Into the future: A pilot study combining imaging with molecular profiling to predict resectability in ovarian cancer.

OBJECTIVE: We sought to determine the predictive value of combining tumor molecular subtype and computerized tomography (CT) imaging for surgical outcomes after primary cytoreductive surgery in advanced stage high-grade serous ovarian cancer (HGSOC) patients. METHODS: We identified 129 HGSOC patients who underwent pre-operative CT imaging and post-operative tumor mRNA profiling. A continuous CT-score indicative of overall disease burden was defined based on six imaging measurements of anatomic involvement. Molecular subtypes were derived from mRNA profiling of chemo-naïve tumors and classified as mesenchymal (MES) subtype (36%) or non-MES subtype (64%). Fischer exact tests and multivariate logistic regression examined residual disease and surgical complexity. RESULTS: Women with higher CT-scores were more likely to have MES subtype tumors (p = 0.014). MES subtypes and a high CT-score were independently predictive of macroscopic disease and high surgical complexity. In multivariate models adjusting for age, stage and American Society of Anesthesiologists (ASA) score, patients with a MES subtype and high CT-score had significantly elevated risk of macroscopic disease (OR = 26.7, 95% CI = [6.42, 187]) and were more likely to undergo high complexity surgery (OR = 9.53, 95% CI = [2.76, 40.6], compared to patients with non-MES tumor and low CT-score. CONCLUSION: Preoperative CT imaging combined with tumor molecular subtyping can identify a subset of women unlikely to have resectable disease and likely to require high complexity surgery. Along with other clinical factors, these may refine predictive scores for resection and assist treatment planning. Investigating methods for pre-surgical molecular subtyping is an important next step.

Clinical outcomes in patients with COVID-19 and gynecologic cancer: A society of gynecologic oncology COVID-19 and gynecologic cancer registry study.

OBJECTIVES: Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS: The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS: Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS: Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy?

OBJECTIVES: Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/-RAD. METHODS: This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/-lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/-RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/-RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/-RAD (HR = 0.18, 95% CI: 0.09-0.39) and RAD (HR = 0.31, 95% CI: 0.18-0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/-RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12-0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03-0.32). Overall survival did not differ by treatment. CONCLUSIONS: In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone.

Adjuvant treatment improves overall survival in women with high-intermediate risk early-stage endometrial cancer with lymphovascular space invasion.

BACKGROUND: Adjuvant therapy in early-stage endometrial cancer has not shown a clear overall survival benefit, and hence, patient selection remains crucial. OBJECTIVE: To determine whether women with high-intermediate risk, early-stage endometrial cancer with lymphovascular space invasion particularly benefit from adjuvant treatment in improving oncologic outcomes. METHODS: A multi-center retrospective study was conducted in women with stage IA, IB, and II endometrial cancer with lymphovascular space invasion who met criteria for high-intermediate risk by Gynecologic Oncology Group (GOG) 99. Patients were stratified by the type of adjuvant treatment received. Clinical and pathologic features were abstracted. Progression-free and overall survival were evaluated using multivariable analysis. RESULTS: 405 patients were included with the median age of 67 years (range 27-92, IQR 59-73). 75.0% of the patients had full staging with lymphadenectomy, and 8.6% had sentinel lymph node biopsy (total 83.6%). After surgery, 24.9% of the patients underwent observation and 75.1% received adjuvant therapy, which included external beam radiation therapy (15.1%), vaginal brachytherapy (45.4%), and combined brachytherapy + chemotherapy (19.1%). Overall, adjuvant treatment resulted in improved oncologic outcomes for both 5-year progression-free survival (77.2% vs 69.6%, HR 0.55, p=0.01) and overall survival (81.5% vs 60.2%, HR 0.42, p<0.001). After adjusting for stage, grade 2/3, and age, improved progression-free survival and overall survival were observed for the following adjuvant subgroups compared with observation: external beam radiation (overall survival HR 0.47, p=0.047, progression-free survival not significant), vaginal brachytherapy (overall survival HR 0.35, p<0.001; progression-free survival HR 0.42, p=0.003), and brachytherapy + chemotherapy (overall survival HR 0.30 p=0.002; progression-free survival HR 0.35, p=0.006). Compared with vaginal brachytherapy alone, external beam radiation or the addition of chemotherapy did not further improve progression-free survival (p=0.80, p=0.65, respectively) or overall survival (p=0.47, p=0.74, respectively). CONCLUSION: Adjuvant therapy improves both progression-free survival and overall survival in women with early-stage endometrial cancer meeting high-intermediate risk criteria with lymphovascular space invasion. External beam radiation or adding chemotherapy did not confer additional survival advantage compared with vaginal brachytherapy alone.

Should mucosal bowel invasion in ovarian cancer be assigned to FIGO stage IV disease?

