Analysis of the Understanding and Worry about Lymphedema of Patients with Breast Cancer.

BACKGROUND: Lymphedema is a potential lifelong sequela of breast cancer treatment. We sought to: (1) evaluate the worry and knowledge of patients about lymphedema, (2) quantify patients reporting lymphedema education and screening, and (3) determine willingness to participate in lymphedema screening and prevention programs. PATIENTS AND METHODS: A survey evaluating lymphedema-related knowledge and worry was sent to patients treated for stage 0-III breast cancer. Exclusion criteria included > 10 years since diagnosis, missing clinical staging, and those without axillary surgery. Responses were linked with clinicopathologic information. RESULTS: Of 141 patients meeting inclusion criteria, 89% of those without lymphedema were not at all or slightly worried about lymphedema. Higher levels of worry were associated with clinical stage II-III disease [odds ratio (OR) 2.63, p = 0.03], a history of axillary lymph node dissection (ALND) (OR 4.58, p < 0.01), and employment (OR 2.21, p = 0.05). A total of 102 (72%) patients recalled receiving lymphedema education. Lymphedema knowledge was limited, with < 25% of respondents answering > 50% of the risk factor questions correctly. Worry and knowledge were not significantly associated. Of patients without lymphedema, 36% were interested in learning more about lymphedema and 64% were willing to participate in or learn more about a screening program. Most (66%) felt that lymphedema information should be provided before and after cancer treatment. DISCUSSION: A majority of our breast cancer survivors had limited knowledge about lymphedema risk factors. While most patients were not worried about developing lymphedema, higher worry was seen in patients with a higher clinical stage at diagnosis, ALND, and employment. Our findings suggest potential targets and timing for patient-centered educational interventions.

Multimodal analgesia after thyroid or parathyroid surgery: A randomized controlled trial.

BACKGROUND: The opioid epidemic prompted reevaluation of surgeons' opioid prescribing practices. This study aimed to demonstrate noninferiority of a staged analgesic regimen after endocrine surgery. METHODS: We conducted a randomized controlled trial comparing analgesic regimens after thyroidectomy and/or parathyroidectomy. Adult patients (≥18 years) were randomized to study arm (A) as-needed acetaminophen + codeine or (B) scheduled acetaminophen/as-needed tramadol. Patients recorded pain scores and analgesics consumed in a study log. Clinical variables were collected from the medical record. RESULTS: Target enrollment was achieved (n = 126), and randomization was even (A: 44.5%, B: 55.6%). There was no difference between enrolled patients and those who returned the study log (52.4%) by sex (P = .667), age (P = .513), final pathology (P = .137), procedure (P = .667), or randomization arm (P = .795). Most patients (50.8%) reported moderate pain scores (4-6) with no difference between study arms (P = .451). There was no difference in average consumption by morphine milligram equivalents (A: 11.5 ± 12.1 vs B: 12.49 ± 18.07; P = .792) nor total analgesic doses (A: 7.29 ± 7.48 vs B: 8.5 ± 5.36; P = .445). However, a significant difference in average percentage of opioid doses was noted (A: 79.71 ± 33.31 vs B: 27.38 ± 31.88; P < .001). CONCLUSION: Patients reported moderate pain scores with low requirements for analgesics after endocrine surgery. The staged analgesic regimen is noninferior to combination opioids and led to reduced overall consumption.

A Review of Postoperative Pain Management for Thyroid and Parathyroid Surgery.

