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The retina has a complex structure with a diverse collection of component cells that work together to facilitate vision. The retinal capillaries supplying the nutritional requirements to the inner retina have an intricate system of neural, glial and vascular elements that interconnect to form the neurovascular unit (NVU). The retina has no autonomic nervous system and so relies on the NVU as an interdependent, physical and functional unit to alter blood flow appropriately to changes in the physiological environment. The importance of this is demonstrated by alterations in NVU function being apparent in the blinding disease diabetic retinopathy and other diseases of the retina. It is, therefore, imperative to understand the anatomy of the components of the NVU that underlie its functioning and in particular the nanoscale arrangements of its heterocellular components. However, information on this in three spatial dimensions is limited. In the present study, we utilised the technique of serial block-face scanning electron microscopy (SBF-SEM), and computational image reconstruction, to enable the first three-dimensional ultrastructural analysis of the NVU in mouse retinal capillaries. Mouse isolated retina was prepared for SBF-SEM and up to 150 serial scanning electron microscopy images (covering z-axes distances of 12-8 mm) of individual capillaries in the superficial plexus and NVU cellular components digitally aligned. Examination of the data in the x-, y- and z-planes was performed with the use of semi-automated computational image analysis tools including segmentation, 3D image reconstruction and quantitation of cell proximities. A prominent feature of the capillary arrangements in 3D was the extensive sheath-like coverage by singular pericytes. They appeared in close register to the basement membrane with which they interwove in a complex mesh-like appearance. Breaks in the basement membrane appeared to facilitate pericyte interactions with other NVU cell types. There were frequent, close (

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 μg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 μg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels300 μg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician.

Objective Although robotic surgery decreases pain compared to laparotomy, postoperative pain can be a concern near the site of a larger assistant trocar site. The aim of this study was to determine the efficacy of transversus abdominis plane (TAP) block on 24-hour postoperative opiate use after robotic surgery for gynecologic cancer. Methods Sixty-four subjects with gynecologic malignancies who were scheduled to undergo robotic surgery were enrolled into the study. They were randomized to receive a unilateral TAP block to the side of the assistant port via ultrasound guidance. The block was comprised of 30cc of 0.25% bupivacaine with 3mcg/mL epinephrine or saline. Opiate use was measured and converted into IV morphine equivalents. Patient-reported pain was measured using the Brief Pain Inventory (BPI) and Visual Analog Scale (VAS). Results The treatment group used a mean of 64.9mg morphine in the first 24h compared to 69.3mg for controls (primary outcome, p =0.52). After age-adjustment, the treatment group used a mean of 11.1mg morphine less than controls ( p =0.09). Postoperative pain scores assessed by the BPI (6.44 vs. 6.97, p =0.37) and the VAS (3.12 vs. 3.61, p =0.30) were equivalent. Block placement was uncomplicated in 98.4% of participants with mean BMI of 35.3kg/m 2 . Linear regression revealed an approximate 8.1mg decrease in morphine equivalents used per additional decade of life ( p =0.0008). There was a positive correlation between the amount of opiates and BMI with an additional 8.8mg of morphine per 10kg/m 2 increase in BMI ( p =0.0012). Conclusions TAP block is safe and feasible in this patient population with a large proportion of morbid obesity. Preoperative TAP block does not significantly decrease opiate use. However; based on these data, a clinically useful nomogram has been created to aid clinicians in postoperative opiate-dosing for patients based on age and BMI.

Objective To provide data from a US center on laparoscopic (LSC) approach to sentinel lymph node (SLN) detection in cervix cancer with detailed time analysis. Methods This prospective trial enrolled patients with stage IA2-IIA cervix cancer undergoing primary radical surgery. Tc-99 radiocolloid was injected the morning of surgery, followed by hybrid SPECT/CT lymphoscintigraphy. Blue dye injection occurred just prior to incision. After bilateral LSC SLN detection, all patients received complete LSC pelvic lymphadenectomy. Institutional SLN protocol was followed for frozen section, hematoxylin and eosin, and cytokeratin staining. Results Between December 2003 and February 2006, 20 enrolled patients received 9 LSC-assisted radical vaginal hysterectomies, 7 radical abdominal hysterectomies, 2 LSC-assisted radical vaginal trachelectomies, and 2 LSC lymphadenectomies alone (secondary to positive lymph nodes). Mean tumor size was 2.5 cm. Nineteen percent of the 64 SLNs were found in unusual sites, including common iliac (11%), presacral (5%) and para-aortic (3%). The negative predictive value was 100%. The combined technique detected SLNs bilaterally in all patients. If blue dye alone was used, this rate would have dropped to 67.5% and was negatively correlated with elapsed surgical time (-0.7; p=0.002). The ability to visualize blue SLNs remained steady for 30 min and was completely gone by 50 min. Conclusions Laparoscopic SLN mapping can be newly introduced into gynecologic oncology centers with high detection rates and negative predictive values. The visualization of blue dye in SLNs is transient, and this negative time correlation may explain the previously reported inferior detection rates with this technique. CLINICAL TRIAL REGISTRATION.: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT 00205010.

