Bifunctional Tumor-Targeted Bioprobe for Phothotheranosis.

Background: Near-infrared (NIR) phototheranostics provide promising noninvasive imaging and treatment for head and neck squamous cell carcinoma (HNSCC), capitalizing on its adjacency to skin or mucosal surfaces. Activated by laser irradiation, targeted NIR fluorophores can selectively eradicate cancer cells, harnessing the power of synergistic photodynamic therapy and photothermal therapy. However, there is a paucity of NIR bioprobes showing tumor-specific targeting and effective phototheranosis without hurting surrounding healthy tissues. Methods: We engineered a tumor-specific bifunctional NIR bioprobe designed to precisely target HNSCC and induce phototheranosis using bioconjugation of a cyclic arginine-glycine-aspartic acid (cRGD) motif and zwitterionic polymethine NIR fluorophore. The cytotoxic effects of cRGD-ZW800-PEG were measured by assessing heat and reactive oxygen species (ROS) generation upon an 808-nm laser irradiation. We then determined the in vivo efficacy of cRGD-ZW800-PEG in the FaDu xenograft mouse model of HNSCC, as well as its biodistribution and clearance, using a customized portable NIR imaging system. Results: Real-time NIR imaging revealed that intravenously administered cRGD-ZW800-PEG targeted tumors rapidly within 4 h postintravenous injection in tumor-bearing mice. Upon laser irradiation, cRGD-ZW800-PEG produced ROS and heat simultaneously and exhibited synergistic photothermal and photodynamic effects on the tumoral tissue without affecting the neighboring healthy tissues. Importantly, all unbound bioprobes were cleared through renal excretion. Conclusions: By harnessing phototheranosis in combination with tailored tumor selectivity, our targeted bioprobe ushers in a promising paradigm in cancer treatment. It promises safer and more efficacious therapeutic avenues against cancer, marking a substantial advancement in the field.

Ultralow Background Near-Infrared Fluorophores with Dual-Channel Intraoperative Imaging Capability.

Two of the most pressing challenges facing bioimaging are nonspecific uptake of intravenously administered contrast agents and incomplete elimination of unbound targeted agents from the body. Designing a targeted contrast agent that shows fast clearance from background tissues and eventually the body after complete targeting is key to the success of image-guided interventions. Here, this work describes the development of renally clearable near-infrared contrast agents and their potential use for dual-channel image-guided tumor targeting. cRGD-ZW800-PEG (800 nm channel) and ZW700-PEG (700 nm channel) are able to visualize tumor margins and tumor vasculature simultaneously and respectively. These targeted agents show rapid elimination from the bloodstream, followed by renal clearance, which together significantly lower off-target background signals and potential toxicity. To demonstrate its applicability, this multispectral imaging is performed in various tumor-bearing animal models including lung cancer, pancreatic neuroendocrine tumors, breast, and ovarian cancer.

Spiders and mushrooms: Reporting bowel endometriosis shape on preoperative MRI to flag surgical complexity.

INTRODUCTION: Preoperative imaging of patients with endometriosis allows adequate counselling, referral to appropriate centres of expertise and workforce planning. The objective of this study was to assess the feasibility of simplified three-category preoperative endometriosis MRI morphological descriptors to predict subsequent surgical management. METHODS: A single-centre observational study in 76 patients (median age 38 years, range 18-55) with preoperative endometriosis mapping MRI between 1 Jan 2015 and 31 Dec 2019. MRI studies were prospectively re-read blind-to-surgical outcome to categorise rectosigmoid morphology as normal, spider-shaped (linear T2-dark fibrotic bands) superficial endometriosis or typical crescentic or mushroom-shaped deep infiltrating endometriosis (DIE). Bowel motility was similarly categorised as normal, tethered or distorted/fixed. The reference standard was subsequent surgery within 3 years of MRI, categorised as no bowel surgery, adhesiolysis only or more complex surgeries. RESULTS: Despite three-quarters of surgical cases having normal bowel morphology on preoperative MRI (72%, 55/76; 12% linear superficial endometriosis, 10% crescentic and 5% mushroom-shaped DIE) more than half showed bowel tethering (54%, 41/76) or distortion/fixation (10%, 8/76) and most patients underwent adhesiolysis (79%, 60/76). Complex surgery such as bowel resection, laparotomy conversion or complex adhesiolysis is predicted by morphology (crescentic or mushroom-shaped DIE, P < 0.001) and motility (tethered or distorted bowel, P = 0.002) descriptors. CONCLUSIONS: Comprehensive and clinically relevant diagnostic reporting does not have to be convoluted to have clinical impact: in our study population, categorising bowel morphology as normal, spider-shaped (superficial) or crescentic/mushroom-(DIE) shaped and motility as normal, tethered (superficial) or distorted/fixed (deep endometriosis) correlates to subsequent surgical complexity.