BACKGROUND: Perioperative opioid use has been linked to abuse potential by patients, leading surgeons to scrutinize their postoperative prescribing practices. The goal of the study was to review analgesic regimens for patients undergoing thyroidectomy and parathyroidectomy and extrapolate changes that could be made to decrease opioid use while maintaining adequate pain control. MATERIALS AND METHODS: A literature review was performed. Inclusion criteria were studies 1) written in English, 2) published within the last 20 years, and 3) that included human subjects. Exclusion criteria were studies that 1) evaluated anesthesia regimens exclusively, 2) compared surgical approaches and their effects on pain (e.g., open neck exposure vs. transoral route for thyroidectomy), or 3) included patients undergoing concurrent lateral neck dissection. Of 951 studies originally identified, 10 studies met the criteria. RESULTS: Ten studies were identified, and each evaluated a different analgesic regimen. Five of the studies found a decrease in pain with multimodal regimens. Of the remaining studies, three found no difference in pain control, one found an increase in pain when only an opioid patient-controlled analgesia was used, and one found that 93% of patients required less than 20 oral morphine equivalents postoperatively. CONCLUSIONS: There is no postoperative analgesic regimen that has been established as optimal for patients undergoing parathyroidectomy and thyroidectomy in the current medical literature. However, half of the studies included in this review found that nonopioid adjuncts decreased patients' need for postoperative opioids.

Xenotransplantation of pre-pubertal ovarian cortex and prevention of follicle depletion with anti-Müllerian hormone (AMH).

OBJECTIVE: To determine whether recombinant AMH (rAMH) could prevent post-transplant follicular depletion by acting on the stemness markers Oct-4, Sox2, and NANOG. MATERIALS AND METHODS: This was an experimental study where 12 ovariectomized nude mice were xenotransplanted with vitrified/warmed ovarian cortex obtained from a pre-pubertal girl and Alzet pumps delivering rAMH, or placebo (control), were inserted intra-abdominally. Previously vitrified/warmed ovarian cortex fragments were transplanted after 7 days and then harvested after 14 days from pump placement. We performed real-time RT-PCR analyses, ELISA for AMH, FSH, and estradiol, histologic measurement of ovarian follicles, and immunohistochemistry for Ki67 and TUNEL. The main outcome measures were serum levels and tissue expression of the parameters under investigation and follicle count. RESULTS: Serum AMH, FSH, and estradiol reflected post-ovariectomy profiles and were mildly influenced by rAMH administration. Ovarian cortex expression of AMH, AMH-R2, VEGF, GDF9, Oct-4, and Sox2 was lower in rAMH mice than in controls, while NANOG was upregulated. There was a non-significant decrease in primordial follicles after vitrification-warming, and xenotransplantation further decreased this number. There were lower cell replication and depressed apoptosis in the rAMH group. CONCLUSIONS: Administration of recombinant AMH in the peri-transplant period did not protect the initial follicular depletion but decreased apoptosis and cellular activation and regulated stem cell markers' tissue expression. These results aid our understanding of the inhibitory effects of AMH on follicular development and show the benefit of administering exogenous AMH at the time of pre-pubertal ovarian cortex transplant to protect the follicles from pre-activation and premature depletion.

Anti-Müllerian Hormone (AMH) May Stall Ovarian Cortex Function Through Modulation of Hormone Receptors Other Than the AMH Receptor.

OBJECTIVE: To test whether recombinant anti-Müllerian hormone (AMH) can inhibit ovarian cortex function by modulating the expression of other hormone receptors. MATERIALS AND METHODS: Pilot experimental study with ovarian cortex obtained from 5 patients. Immediately after explant, the ovarian cortex specimens were divided into 5 equal fragments. One fragment was flash-frozen (uncultured) and 4 were incubated for 48 hours at 37°C in a pH-adjusted gamete buffer medium with increasing AMH concentrations of 0, 5, 25, and 50 ng/mL. After incubation, all specimens were rinsed and flash-frozen for polymerase chain reaction (PCR) executed in triplicates. We utilized real-time reverse transcription-polymerase chain reaction (RT-PCR) to determine messenger RNA (mRNA) levels of AMH and its receptor Anti-Müllerian Hormone-Receptor 2 (AMH-R2), follicle stimulating hormone receptor (FSH-R), luteinizing hormone receptor (LH-R), inhibin B, and insulin-like growth factor 1 receptor 1 (IGF1-R1) in ovarian cortex tissue. In addition, we performed Ki-67 immunostaining to evaluate cell proliferation in the treatment groups. RESULTS: Absence of recombinant human AMH (rAMH) caused upregulation of all markers. Exposure to increasing rAMH concentrations caused tissue AMH expression downregulation ( P = .024), while AMH-R2 ( P = .005), FSH-R ( P = .009), LH-R ( P = .003), and inhibin B ( P = .001) mRNA expression followed a bell-shaped response with an increased expression at low dose, followed by a decreased expression at higher doses. Expression of IGF1-R1 was independent ( P = .039) of rAMH exposure. The Ki-67 immunostaining showed an increased cell proliferation in the media control compared to the uncultured and the tissue cultured with rAMH. CONCLUSIONS: Culture with increasing rAMH concentrations caused downregulation of its own, as well as other hormone receptors, and a decreased ovarian cortex cell proliferation. These results help understanding the inhibitory effects of AMH on follicular development.

