of which were preterm), using weighted values for 27 biomarkers, a score was created that classified 73% of preterm deliveries. Soluble TNF-R1, NT-3, MCP-1, BDNF, IL-4, MMP-9, TREM-1, TNF-α, IL-5 and IL-10 were most influential. Our model was more sensitive for birth <34 weeks (sensitivity 89.5%, specificity 76.9%). IL-10, TNF-α, BDNF, NT-3, MMP-9, sTNF-R1 and MCP-1 were significantly predictive of NEC, IVH, sepsis and infections. CONCLUSION: We developed a novel mathematical model of 27 biomarkers associated with adverse neonatal outcomes in neonates born preterm.

In Vitro Activation: A Possible New Frontier for Treatment of Primary Ovarian Insufficiency.

In vitro activation (IVA) represents a new frontier in the treatment of women with primary ovarian insufficiency as well as patients with cancer desiring fertility preservation. Here, we review the biological basis of IVA and the recent translation of IVA to humans by targeting Hippo and Akt-signaling pathways. We then provide a new integrated viewpoint on IVA, highlighting basic science research on the aspects of follicular development and ovarian tissue transplantation which may potentially optimize future translational research on IVA. Specific topics discussed include cryopreservation techniques, additional IVA pathway targets, the roles of actin polymerization, paracrine and endocrine factors, and the role of mechanical signaling and associated tissue rigidity in controlling ovarian follicular activation. Further research and improved understanding is needed to optimize success of IVA.

Infections and Brain Development.

Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner.

Measurement of antral follicle count in patients undergoing in vitro fertilization treatment: results of a worldwide web-based survey.

PURPOSE: The purpose of the present study was to identify trends in the therapeutic approaches used to measure antral follicle count (AFC) in patients undergoing in vitro fertilization (IVF) treatment worldwide. METHODS: A retrospective evaluation utilizing the results of a web-based survey, IVF-Worldwide ( www.IVF-Worldwide.com ), was performed. RESULTS: Responses from 796 centers representing 593,200 cycles were evaluated. The majority of respondents (71.2 %) considered antral follicle count as a mandatory part of their practice with most (69.0 %) measuring AFC in the follicular phase. Most respondents (89.7 %) reported that they would modify the IVF stimulation protocol based on the AFC. There was considerable variation regarding a limit for the number of antral follicles required to initiate an IVF cycle with 46.1 % designating three antral follicles as their limit, 39.9 % selecting either four or five follicles as their limit, and 14.0 % reporting a higher cutoff criteria. With respect to antral follicle size, 61.5 % included follicles ranging between 2 and 10 mm in the AFC. When asked to identify the best predictor of ovarian hyper-response during IVF cycles, AFC was selected most frequently (49.4 %), followed by anti-Mullerian hormone level (42.7 %). Age was selected as the best predictor of ongoing pregnancy rate in 81.7 % of respondents. CONCLUSIONS: While a large proportion of respondents utilized AFC as part of their daily practice and modified IVF protocol based on the measurement, the majority did not consider AFC as the best predictor of ongoing pregnancy rate.

Herpes Simplex Virus Cervicitis Mimicking Preterm Premature Rupture of Membranes.

BACKGROUND: The diagnosis of preterm premature rupture of membranes (PROM) is based on pooling, ferning, and Nitrazine tests; definitive diagnosis is made with a blue dye test. CASE: A 21-year-old woman, gravida 1 para 0, at 25 5/7 weeks of gestation was admitted for preterm PROM with positive findings of pooling, Nitrazine, and ferning. Her cervix was bluish with white plaques. Amniotic fluid volume was normal. On hospital day 8, her discharge ceased; examination was negative for pooling, Nitrazine, and ferning. A blue dye tampon test was negative. A Pap test result from her hospitalization returned consistent with herpes infection. CONCLUSION: The diagnosis of preterm PROM should be constantly reevaluated in the setting of a normal amniotic fluid volume.

Nipple-Sparing Mastectomy via an Inframammary Fold Incision with Implant-Based Reconstruction in Patients with Prior Cosmetic Breast Surgery.