MRI sliding sign: Using MRI to assess rectouterine mobility in pelvic endometriosis.

INTRODUCTION: Surgical excision of deep infiltrating endometriosis (DIE) is complex and associated with morbidity. Diagnostic imaging plays an important role in the preoperative workup. We sought to determine the utility of single sagittal T2-weighted MRI motion sequence in the preoperative assessment of pelvic mobility in patients with endometriosis. METHODS: An observational study at a single tertiary public referral centre in Australia. Eighty-one MRI studies from 1 May 2019 to 3 December 2019, were enrolled. Studies were included if they were performed to stage endometriosis, including a T2-weighted motion series, adequately covering a uterus, cervix and rectum. Fifty-seven studies met inclusion criteria. The reference standard was a contemporaneous transvaginal ultrasound (TVUS) reporting on pelvic organ mobility. Three subspecialist radiologists were then blindly asked to identify, on the cine loop: rectouterine immobility, superficial endometriosis (pelvic bowel adhesions), rectosigmoid Deep Infiltrating Endometriosis (DIE). Fleiss' Kappa assessed interobserver agreement. Consensus MRI sensitivity and specificity were estimated against the reference standard (TVUS). RESULTS: Median age was 35 years (range 19-51). Forty-three cases had a contemporaneous TVUS; 14 reporting a sliding sign, 29 with fixed pelves. Interobserver agreement was 'substantial' (k = 0.79) for absent MRI sliding sign and 'almost perfect' (k = 0.90) for absence of DIE. Consensus MRI had 90% sensitivity (95% CI 73-98%) for pelvic immobility at TVUS (absent sliding sign). Interobserver agreement and consensus MRI sensitivity were higher for adhesions and immobility than normal findings. CONCLUSION: An MRI motion sequence can identify patients with pelvic adhesions and immobility, helping determine surgical difficulty when TVUS is not diagnostic.

Caesarean scar ectopic pregnancy: Evolution from medical to surgical management.

BACKGROUND: Caesarean scar ectopic pregnancy (CSP) is defined as blastocyst implantation occurring in a uterine scar. The incidence of CSP continues to rise with increasing caesarean section rates; prevalence is estimated to be 1:1800 to 1:2226 of all pregnancies. To date, over 30 treatment regimens have been published. The Royal College of Obstetricians and Gynaecologists guidelines (2016) state there is insufficient evidence to support one specific intervention over another. AIM: To review outcomes of medical and surgical management of CSP cases at a single tertiary centre over a nine-year period, in order to establish the safest and most effective management approach. MATERIALS AND METHODS: An audit was undertaken of patients treated for CSP between January 2009 and March 2017 at King Edward Memorial Hospital, Western Australia. Patient demographic and treatment outcome data were extracted from medical records. RESULTS: Fifty-one patients were identified as having CSP diagnosed during this time period, of which five were excluded due to lack of data, leaving a total of 46 cases. The majority of patients (52%, n = 24) elected for initial surgical management, while 41% (n = 19) trialled medical management. Seven percent (n = 3) opted for conservative management. Success rates of surgical, medical and conservative management were 100%, 53% and 0% respectively (P < 0.001). Medical management was associated with prolonged follow-up; there was no difference in complication rates between surgical and medical managements. CONCLUSIONS: In this audit, surgical management was the most effective way to manage CSP. There was no significant difference in complication rates between the two groups.

Advanced Training of Gynecologic Surgeons and Incidence of Intraoperative Complications after Total Laparoscopic Hysterectomy: A Retrospective Study of More Than 2000 Cases at a Single Institution.

