Development of a single-visit protocol for the management of pregnancy of unknown location following in vitro fertilization: a retrospective study.

STUDY QUESTION: Can women with pregnancy of unknown location (PUL) following in vitro fertilization (IVF) be risk-stratified regarding the subsequent need for medical intervention, based on their demographic characteristics and the results of serum biochemistry at the initial visit? SUMMARY ANSWER: The ratio of serum hCG to number of days from conception (hCG/C) or the initial serum hCG level at ≥5 weeks' gestation could be used to estimate the risk of women presenting with PUL following IVF and needing medical intervention during their follow-up. WHAT IS KNOWN ALREADY: In women with uncertain conception dates presenting with PUL, a single serum hCG measurement cannot be used to predict the final pregnancy outcomes, thus, serial levels are mandatory to establish a correct diagnosis. Serum progesterone levels can help to risk-stratify women at their initial visit but are not accurate in those taking progesterone supplementation, such as women pregnant following IVF. STUDY DESIGN, SIZE, DURATION: This was a retrospective study carried out at two specialist early pregnancy assessment units between May 2008 and January 2021. A total of 224 women met the criteria for inclusion, but 14 women did not complete the follow-up and were excluded from the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: We selected women who had an IVF pregnancy and presented with PUL at ≥5 weeks' gestation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 30/210 (14.0%, 95% CI 9.9-19.8) women initially diagnosed with PUL required surgical intervention. The hCG/C was significantly higher in the group of women requiring an intervention compared to those who did not (P = 0.003), with an odds ratio of 3.65 (95% CI 1.49-8.89, P = 0.004). A hCG/C <4.0 was associated with a 1.9% risk of intervention, which accounted for 25.7% of the study population. A similar result was obtained by substituting hCG/C <4.0 with an initial hCG level <100 IU/l, which was associated with 2.0% risk of intervention, and accounted for 23.8% of the study population (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is that it is retrospective in nature, and as such, we were reliant on existing data. WIDER IMPLICATIONS OF THE FINDINGS: A previous study in women with PUL after spontaneous conception found that a 2% intervention rate was considered low enough to eliminate the need for close follow-up and serial blood tests. Using the same 2% cut-off, a quarter of women with PUL after IVF could also avoid attending for further visits and investigations. STUDY FUNDING/COMPETING INTEREST(S): No external funding was required for this study. No conflicts of interest are required to be declared. TRIAL REGISTRATION NUMBER: N/A.

Predictive value of presence of amniotic sac without visible embryonic heartbeat in diagnosis of early embryonic demise.

OBJECTIVES: To assess the diagnostic value and impact on management of visualizing on ultrasound an amniotic sac without a live embryo (amniotic sac sign). We also examined the potential effect on the number of follow-up visits in early pregnancy units of incorporating this sign into current diagnostic algorithms. METHODS: This was a prospective cohort study of all pregnant women who attended a single specialist early pregnancy unit from July 2017 to November 2018 with symptoms of pain and/or bleeding, or with a history of ectopic pregnancy or miscarriage, at < 14 weeks' gestation. Detailed initial ultrasound findings were documented, including whether an amniotic sac was present in a normally sited intrauterine pregnancy with absence of a live embryo. Women were followed up until a conclusive diagnosis was made. RESULTS: The study included 6012 women who attended our unit with early pregnancy complications during the study period. A conclusive diagnosis was reached on the initial scan in 4221 (70.2%), whilst 1135 (18.9%) women had a pregnancy of uncertain viability and 656 (10.9%) had a pregnancy of unknown location (PUL). All women with a pregnancy of uncertain viability required follow-up ultrasound scans to differentiate between a live pregnancy and early embryonic demise. An amniotic sac in the absence of a live embryo was found in 174/1135 (15.3%) women with a pregnancy of uncertain viability at the initial ultrasound scan. The diagnosis of early embryonic demise was confirmed in all 134 of these women who attended their follow-up scans. The presence of an amniotic sac without a live embryo at the initial visit had a specificity of 100% (95% CI, 98.53-100.00%) and positive predictive value of 100% (95% CI, 97.2-100.0%) for the diagnosis of early pregnancy failure. A total of 1403/6012 (23.3%) women were asked to attend for a follow-up ultrasound scan to resolve diagnostic uncertainties, including 268/656 (40.9%) women with a PUL. The majority of follow-up scans needed to reach a conclusive diagnosis were in women with a pregnancy of uncertain viability (1135/1403 (80.9%)). By using the presence of the amniotic sac sign to diagnose early pregnancy failure at the first visit, the number of follow-up scans for pregnancies of uncertain viability would be reduced by 14.4%, which accounted for 11% of all follow-up scans during the study period. CONCLUSIONS: The finding on ultrasound of an amniotic sac without a live embryo (amniotic sac sign) is a reliable marker of early pregnancy failure and could reduce the number of follow-up scans by 11% in cases of diagnostic uncertainty. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Intra- and interobserver reproducibility of pelvic ultrasound for the detection and measurement of endometriotic lesions.