A safe and effective management strategy for blunt cerebrovascular injury: Avoiding unnecessary anticoagulation and eliminating stroke.

BACKGROUND: Few injuries have produced as much debate with respect to management as have blunt cerebrovascular injuries (BCVIs). Recent work (American Association for the Surgery of Trauma 2013) from our institution suggested that 64-channel multidetector computed tomographic angiography (CTA) could be the primary screening tool for BCVI. Consequently, our screening algorithm changed from digital subtraction angiography (DSA) to CTA, with DSA reserved for definitive diagnosis of BCVI following CTA-positive study results or unexplained neurologic findings. The current study was performed to evaluate outcomes, including the potential for missed clinically significant BCVI, since this new management algorithm was adopted. METHODS: Patients who underwent DSA (positive CTA finding or unexplained neurologic finding) over an 18-month period subsequent to the previous study were identified. Screening and confirmatory test results, complications, and BCVI-related strokes were reviewed and compared. RESULTS: A total of 228 patients underwent DSA: 64% were male, with mean age and Injury Severity Score (ISS) of 43 years and 22, respectively. A total of 189 patients (83%) had a positive screening CTA result. Of these, DSA confirmed injury in 104 patients (55%); the remaining 85 patients (45%) (false-positive results) were found to have no injury on DSA. Five patients (4.8%) experienced BCVI-related strokes, unchanged from the previous study (3.9%, p = 0.756); two were symptomatic at trauma center presentation, and three occurred while receiving appropriate therapy. No patient with a negative screening CTA result experienced a stroke. CONCLUSION: This management scheme using 64-channel CTA for screening coupled with DSA for definitive diagnosis was proven to be safe and effective in identifying clinically significant BCVIs and maintaining a low stroke rate. Definitive diagnosis by DSA led to avoidance of potentially harmful anticoagulation in 45% of CTA-positive patients (false-positive results). No strokes resulted from injuries missed by CTA. LEVEL OF EVIDENCE: Diagnostic study, level III.

Fertility biomarkers to estimate metabolic risks in women with polycystic ovary syndrome.

PURPOSE: We sought to evaluate the relationship between the polycystic ovary syndrome (PCOS)-defining characteristics and the risk of developing metabolic complications in women presenting with complaints of infertility and/or menstrual irregularities and subsequently diagnosed with PCOS. METHODS: This was a cross-sectional study. Women presenting with complaints of infertility and/or irregular menses and diagnosed with PCOS by the Rotterdam criteria, underwent endocrine, metabolic, and ultrasound assessment in the early follicular phase. Reproductive and metabolic parameters were included in regression analysis models with the PCOS-defining characteristics; ROC curves were calculated for the significant predictors. RESULTS: Three hundred and seventy-four women with PCOS were included in our study. Oligo-anovulation, menstrual irregularities, and hirsutism were not predictive of any of the variables. Ovarian volume, follicle count, and biochemical hyperandrogenism were predictors for hormonal, metabolic, and endometrial complications. The relationships were independent of age and body mass index. ROC curves identified lower cut-off values of the PCOS-defining characteristics to predict patients' risks of hyperinsulinemia, dyslipidemia, and glucose intolerance. CONCLUSIONS: Adverse metabolic effects of PCOS are already present in women at the time they present complaining of infertility and/or irregular menses. Hyperandrogenism and ultrasound can assist in predicting the patients' concomitant metabolic abnormalities and can aid physicians in tailoring counseling for effective preventive strategies.