STUDY OBJECTIVE: To investigate whether surgeon factors including level of training undertaken in laparoscopic surgery, time in specialist practice, and case volume were associated with surgical morbidity for total laparoscopic hysterectomy (TLH). DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A tertiary care setting in Western Australia. PATIENTS: Two thousand thirteen patients who underwent TLH for benign or malignant indications. INTERVENTIONS: Women undergoing TLH were allocated to 1 of 3 groups of surgeons: general gynecologists, gynecologic endoscopists, and subspecialists. MEASUREMENTS AND MAIN RESULTS: All patients undergoing elective TLH at St John of God Subiaco Hospital, Subiaco, Perth, Western Australia, between January 1, 2011, and December 31, 2016, were included for analysis. Variables recorded included cystotomy, ureteric injury, enterotomy/colostomy, bowel serosa injury, vascular injury, conversion to laparotomy, return to the operating room, hemorrhage, blood transfusion, operating time, length of stay, and postoperative complications to 42 days. The primary outcome was any major intraoperative complication. The incidence of any major intraoperative complication was 1.8% (36/2013 cases). Forty-five patients (2.2%) had a postoperative complication, and 74 (3.7%) patients were readmitted to the hospital after discharge. The incidence of any major intraoperative complication was significantly higher among general gynecologists compared with subspecialists (3.3% vs 1.1%, p = .002). No association was found between time in specialist practice and the incidence of major intraoperative complications (p = .629). A significant association for major intraoperative complications was observed for surgeons who had performed <100 laparoscopic hysterectomies during the study period (p = .032). CONCLUSION: In this study, despite a higher level of surgical acuity and the performance of additional and more complex procedures, surgical morbidity was lower in patients undergoing TLH by gynecologic surgeons with a higher level of subspecialist training.

Pregnancy-related outcomes for women with polycystic ovary syndrome.

The polycystic ovary syndrome is a common endocrine disorder that has profound implications for women throughout their reproductive years. A diagnosis of polycystic ovary syndrome is associated with reproductive challenges including a difficulty in conceiving as well as the pregnancy-related complications of miscarriage, hypertensive disorders, gestational diabetes and prematurity. Consequently, polycystic ovary syndrome has profound implications for women and their offspring with regard to reproductive function in the short term and in the longer term the risk of chronic illness and congenital anomalies, and health care resources should be directed accordingly to mitigate against these risks.

Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility.

BACKGROUND: Ten per cent to 15% of couples have difficulty in conceiving. A proportion of these couples will ultimately require assisted reproduction. Prior to controlled ovarian hyperstimulation (COH) a baseline ultrasound is performed to detect the presence of ovarian cysts.Previous research has suggested that there is a relationship between the presence of an ovarian cyst prior to COH and poor outcome during IVF. OBJECTIVES: The aim of this review was to determine the effectiveness and safety of functional ovarian cyst aspiration prior to ovarian stimulation versus a conservative approach in women with an ovarian cyst who were undergoing IVF or ICSI. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, Google Scholar and PubMed. The evidence was current to April 2014 and no language restrictions were applied. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing functional ovarian cyst aspiration versus conservative management of ovarian cysts that have been seen on transvaginal ultrasound (TVS) prior to COH for IVF or ICSI. Ovarian cysts were defined as simple, functional ovarian cysts > 20 mm in diameter. Oocyte donors and women undergoing donor oocyte cycles were excluded. DATA COLLECTION AND ANALYSIS: Study selection, data extraction and risk of bias assessments were conducted independently by two review authors. The primary outcome measures were live birth rate and adverse events. The overall quality of the evidence for each comparison was rated using GRADE methods. MAIN RESULTS: Three studies were eligible for inclusion (n = 339), all of which used agonist protocols. Neither live birth rate nor adverse events were reported by any of the included studies. There was no conclusive evidence of a difference between the group who underwent ovarian cyst aspiration and the conservatively managed group in the clinical pregnancy rate (OR 1.40, 95% CI 0.67 to 2.94, 3 studies, 339 women, I(2) = 0%, low quality evidence). This suggested that if the clinical pregnancy rate in women with conservative management was assumed to be 5%, the chance following cyst aspiration would be between 4% and 14%. There was no evidence of a difference between the groups in the mean number of follicles recruited (0.55 follicles, 95% CI -0.48 to 1.59, 2 studies, 159 women, I(2) = 0%, low quality evidence) or mean number of oocytes collected (0.41 oocytes, 95% CI -0.04 to 0.85, 3 studies, 339 women, I(2) = 0%, low quality evidence). Findings for the cancellation rate (two studies) were inconsistent but neither study reported a benefit for the aspiration group. The main limitations of the evidence were imprecision, inconsistency, questionable applicability, and poor reporting of study methods. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether drainage of functional ovarian cysts prior to controlled ovarian hyperstimulation influences live birth rate, clinical pregnancy rate, number of follicles recruited, or oocytes collected in women with a functional ovarian cyst. The findings of this review do not provide supportive evidence for this approach, particularly in view of the requirement for anaesthesia, extra cost, psychological stress and risk of surgical complications.