STUDY QUESTION: What is the interobserver and intraobserver reproducibility of pelvic ultrasound for the detection of endometriotic lesions? SUMMARY ANSWER: Pelvic ultrasound is highly reproducible for the detection of pelvic endometriotic lesions. WHAT IS KNOWN ALREADY: Transvaginal ultrasound (TVS) has been widely adopted as the first-line assessment for the diagnosis and assessment of pelvic endometriosis. Severity of endometriosis as assessed by ultrasound has been shown to have good concordance with laparoscopy (kappa 0.79). The reproducibility of TVS for assessment of ovarian mobility and pouch of Douglas obliteration using the 'sliding sign' has already been described in the literature. However, there is no available data in the literature to demonstrate the intraobserver repeatability of measurements for endometriotic cysts and nodules. STUDY DESIGN SIZE DURATION: This was a prospective observational cross-sectional study conducted over a period of 12 months. We included 50 consecutive women who were all examined by two operators (A and B) during their clinic attendance. PARTICIPANTS/MATERIALS SETTING METHODS: The study was carried out in a specialist endometriosis centre. We included all consecutive women who had ultrasound scans performed independently by two experienced operators during the same visit to the clinic. The outcomes of interest were the inter- and intraobserver reproducibility for the detection of endometriotic lesions. We also assessed repeatability of the measurements of lesion size. MAIN RESULTS AND THE ROLE OF CHANCE: There was a good level of agreement between operator A and operator B in detecting the presence of pelvic endometriotic lesions (k = 0.72). There was a very good level of agreement between operators in identifying endometriotic cysts (k = 0.88) and a good level of agreement in identifying endometriotic nodules (k = 0.61). The inter- and intraobserver repeatability of measuring endometriotic cysts was excellent (intra-class correlation (ICC) ≥ 0.98). There was good interobserver measurement repeatability for bowel nodules (ICC 0.88), but the results for nodules in the posterior compartment were poor (ICC 0.41). The intraobserver repeatability for nodule size measurements was good for both operators (ICC ≥0.86). LIMITATIONS REASONS FOR CAUTION: Within this cohort, there was insufficient data to perform a separate analysis for nodule size in the anterior compartment. All examinations were performed within a specialised unit with a high prevalence of deep endometriosis. Our findings may not apply to operators without intensive ultrasound training in the diagnosis of pelvic endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: These findings are important because ultrasound has been widely accepted as the first-line investigation for the diagnosis of pelvic endometriosis, which often determines the need for future investigations and treatment. The detection and measurement of bowel nodules is essential for anticipation of surgical risk and planning surgical excision. STUDY FUNDING/COMPETING INTERESTS: The authors have no conflict of interest. No funding was obtained for this work.

Effect of morphological type of extrauterine ectopic pregnancy on accuracy of preoperative ultrasound diagnosis.

OBJECTIVES: To assess the overall accuracy of transvaginal ultrasound (TVS) for diagnosis of all types of extrauterine ectopic pregnancy (EUEP) in a large group of women who were managed surgically. We also aimed to assess the positive predictive value (PPV) of TVS for each of the different ultrasound morphological types of EUEP. METHODS: This was a retrospective observational study of all pregnant women who underwent emergency surgery following ultrasound diagnosis of EUEP at a single early pregnancy unit between January 2009 and December 2017. The preoperative TVS findings were recorded, including the exact location and morphological type (Type I-V; defined using ultrasound criteria) of EUEP. TVS findings were compared with operative and histological findings. The performance of ultrasound in diagnosing EUEP overall and according to morphological type was assessed, using visual confirmation of ectopic pregnancy at surgery as the reference standard. RESULTS: A total of 26 401 women presented with early-pregnancy complications during the study period, including 1241 (4.7%; 95% CI, 4.5-5.0%) women with a conclusive diagnosis of EUEP on TVS or a presumed diagnosis based on severe pain and significant hemoperitoneum. Surgery was performed in 721/1241 (58.1%; 95% CI, 55.3-60.8%) cases, of which 710 (98.5%; 95% CI, 97.6-99.4%) had a conclusive diagnosis of EUEP on preoperative TVS. The remaining 11 women had severe pain and significant hemoperitoneum and were managed surgically on clinical grounds as an emergency, without an ectopic pregnancy having been identified on ultrasound examination. At laparoscopy, the diagnosis of EUEP was confirmed in 706/710 (99.4%; 95% CI, 98.6-99.8%) women with a positive ultrasound diagnosis and in all 11 women with a presumed ultrasound diagnosis of EUEP. The PPV of preoperative ultrasound for the diagnosis of EUEP was 99.4% (95% CI, 98.6-99.8%) with sensitivity of 98.5% (95% CI, 97.3-99.1%). There was no statistically significant difference in the accuracy of preoperative ultrasound diagnosis between the five morphological types (P = 0.76). CONCLUSIONS: The accuracy of preoperative ultrasound for diagnosis of EUEP is high. The morphological type of EUEP on TVS had no significant effect on the accuracy of preoperative diagnosis. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Models of self and others and their relation to positive and negative caregiving responses.