Goserelin fosters bone elongation but does not prevent ovarian damage in cyclophosphamide-treated prepubertal mice.

OBJECTIVE: To evaluate whether administration of goserelin, a gonadotropin-releasing hormone (GnRH) agonist, could prevent acute or chronic ovarian insufficiency from cyclophosphamide (CTX) administration to prepubertal mice. DESIGN: Animal study. SETTING: University center. ANIMAL(S): C57BL/6J mouse strain. INTERVENTION(S): Goserelin administered on day 13 of life, CTX on day 18 of life, euthanasia on day 20 (prepubertal), 56 (pubertal), or 92 of life (mature), measurements of body weight, length, uterine weight, serum antimüllerian hormone and follicle-stimulating hormone, and histologic assessment of ovarian follicles and femur growth, and apoptotic rates by TUNEL. MAIN OUTCOME MEASURE(S): Assessment of prevention of ovarian insufficiency and defective bone elongation from CTX administration. RESULT(S): Prepubertal mice were randomly assigned to three groups: control (G1), CTX (G2), and goserelin + CTX (GG). A total of 63 mice were euthanized in the three groups. Body weight and length, and uterine weight did not differ among groups at any age. Ovarian size was not different in the three groups. There were fewer primordial and primary follicles/mm(2) in groups GG and G2 than in group G1 at all ages, but there was no difference between groups GG and G2. Corpora lutea/mm(2) were decreased in group GG versus G2. Femur length was statistically significantly greater in groups G1 and GG than group G2. CONCLUSION(S): Goserelin administered to prepubertal mice during CTX treatment fosters maintenance of bone elongation but does not protect the ovaries from follicular depletion.

Serum markers of ovarian reserve and ovarian histology in adult mice treated with cyclophosphamide in pre-pubertal age.

PURPOSE: AMH is used to quantify the extent of follicular pool in postpubertal women, but its value after chemotherapy is unclear. We tested AMH as a marker of follicular reserve in adult mice treated with cyclophosphamide (CTX) in prepubertal age. METHODS: Mice received placebo or CTX at age 18 days. AMH and FSH were assessed on day 43, 56, and 95 of life. Ovaries were fixed in formalin, embedded in paraffin, and stained with H&E and TUNEL. Follicular apoptosis was graded. RESULTS: All mice exposed to CTX had a decreased number of follicles/mm(2) and significantly decreased AMH, but only 48 % of pubertal and 81 % of adult mice had increased FSH. Over time, there was an increase in FSH (p < 0.05), but not a concurrent decrease in AMH, while in controls, FSH remained stable and AMH decreased. There was no correlation between histological and serological markers. CONCLUSIONS: CTX administration to pre-pubertal mice caused various degrees of residual function, which were reflected by FSH, but not by AMH or by the number of ovarian follicles. AMH served as a marker of quantitative, and FSH of qualitative, residual ovarian function.

Somatic and reproductive development in pre-pubertal mice treated with cyclophosphamide and subsequent estrogen replacement.