BACKGROUND: Nipple-sparing mastectomy through an inframammary fold incision (NSM-IMF) with implant-based reconstruction (IBR) is a cosmetically preferable approach to breast cancer treatment in appropriate candidates. However, patients who have undergone prior cosmetic breast surgery (CBS) may be at increased risk for postoperative complications secondary to existing surgical scars. OBJECTIVE: To assess whether prior CBS increases the risk of complications following NSM-IMF with IBR. METHODS: A retrospective chart review was conducted for 398 NSM-IMFs with IBR performed between July 2006 and December 2013. CBS cases were identified. Outcomes were reviewed. RESULTS: Of 398 NSM-IMF cases, 41 had prior CBS: 24 augmentations, 12 reductions, three mastopexies, and two augmentation mastopexies. NSM-IMF was performed an average of 8 years following CBS. CBS cases had lower BMIs (P = .040), more breast tissue resected (P = .021), wider breast bases (P = .0002), more single-stage reconstructions (P < .0001), more ADM use (P < .0001), and larger permanent implants (P = .0051) than those without CBS. Postoperatively, CBS cases had higher rates of mastectomy flap ischemia (P = .0392) and hematoma (P = .0335). Among CBS cases, single-stage reconstruction was associated with increased full-thickness flap ischemia (P = .0066). Compared to prior augmentation cases, prior reduction/mastopexy cases had higher rates of capsular contracture (P = .0409) and seroma (P = .0226). CONCLUSIONS: This series is the largest to date to evaluate the success of NSM-IMF with IBR in CBS patients. These women should be cautiously considered for IBR, particularly in the setting of single-stage reconstruction. LEVEL OF EVIDENCE: 4 Therapeutic.

Perinatal biomarkers in prematurity: early identification of neurologic injury.

Over the past few decades, biomarkers have become increasingly utilized as non-invasive tools in the early diagnosis and management of various clinical conditions. In perinatal medicine, the improved survival of extremely premature infants who are at high risk for adverse neurologic outcomes has increased the demand for the discovery of biomarkers in detecting and predicting the prognosis of infants with neonatal brain injury. By enabling the clinician to recognize potential brain damage early, biomarkers could allow clinicians to intervene at the early stages of disease, and to monitor the efficacy of those interventions. This review will first examine the potential perinatal biomarkers for neurologic complications of prematurity, specifically, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and posthemorrhagic hydrocephalus (PHH). It will also evaluate knowledge gained from animal models regarding the pathogenesis of perinatal brain injury in prematurity.

Demystifying trans-axillary augmentation/periareolar mastopexy: a novel, two-stage, single-operation approach to management of the contralateral breast in implant reconstruction.

BACKGROUND: Following unilateral tissue expander/implant reconstruction, combined augmentation/mastopexy of the contralateral breast may be performed in an attempt to improve breast symmetry. Combined augmentation/mastopexy can be a very difficult operation, even for the surgeon with substantial experience. To simplify the technical approach to this complex problem, the senior author (PGC) has developed a 'two-stage, single-operation' approach. The purpose of this study is to review the safety and efficacy of this approach to the contralateral breast in the setting of unilateral, implant-based reconstruction. METHODS: A retrospective review of all combined trans-axillary augmentation/periareolar mastopexies performed from 1998 to 2007 was undertaken. Only patients who had a history of prior unilateral mastectomy and immediate expander placement were included. Photographic documentation of long-term aesthetic results was evaluated by two independent observers. RESULTS: In total, 26 combined, trans-axillary augmentation/periareolar mastopexies were performed in patients, who had initiated unilateral, postmastectomy, tissue expander/implant reconstruction on the contralateral side. No patient desired revisional surgery for inadequate ptosis correction or malpositioning of the nipple. A total of 69% of patients had a 'very good to excellent' overall aesthetic result. Of those patients who were deemed to have a 'good' aesthetic result, the development of a capsular contracture in the reconstructed breast detracted from the overall aesthetics. CONCLUSION: The two-stage, single-operation approach to unilateral augmentation/mastopexy described here can produce a good aesthetic result and allow for adequate oncologic follow-up. In particular, excellent results are seen in patients with grade I or II ptosis and good-quality skin preoperatively. Monitoring of the breast for cancer, using mammography, is still possible with this technique.

A quantitative comparison of psychological and emotional health measures in 360 plastic surgery candidates: is there a difference between aesthetic and reconstructive patients?