The burden of providing informal care to a family member can lead to caregiver depression and potentially harmful caregiving behavior. Given the interpersonal nature of caregiving, the relationship between caregivers and care recipients may impact caregiver responses. We applied attachment theory to understanding caregiver depression, and both potentially harmful and exemplary caregiving responses. We present data from 430 caregivers in the Family Relationships in Late Life (FRILL 2) Project, a multisite, longitudinal study of caregiving. Age, gender, and model of self were related to caregiving responses, suggesting that model of self may help identify caregivers at risk for poor responses.

Redefining lumpectomy using a modification of the "sick lobe" hypothesis and ductal anatomy.

Objectives. The "Sick Lobe" hypothesis states that breast cancers evolve from entire lobes or portions of lobes of the breast where initiation events have occurred early in development. The implication is that some cancers are isolated events and others are truly multi-focal but limited to single lobar-ductal units. Methods. This is a single surgeon retrospective review of early stage breast cancer lumpectomy patients treated from 1/2000 to 2/2005. Ductal endoscopy was used direct lumpectomy surgical margins by defining ductal anatomy and mapping proliferative changes within the sick lobe for complete excision. Results. Breast conservation surgery for stage 0-2 breast cancer with an attempt to perform endoscopy in association with therapeutic lumpectomy was performed in 554 patients (successful endoscopy in 465 cases). With an average followup of >5 years for the entire group, annual hazard rate for local failure in traditional lumpectomy without ductal mapping was 0.97%/yr. and for lumpectomy with ductal mapping and excision of entire sick lobe was 0.18%/yr. With endoscopy, 42% of patients were found to have extensive disease within their "sick lobe." Conclusions. Targeting breast cancer lumpectomy using endoscopy and excision of regional associated proliferation seems associated with lower recurrence in this non-randomized series.

Clinical series of oncoplastic mastopexy to optimize cosmesis of large-volume resections for breast conservation.

BACKGROUND: Oncoplastic mastopexy has been popularized as a method to hide the cosmetic effects of central or large-volume resections associated with breast conservation surgery for breast cancer. MATERIALS AND METHODS: This review was undertaken to study the uses and limitations of these techniques in providing adequate breast conservation lumpectomy for breast cancer of any stage in a single surgeon's practice. A review of breast cancer cases March 2004 through December 2009 were analyzed for the use of oncoplastic reconstruction in breast conservation surgery. RESULTS: A total of 167 patients had lumpectomies during this period associated with oncoplastic mastopexy reconstruction. The average age was 55.6 years with a range of 33-85 years. Stage 0 breast cancer accounted for 33 cases (19.8%), and 134 cases were invasive cancers stages 1-3 (stage 1, 34.1%; stage 2, 30.6%; and stage 3, 15.6%). The most common oncoplastic techniques used were, in order of frequency: batwing mastopexy, parallelogram mastopexy, and Modified Wise pattern mastopexy. Positive or close margins (≤ 2 mm) were present in 37 of 167 cases (22%). Positive margins were most associated with higher stage, positive nodes, positive lymphovascular invasion (LVI), use of neoadjuvant chemotherapy, and larger initial T stage, positive estrogen receptor (ER), and younger age. Of these higher stage, node positive, and use of neoadjuvant chemotherapy were statistically significant in this small series (P values = 0.034, 0.016, and 0.022, respectively). Ki-67 and HER2 status were not associated with positive margins. Positive margins were manageable by local re-excision of a solitary face of the prior resection wall in more than 2/3 of cases to achieve negative pathologic margins. Only 11 of 167 required mastectomy because of failure to achieve adequate margins for oncologic control. CONCLUSIONS: Oncoplastic mastopexy allows the surgeon to address large tumors or tumors in cosmetically difficult sites adequately for breast conservation. Careful margin marking and re-excision of close or positive margins is still often feasible to achieve adequate negative margin with acceptable cosmesis in spite of the large initial volumes of resection.