We tested the hypothesis that chemotherapy would prevent the expected pubertal development of uterus, ovaries, and long bones, and that estrogen replacement subsequent to treatment with chemotherapy would restore uterine and bone development to expected sizes. Pre-pubertal female C57BL/6J mice (n = 78) were assigned to receive placebo (controls), 200 mg/kg (group A), or 120 mg/kg (group B) of cyclophosphamide (CTX) on postnatal day 18. Mice were subsequently randomized to receive estradiol placebo or long-release estradiol pellet insertion on day 22 (early estradiol dose), day 45 (mid estradiol dose), or day 67 (late estradiol dose) of life. Body weight and length, uterine and ovarian weight, and right femur length and weight were measured. Mice treated with CTX had shorter and lighter femurs and lighter ovaries than controls (13.46 cm ± 1.51 cm vs. 15.00 cm ± 1.10 cm, 57.70 mg ± 9.71 mg vs. 65.30 mg ± 3.68 mg, and 5.16 mg ± 3.00 mg vs. 10.05 mg ± 2.31 mg, respectively; p < 0.05). Mice receiving estrogen replacement had a larger average body weight, BMI, and uterine weight than those that received placebo estrogen (19.56 g ± 1.82 g vs. 18.10 g ± 2.08 g, 26.53 g/cm(2) ± 2.91 g/cm(2) vs. 23.47 g/cm(2) ± 3.06 g/cm(2), 101.19 mg ± 41.69 mg vs. 50.00 mg ± 9.49 mg, respectively; p < 0.05). Cyclophosphamide treatment in pre-pubertal mice negatively affected femur and reproductive development. Estrogen treatment restored expected uterine development by maturity, regardless of the timing of administration. However, there was no similar recovery of femur length and bone mass was only partially recovered.

Endometrial signaling pathways during ovarian stimulation for assisted reproduction technology.

OBJECTIVE: To determine the effects of different hormonal levels on endometrial biochemical development during ovulation induction for assisted reproduction technology (ART) cycles. DESIGN: Prospective controlled study. SETTING: University center. PATIENT(S): Nine women during a natural cycle (control) and 9 oocyte donors (treated) during an ART cycle. INTERVENTION(S): At the time consistent with day 3 embryo transfer (LH+5 in control, hCG+5 in treated), transvaginal ultrasound, endometrial biopsy, and blood sampling were performed. Real-time reverse-transcription polymerase chain reaction was used to measure mRNA levels for insulin receptor (InsR), type I IGF receptor (IGFRI), prolactin receptor (PRL-R), androgen receptor (AR), TSH receptor (TSHR), nuclear receptors for T3 and T4 (TRα1, TRα2, and TRß1), iodothyronine deiodinase (DIO2), and 1,25-dihydroxyvitamin D3 receptor (VDR) in the endometrial tissue. MAIN OUTCOME MEASURE(S): Biochemical endometrial development. RESULT(S): IGFRI mRNA levels were 69% lower in treated patients than in control subjects, 0.12 ± 0.005 pg/µg RNA versus 0.39 ± 0.01 pg/µg RNA. TSHR mRNA was 57% lower, 2.6 ± 0.1 fg/µg RNA versus 6.0 ± 0.2 fg/µg RNA. TRα1 and TRα2 mRNA did not change, but TRß1 mRNA levels were 63% higher. DIO2 mRNA was 63% lower, 1.2 ± 0.07 pg/µg RNA versus 3.2 ± 0.2 pg/µg RNA. InsR mRNA levels, despite being 68% lower in treated patients, did not reach significance, and PRL-R, AR, and VDR did not significantly change. CONCLUSION(S): Exposure of the endometrium to ovarian stimulation appears to influence insulin and thyroid hormone signaling pathways in the decidua at day 3 embryo transfer, whereas prolactin, androgen, and vitamin D pathways are uninfluenced. These findings echo the known delayed endometrial maturation during ovarian stimulation.

Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age.