Clinicopathologic correlation of cutaneous metastases: experience from a cancer center.

OBJECTIVE: To analyze the clinical, histopathologic, and immunohistochemical characteristics of skin metastases. DESIGN: Retrospective analysis (January 1, 1990, to December 31, 2005). SETTING: Comprehensive cancer center. PATIENTS: Fifty-one patients (21 men and 30 women) with biopsy-proven skin metastases and correlative clinical data. INTERVENTIONS: Four dermatopathologists reviewed a random mixture of metastases and primary skin tumors. Immunohistochemical studies for 12 markers were performed on the metastases, with skin adnexal tumors as controls. MAIN OUTCOME MEASURES: Clinical characteristics of cutaneous lesions, clinical outcomes, histologic features, and immunohistochemical markers. RESULTS: Eighty-six percent (43 of 50) of the patients had known stage IV cancer, and skin metastasis was the presenting sign in 12% (6 of 50). In 45% (21 of 47) of the biopsies, the lesions were not suspected of being metastases owing to unusual clinical presentations. Seventy-six percent of the patients died of disease (median survival, 5 months). On pathologic review, many metastases from adenocarcinomas were either recognized or suspected, but the primary site was not easily identified based on histologic findings alone. Metastases from small cell carcinomas and sarcomas were histologically misinterpreted as primary skin tumors. Immunohistochemical analysis using a panel including p63, B72.3, calretinin, and CK5/6 differentiated metastatic carcinoma from primary skin adnexal tumors. CONCLUSIONS: Cutaneous metastases can have variable clinical appearances and can mimic benign skin lesions. They are usually seen in patients with advanced disease, but they can be the presenting lesion. Although many metastatic adenocarcinomas can be recognized based on histologic findings alone, immunohistochemical analysis is an important diagnostic adjunct in some cases.

Clinical significance of performing immunohistochemistry on cases with a previous diagnosis of cancer coming to a national comprehensive cancer center for treatment or second opinion.

Immunohistochemistry (IHC) is an important adjunctive test in diagnostic surgical pathology. We studied the clinical significance and outcomes in performing IHC on cases with a previous diagnosis of cancer who are coming to the Fox Chase Cancer Center (FCCC), a National Cancer Institute designated National Comprehensive Cancer Center (NCCC), for treatment and/or second opinion. We reviewed all the outside surgical pathology slide review cases seen at the FCCC for 1998 and 1999 in which IHC was performed. Cases were divided into the following: confirmation of outside diagnoses without and with prior IHC performed by the outside institution (groups A and B, respectively) and cases with a significant change in diagnosis without and with prior IHC performed by the outside institution (groups C and D, respectively). During 1998 and 1999, 6678 slide review cases were reviewed at the FCCC with an overall significant change in diagnosis in 213 cases (3.2%). IHC was performed on 186 of 6678 (2.7%) slide review cases with confirmation of the outside diagnosis in 152 (81.7%) cases and a significant change in diagnosis in 34 (18.3%) cases. Patient follow-up was obtained in 32 of 34 (94.1%) cases with a significant change in diagnosis (groups C and D), which confirmed the correctness of our diagnosis in 26 of 27 cases (96%; in five cases follow-up was inconclusive). We repeated the identical antibodies performed by the outside institutions in group D (37 antibodies) and group B (133 antibodies) with different results in 48.6% and 13.5%, respectively (overall nonconcordance 21.2%). In group D additional antibody tests beyond that performed by the outside institution were needed in 88.8% of cases to make a change of diagnosis. In the setting of a NCCC, reperforming and/or performing IHC on cases with a previous diagnosis of cancer is not a duplication of effort or misuse of resources. Repeating and/or performing IHC in this setting is important in the care and management of patients with cancer.