Caregiver mental health and potentially harmful caregiving behavior: the central role of caregiver anger.

PURPOSE: Caregivers feeling stress and experiencing mental health problems can be at risk for engaging in abusive acts against elderly care recipients. Potentially harmful behavior (PHB) was used as a measure of caregivers' engagement in, or fear of engagement in, behavior that places dependent care recipients at risk of physical and/or psychological maltreatment and may be seen as an antecedent of, or a proxy for, identifiably abusive behavior. The study examined the ability of anger to mediate and moderate the relations of depression, resentment, and anxiety with PBH. DESIGN AND METHODS: Data are from the first wave of the second Family Relationships in Late Life study of caregivers of community-dwelling elderly care recipients with whom they coreside. Caregivers (N = 417) completed face-to-face interviews. RESULTS: Anger was found to mediate the relation between anxiety and PHB. Anger both mediates and moderates the relations of both depression and resentment with PHB in a dynamic way such that the mediating effect of anger increases substantially with increased scores on both depression and resentment. IMPLICATIONS: Identifying anger levels among caregivers who report symptoms of depression is warranted. Reducing depression in caregivers who report high levels of anger may result in reductions of PHB. Screening for resentment is warranted, as the relation between resentment and anger is similar to that between depression and anger.

Endorsement of proactively aggressive caregiving strategies moderates the relation between caregiver mental health and potentially harmful caregiving behavior.

This research tested the proposition that the oft-reported relation between caregiver mental health outcomes (i.e., resentment, depression) and potentially harmful caregiver behavior (PHB) would be mediated or moderated by caregiver endorsement of proactively aggressive caregiving strategies (PA). Caregiver resentment was the strongest predictor of PHB in the sample of 417 informal caregivers who resided with their care recipients; in fact, resentment mediated the impact of caregiver depression, thus suggesting that depressed affect was associated with PHB only if depressed caregivers resented their caregiving burdens. As predicted, caregiver endorsement of PA moderated the relation between resentment and PHB, such that links between these two constructs were strongest when caregivers were high in both resentment and PA. Endorsement of PA also mediated the relations between demographic or contextual variables (i.e., income, care recipient dementia) and PHB. Implications of these results for research and intervention are discussed.

Caregiver cognitive status and potentially harmful caregiver behavior.

The association between caregiver cognitive status and potentially harmful caregiver behavior was assessed in a sample of 180 caregiver-care recipient dyads. Compromised cognitive status was identified in 39% of these informal caregivers. Beyond variance explained by demographic factors, amount of care provided, care recipient cognitive status, and caregiver depressed affect, care recipients reported more frequently being subjected to potentially harmful caregiver behavior when their caregivers evidenced compromised cognitive status. While preliminary, critical areas of caregiver cognition appeared to be deficits in language comprehension and memory. Results indicate that compromised cognitive status is common among informal caregivers of impaired elders and that this may adversely influence the quality of care they provide.

Success of sentinel lymph node mapping after breast cancer ablation with focused microwave phased array thermotherapy.

BACKGROUND: Breast cancer tumor ablation as part of a multimodality approach in the treatment of breast cancer is the subject of recent interest. This study was conducted to determine if the ability to perform sentinel node biopsy was impaired after thermal-induced ablation of breast cancer. METHODS: We studied patients who had sentinel node biopsy after preoperative focused microwave phased array for breast cancer ablation. RESULTS: Twenty-one patients with T1-T2 breast cancer and clinically negative axilla underwent wide local excision and sentinel node biopsy guided by blue dye and sulfur colloid. Surgery was done an average of 17 days after microwave ablation. Fifteen of 22 patients (68%) had histologic evidence of tumor necrosis. Sentinel lymph node mapping was successful in 19 of 21 patients (91%). Axillary metastases were detected in 42% of cases. CONCLUSIONS: This study documents successful sentinel lymph node mapping for patients treated with antecedent local tumor ablation using focused microwave phased array ablation.

Association of maspin expression with the high histological grade and lymphocyte-rich stroma in early-stage breast cancer.