Objective Results of the ICON4/AGO-OVAR-2.2 trial suggest that a platinum/taxane combination provides a survival benefit in relapsed, platinum-sensitive ovarian cancer compared to platinum alone. The optimal specific combination has yet to be determined. The current study evaluates weekly docetaxel and carboplatin in this setting. Methods Using a prospective phase II design, patients received weekly docetaxel (35 mg/m2) and carboplatin (AUC=2) administered days 1, 8, and 15 of a 28-day cycle. Initial treatment with a platinum-based regimen was required, with a treatment-free interval of at least 3 months. Patients could have received one prior regimen for recurrence. Biologically evaluable disease (CA-125) could be followed only if measurable disease was not present. Quality of life analysis utilized the FACT-O and FACT/GOG-Ntx scales. Results Thirty-six patients enrolled in the trial over 29 months. The majority had ovarian cancer (89%) and stage III/IV (97%) disease, with a median initial disease-free interval of 12 months. Most subjects were treated for first recurrence (81%) and had measurable disease (58%). The overall response rate was 67% (PR=52%, CR=15%), with 22% stable disease. Grade 3/4 neutropenia was common (48%) while serious anemia and thrombocytopenia were not. Neuropathy was generally mild and manageable. Carboplatin hypersensitivity led to 11 subjects coming off trial (31%). Diphenhydramine premedication produced a nonsignificant decrease in reaction rate. There was no detectable difference in quality of life due to therapy. Conclusion The weekly regimen of carboplatin and docetaxel has a good response rate with an acceptable toxicity profile.

To assess subsequent utilization of fertility treatment in reproductive-age women with cervical cancer (CC) who underwent ovarian transposition (OT) to preserve fertility prior to pelvic radiation.This is a case series of 216 CC patients seen in a comprehensive cancer center. Sixteen patients underwent OT for fertility preservation prior to pelvic radiation. Patients were assessed for utilization of fertility treatment, follicle-stimulating hormone (FSH) levels as a measure of ovarian reserve, and functional assessment of chronic illness therapy-cervix cancer (FACT-CX) to assess quality of life after OT.Of the patients, 94% of patients [corrected] maintained regular menstrual cycles 3 years after ovarian transposition (OT) [corrected] surgery (15/16). When measured (n = 5), serum FSH was normal at baseline and showed a transient elevation at 3 months following chemoradiation, with a return to normal levels at 6 months (means, 6.33 ± 2.94, 48.44 ± 18.63, and 12.52 ± 8.25 mIU/mL, respectively). Only 1 patient in this series attempted fertility treatment (in vitro fertilization) following OT, and she did not become pregnant. FACT-CX indicated that quality of life did not change significantly over the 6 months' duration following OT and chemoradiation therapy.OT preserves menstrual cycle regularity without negatively impacting patients' quality of life. The utility of OT as an effective fertility preservation option is hampered by the low utilization rate of in vitro fertilization and lack of ovarian reserve assessment following OT.

ObjectiveDuring saline-infused sonohysterography (SIS), the distension fluid is typically discarded. If cytology analysis could identify those patients with endometrial cancer, many women would be spared from further procedures.MethodsThirty consecutive patients with clinical stage I or II endometrial adenocarcinoma were prospectively recruited preoperatively. Saline-infused sonohysterography was performed by instilling 5 mL of saline, withdrawing and sending for analysis. Saline was reinfused until complete SIS images were obtained and sent separately for cytology.ResultsOf the 30 women enrolled, SIS was technically successful in 29. Demographics included mean age (60.5 ± 6.99 years), body mass index (35.55 ± 8.18 kg/m2), endometrioid histology (76%), and grade (grade 1, 67%). Prestudy diagnostic method included biopsy (70%), dilatation and curettage (17%), and hysteroscopy (10%). Adequate cytology specimens were obtained in 66% of the 5 mL flushes and 72% of the complete SIS collections. Of adequate specimens, the sensitivities to detect endometrial cancer for the 5-mL, complete, and combined fluid samples were 26% (95% confidence interval, 9%–51%), 36% (17%–59%), and 42% (22%–63%). Sensitivity based on the whole study sample (N = 30) was 33% (17%–53%). Statistical significance was not found in the association between a positive test and age, body mass index, grade, diagnostic method, or volume instilled or aspirated.ConclusionsMost patients with early endometrial cancer can undergo SIS procedures with adequate cytology specimens obtained from distention media. However, the sensitivity is low, and refinements are necessary before utilizing as a diagnostic test. In cases with positive results, the patient may be able to avoid other costly and painful procedures.