This study examines the utility of the aesthetic and reconstructive categorization for making treatment decisions in patients seeking facial surgery. A total of 360 patients with aesthetic or combined functional aesthetic deficits were included. Validated psychological scales were used as outcome measures. All subjects showed clinically significant levels of appearance-related distress, with highest levels in the aesthetic and lowest levels in the functionally impaired group. Significant gender differences were not found on any psychological measures. A small negative correlation was found between age and distress. These findings challenge the validity of restricting treatment on the basis of an aesthetic distinction, since this is the group demonstrating the highest level of need. Neither age nor gender is a reliable discriminator. Subjective assessment of noticeability of disfigurement and associated psychological distress may be more useful in prioritizing treatment in systems with limited resources.

The vertically oriented free myocutaneous gracilis flap in head and neck reconstruction.

Oncologic resections in the head and neck can result in a variety of complex defects. Many free tissue transfers have been described for soft-tissue reconstruction in this area. The pedicled, vertical gracilis myocutaneous flap has been well described for use in the perineum, but is rarely used as a free tissue transfer because of previously documented unreliability of the skin island. The objective of this study was thus to review a single author's experience with reconstruction of complex head and neck defects using the vertically oriented free myocutaneous gracilis flap. A retrospective review of all head and neck reconstructions at a major cancer center from 2003-2006 was performed. Demographic, oncologic and reconstructive data were retrieved from a prospectively maintained clinical database. Ten patients (mean age, 57 years; range, 33-84 years) with complex defects of the head and neck were reconstructed using a gracilis myocutaneous flap with a vertically oriented skin paddle. Seven patients had a malignant skin tumor; 3 patients had a parotid gland tumor. Mean surface area requirements were 88.6 cm. Composite resections were common and included skin, facial nerve, mandibular and/or temporal bone, partial glossectomy, parotidectomy, and/or orbital exenteration. Six patients had a history of prior irradiation; 6 patients received postoperative radiotherapy. Mean follow-up was 8 months (range, 2-20 months). Total flap survival was 100%. There were no partial flap losses. Primary wound healing occurred in all cases. The vertically oriented free myocutaneous gracilis flap is a reliable option for reconstruction of moderate volume and surface area defects in the head and neck. It represents an underutilized flap that should be more commonly considered for soft-tissue reconstruction of complex defects in the head and neck.

Squamous cell carcinoma related oncogene regulates angiogenesis through vascular endothelial growth factor-A.

BACKGROUND: Squamous cell carcinoma related oncogene expression (SCCRO) correlates with vascular endothelial growth factor-A expression. This data is validated in human lung tumors and provides a putative pathway for angiogenesis in a subset of squamous cell carcinomas. Squamous cell carcinoma related oncogene is a novel oncogene identified by positional cloning of a recurrent amplification at 3q26.3. It is over-expressed in 39.8% of lung, head and neck, cervical, and ovarian carcinomas. SCCRO imparts an aggressive phenotype to affected cancers, which may be related to increased angiogenesis due to SCCRO expression. Our previous work has demonstrated a link between SCCRO and vascular endothelial growth factor-A (VEGF-A) expression in vitro, suggesting a mechanism for SCCRO-induced angiogenesis. The present study aims to confirm and validate this link between SCCRO and VEGF-A expression in an ex vivo human tumor cohort. METHODS: Fresh tissue was collected at Memorial Sloan-Kettering Cancer Center from 34 patients undergoing primary resection of lung squamous cell carcinomas. RNA was extracted from this tissue, reverse-transcribed, and real-time polymerase chain reaction (RT-PCR) was carried out using a BioRad iQ iCycler with SYBR green fluorophore. Microvessel counting was performed on the tumor specimens using CD34 immunohistochemistry. RESULTS: The expression of both SCCRO and VEGF-A mRNA varies widely in both tumor and normal tissue. SCCRO and VEGF-A co-expression was significantly correlated (R(2) = 0.63; P < 0.032). Microvessel counts were not associated with expression of SCCRO or VEGF-A and failed to significantly predict survival. VEGF-A expression in this patient group is a predictor of overall survival (P < 0.032). CONCLUSIONS: VEGF-A expression correlates with SCCRO expression in these primary human lung squamous cell carcinomas and is a predictor of clinical behavior. This data supports the association of SCRRO and VEGF-A in the induction of angiogenesis.