Disruption in the normal timing of female puberty, such as in pre-pubertal cancer treatments, can cause abnormal somatic development. We sought to evaluate the impact of cyclophosphamide (CTX) on the somatic, uterine, and ovarian, development of pre-pubertal mice. Pre-pubertal (day 18 of life) C57BL/6J female mice were randomized to receive placebo (group 1A and 1B), 200 mg/kg CTX (group 2A), or 120 mg/kg CTX (group 2B). Mice were euthanized on day 56 (A groups) or 95 (B groups) of life. Body weight and length, uterine and ovarian weight and right femur length and weight were measured, and ovarian insufficiency was assessed. Data were analyzed using ANOVA and t-test. Body weight and length did not differ among groups at time of euthanasia. The femur was shorter and weighed less in mice treated with CTX than in controls. Uterine weight was lower in group 2B than 1B (46.1 mg, 95% CI: 42.9-49.4, vs. 62.2 mg, 95% CI: 58.5-65.8, respectively; p = 0.005) and was lower in mice that developed ovarian insufficiency than in mice that did not (p < 0.05). Ovarian weight was lower in mice treated with CTX, regardless of whether they developed ovarian insufficiency. Even with no observable effect on adult body length and weight, CTX treatment in pre-pubertal mice appears to negatively affect femur, uterine, and ovarian development. However, uterine development seems to be dependent on the hormonal status created by CTX more than on its direct effect.

Deliberative assessment of surrogate consent in dementia research.

BACKGROUND: Research involving incapacitated persons with dementia entails complex scientific, legal, and ethical issues, making traditional surveys of layperson views on the ethics of such research challenging. We therefore assessed the impact of democratic deliberation (DD), involving balanced, detailed education and peer deliberation, on the views of those responsible for persons with dementia. METHODS: One hundred and seventy-eight community-recruited caregivers or primary decision-makers for persons with dementia were randomly assigned to either an all-day DD session group or a control group. Educational materials used for the DD session were vetted for balance and accuracy by an interdisciplinary advisory panel. We assessed the acceptability of family-surrogate consent for dementia research ("surrogate-based research") from a societal policy perspective as well as from the more personal perspectives of deciding for a loved one or for oneself (surrogate and self-perspectives), assessed at baseline, immediately post-DD session, and 1 month after DD date, for four research scenarios of varying risk-benefit profiles. RESULTS: At baseline, a majority in both the DD and control groups supported a policy of family consent for dementia research in all research scenarios. The support for a policy of family consent for surrogate-based research increased in the DD group, but not in the control group. The change in the DD group was maintained 1 month later. In the DD group, there were transient changes in attitudes from surrogate or self-perspectives. In the control group, there were no changes from baseline in attitude toward surrogate consent from any perspective. CONCLUSIONS: Intensive, balanced, and accurate education, along with peer deliberation provided by democratic deliberation, led to a sustained increase in support for a societal policy of family consent in dementia research among those responsible for dementia patients.

Fetal transfusion: the spectrum of clinical research in the past year.

PURPOSE OF REVIEW: Our goal is to review recent articles that examine the current state of fetal transfusion therapy from technique to education. RECENT FINDINGS: Even as technology facilitates physicians' diagnosis and treatment of rare disorders requiring fetal transfusion therapy, longstanding questions remain such as the use of intravascular versus intraperitoneal transfusion sites. However, the recent progress seen with molecular techniques, disease markers, and mathematical models demonstrates that despite unanswered questions, there is much to be hopeful about in improving our understanding of fetal transfusions and their application to a variety of diseases. SUMMARY: Systematic and collaborative approaches to studying low-frequency disorders treatable by fetal transfusions are necessary. Continued refinement of techniques should improve the timeliness and accuracy of diagnosis, as well as assist in determining the appropriate timing, site, and duration of treatments.

Effect of the ABO blood group on the proliferative and clonogenic capacity of umbilical cord stem cells.

Possible effects of the ABO blood group on the proliferative and self-renewal capacity of umbilical cord CD34+ cells were evaluated. A, B and O (all Rh D+) CD34+ cells isolated from three placental blood samples were cultured in four platforms with hematopoietic growth factors on a 3-dimensional biocompatible matrix. Results from this study suggest that proliferation of CD34+ cells with the O phenotype may be greater than that of cells with the A or B phenotypes. Further ex vivo studies are required to confirm this finding and to determine the effect of the number and type of other genetically determined cell surface antigens on the capacity of hematopoietic stem cells to respond to cytokines. In addition, clinical studies aimed at determining if the CD34+ donor blood group affects the time to functional hematological reconstitution are recommended.