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles. TRIAL REGISTRATION: http://NCT00132522.

Objective The aim of the current study was to evaluate the safety and efficacy of a widely available bupivacaine continuous wound infusion system in gynecologic oncology patients undergoing laparotomy. Methods A prospective, randomized, double-blind, placebo-controlled trial was performed. After closure of the fascia, flexible soaker catheters were placed in the deep subcutaneous space. The infusion pump was filled with 290 mL of either 0.5% bupivacaine or normal saline, to infuse over 72 hours. Daily assessments of pain scores utilized the Wisconsin Brief Pain Inventory. All patients received intravenous narcotics via patient-controlled devices. Results Eighty surgeries were evaluated in a total of 79 women (40 per arm). Mean age was 56 years, with 79% having invasive gynecologic pathology. The two groups were not significantly different in terms of type of surgery, length of incision, estimated blood loss, operative time, or medical history. Postoperative outcomes, including wound toxicity, time to flatus, and hospital stay, did not differ. Study patients averaged 75 mg intravenously and 107 mg total narcotic use (morphine equivalent), whereas controls averaged 60 mg intravenously and 86 mg total (P = .40 intravenously; P = .25 total). Acetaminophen and intravenous ketorolac consumption were equal between groups. The Brief Pain Inventory score for "current pain" was 2.84 for bupivacaine patients and 3.14 for controls (P = .46; least = 0, most = 10). There was no individual postoperative day when "current pain" BPI scores differed. "Worst pain" and "least pain" Brief Pain Inventory scores showed similar results. Conclusion The results suggest that although the continuous infusion system seems safe, it is not efficacious in this patient population.

Objectives: To characterize those seeking treatment at a female sexual medicine (FSM) program and examine their sexual/vaginal health issues. The program was established to address the consequences of cancer treatment on vaginal health and sexuality. Methods: A limitedwaiver of authorizationwas obtained to evaluate the FSM Program. Demographic and medical information and FSM clinical assessment forms from 509 new visits were analyzed. The FSM clinical assessment form consists of a clinician evaluation form with the Vaginal Assessment Scale (VAS); patient-reported outcomes (PROs), including the Sexual ActivityQuestionnaire (SAQ), Sexual Self-SchemaScale (SSSS), and Female Sexual Function Index (FSFI); and exploratory items. Results: Of the 509 patients, 493 (97%) completed PROs. Due to staff changes, 253 of these women also received pelvic examinations. Most of the women seeking treatment had histories of breast (260 [51%]) or gynecologic (190 [37%]) cancer. Other cancers included colorectal/anal (35 [7%]), skin (20 [4%]), gastric/genitourinary (17 [3%]), andhematologic (17 [3%]). Eighty-one percent of patients weremarried or partnered. The median age was 51.6 years (mean, 51 years). On pelvic examination, approximately two-thirds of patients had elevated vaginal pH scores (5– 6.5 [35%] or 6.5+ [33%]) andminimal (62%) or no (5%) vaginal moisture. Eighty-seven patients (44%) experienced pain during their examinations (25%mild, 12%moderate, 2% severe). Fifty-three percent of patientswere sexually active, but only 43% felt confident about sexual activity. The degree of concern about sexual function/vaginal health was significant, with a mean of 7.9 on a scale of 0 (not at all) to 10 (very much). Approximately half had moderate/severe dryness (133 [51%]) and dyspareunia (120 [46%]) per the VAS. The mean SSSS score was 60.7, indicating a slightly positive sexual self-view. However, 93% (429) had an FSFI score below 26, suggesting sexual dysfunction. Conclusions: At initial consultation, women reported symptoms of vaginal dryness, pain, and sexual dysfunction. Pelvic examinations for many women revealed elevated vaginal pH, lack of moisture, and discomfort with the examination itself. Future analyses will examine changes over time. Our goal is to provide information, strategies, and support to improve symptomswhile promoting confidence about sexual/ vaginal health.