AIMS: Maspin is a recently described member of the serpin family or protease inhibitors that is known to be a tumour suppressor gene product. Loss of maspin expression has been found in most breast cancer cases and is correlated with cell motility and tumour invasiveness. However, its precise role in human breast cancer remains to be discovered. We aimed to evaluate the role of maspin in early-stage breast cancer. METHODS AND RESULTS: We analysed the expression of maspin in 192 stage I and II primary breast cancers by immunohistochemistry. Of these cases, 34.4% showed maspin expression. Maspin expression was more frequently found in invasive ductal carcinoma (36.4%) than in invasive lobular carcinoma (7.1%). High maspin expression was demonstrated in breast cancers showing high histological grade or lymphocyte-rich stroma (P < 0.05). Maspin expression was not associated with overall and disease-free survival rate of breast cancer. CONCLUSIONS: The results indicate that different biological mechanisms may be responsible for maspin expression in histologically distinct types of breast cancer. Our survey suggests that maspin expression in breast cancer might have a compensatory role rather than prognostic one.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Expression of pp32 gene family members in breast cancer.

The pp32 gene family consists of at least three closely related members, pp32, pp32r1 and pp32r2. In spite of a high degree of identity at the nucleotide level, pp32 functionally behaves as a tumor suppressor where as pp32r1 and pp32r2 are pro-oncogenic. The purpose of this pilot study was to determine pp32-related expression and whether alternative gene use among the pp32 family members occurred in human breast cancer. As a first step, in situ hybridization with a riboprobe capable of hybridizing with all the three members showed abundant pp32-related mRNA in benign ducts and acini and in infiltrating ductal carcinomas. A total of 100/102 cases were positive. Further, a detailed molecular analysis by RT-PCR, cloning, and sequencing was performed in five frozen infiltrating breast carcinomas and matched benign breast tissues. Oncogenic pp32r1 (5/5) and pp32r2 (3/5) expression was observed in carcinomas where as benign breast tissues expressed pp32. 4/5 carcinomas continued to express pp32 but one was devoid of pp32 expression. These results suggest that alternative expression of pp32 family members may be common in human breast cancer and the analysis of the profile of pp32-related expression might be helpful in understanding the role of these genes in breast cancer pathogenesis.

Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR.

If detected early, breast cancer is curable. We tested cells collected from the breast ducts by methylation-specific PCR (MSP). Methylated alleles of Cyclin D2, RAR-beta, and Twist genes were frequently detected in fluid from mammary ducts containing endoscopically visualised carcinomas (17 cases of 20), and ductal carcinoma in situ (two of seven), but rarely in ductal lavage fluid from healthy ducts (five of 45). Two of the women with healthy mammograms whose ductal lavage fluid contained methylated markers and cytologically abnormal cells were subsequently diagnosed with breast cancer. Carrying out MSP in these fluid samples may provide a sensitive and powerful addition to mammographic screening for early detection of breast cancer.

Surgery in breast cancer.

This year (1999) has been filled with new information on the prevention of breast cancer and new literature trying to address some of the long-term adverse consequences of our surgical therapies. As the complexities of our therapies continue to increase at exponential rates, we now also have the ability to more accurately predict the consequences of both our therapeutic actions and our failure to act. Nowhere is this more evident than in the literature devoted to long-term consequences of treatment for breast cancer. As we are more successful in achieving our goals of increased survival from this dreaded disease, the future needs of these long-term survivors must play an ever-increasing role in our current management. Advances reported this year are laying down a new basis for efforts to improve the quality of life for breast cancer survivors.

Telomerase activity and prognosis in primary breast cancers.

PURPOSE: Recent studies associate telomerase activity with prognostic factors and survival. We compared quantitative telomerase activity in primary tumors with traditional prognostic factors and outcome in a group of invasive but nonmetastatic breast cancers. PATIENTS AND METHODS: Telomerase activity was measured in 203 invasive breast cancers by the quantitative telomeric repeat amplification protocol method. Telomerase expression was compared with 28S rRNA level, tumor content, and clinical variables, including outcome. For clinical correlations, telomerase activity was standardized by two methods: (1) a correction for cellularity using 28S rRNA levels, and (2) a correction for the histologically determined invasive proportion of the specimen. RESULTS: Telomerase activity was found in 82% of breast cancers with measurable 28S rRNA levels. Telomerase activity was associated with the proliferative index (P <.01) of the tumor but not with any other prognostic variable. Neither uncorrected nor corrected telomerase activity was associated with relapse-free or overall survival in this study. CONCLUSION: Telomerase activity level was associated with the proliferative index of invasive breast cancers, but its measurement in samples from this group of nonmetastatic breast cancer patients did not predict survival.