OBJECTIVES: The FIGO staging consensus agreement from 2012 indicates that bowel mucosal invasion for epithelial ovarian cancer (EOC) should be assigned to stage IV disease. Finding no evidence justifying this recommendation, we examined the impact of recto-sigmoid colonic invasion on survival based on depth of invasion. METHODS: Patients having recto-sigmoid resection to achieve complete gross resection for stage IIIC/IV EOC between 2003 and 2011 were included. For this study, mucosal invasion alone was not considered as stage IV. Degree of bowel invasion was defined as: serosal/subserosal vs. muscularis/submucosa/mucosa. Patients with only mesenteric invasion were excluded. Intraperitoneal disease (IP) dissemination patterns were defined as pelvic, lower abdomen, upper abdomen, and miliary disease. Comparisons between groups were evaluated using the log-rank test for progression-free and overall survival (PFS, OS) and the chi-square test for IP dissemination pattern. RESULTS: Eighty-five patients were included with a mean age of 64.5 years. Most cases were serous (87.1%) and stage IIIC (83.5%). There were 53 (62.4%) patients with serosal/subserosal and 32 (37.6%) with muscularis/submucosa/mucosa invasion. Although not statistically significant, PFS and OS both favored cases with deeper invasion (muscularis/submucosa/mucosa vs. serosal/subserosal invasion: median PFS, 33.5 vs. 18.2 months, p = 0.34; median OS, 82.3 vs. 51.5 months, p = 0.46). When comparing patterns of disease dissemination, we observed that patients with serosal/subserosal invasion (vs. those with deeper invasion) tended to have more upper abdominal or miliary disease (67.9% vs. 48.4%, p = 0.08). CONCLUSIONS: Depth of recto-sigmoid colon wall invasion does not have prognostic significance. Our observations do not support assignment to a higher FIGO stage (IV) based solely on this factor.

Mesenchymal molecular subtype is an independent predictor of severe postoperative complications after primary debulking surgery for advanced ovarian cancer.

OBJECTIVE: To evaluate the contribution of molecular subtype to 30-day postoperative complications and 90-day mortality after primary debulking surgery (PDS) in advanced stage high-grade serous ovarian cancer (HGSOC). METHODS: Patients with stages III-IV HGSOC undergoing PDS from 1994 to 2011 with available molecular subtyping were included. Residual disease (RD) status was categorized as 0, 0.1-0.5, 0.6-1.0, or >1 cm. Surgical complexity scores were calculated as high, intermediate, or low as previously published. Postoperative complications were graded according to the modified Accordion classification 0-4 scale; severe was defined as grade ≥3. Molecular subtypes were derived from Agilent 4 × 44k tumor mRNA expression profiles and categorized as mesenchymal (MES) or non-mesenchymal (non-MES). Logistic regression modeling was used to assess associations. RESULTS: Of 329 patients, 68.7% were stage IIIC, 80.5% had RD ≤1 cm, 28.0% had MES subtype, and 19.5% had a grade 3-4 complication; 90-day mortality was 5.8%. In univariate analysis, patients with MES subtype were more likely to have severe complications compared to non-MES (31.5 vs. 14.8%; OR 2.66, 95% CI 1.51-4.69; p < 0.001). MES subtype remained an independent predictor of complications (adjusted OR 2.14, 95% CI 1.17-3.92; p = 0.01) in a multivariable model which included ASA score, preoperative albumin, and surgical complexity. There was no statistical difference in 90-day mortality in patients with MES compared to non-MES subtype (7.6 vs. 5.1%; OR 1.54, 95% CI 0.59-4.05; p = 0.38). CONCLUSIONS: MES subtype is an independent predictor of severe postoperative morbidity and adds to the potential use of pre-operative molecular testing in planning primary treatment of patients with advanced ovarian cancer.

Using quality improvement to increase the awareness of obesity among endometrial cancer patients.

OBJECTIVE: To increase discussion about obesity and endometrial cancer and referrals to weight loss clinic in patients with newly diagnosed low-risk endometrial cancer. METHODS: A multidisciplinary team used a quality improvement methodology to increase patient awareness about obesity and endometrial cancer. Target population included patients <80 years old with a body mass index ≥30 kg/m2 who underwent surgery at our institution and had a final diagnosis of complex hyperplasia or stage I, grade 1-2 endometrioid endometrial cancer. A toolkit was developed for the intervention. Clinical characteristics, discussion about obesity, and referrals to a weight loss clinic were abstracted for a historic and intervention cohort. Data for the two cohorts were compared using chi-square, Fisher's exact test, and t-test. RESULTS: 54 patients from the historic cohort and 53 from the intervention cohort met inclusion criteria. Clinical characteristics were balanced between the groups. Discussion about obesity increased from 11.1% (6/54) to 79.2% (42/53) after implementing the toolkit (p<0.001). Referrals to the weight loss clinic also increased from 3.7% (2/54) to 26.4% (14/53) after implementing the toolkit (p=0.001), but in both groups only 50% of those referred actually attended the weight loss clinic. No clinical characteristics were identified as associated with being more likely to have documented conversations or referrals. CONCLUSIONS: A multidisciplinary quality-improvement project can be used to increase discussion about obesity and referral to a weight loss clinic in patients with low-risk endometrial cancer. Increasing patient awareness of the connection between obesity and endometrial cancer may have implications on the long-term health of endometrial cancer survivors.

Frozen Section for Detection of Lymph Nodes After Cervical Injection with Indocyanine Green (ICG) for Sentinel Lymph Node Technique in Endometrial Cancer Staging.

OBJECTIVE: The aim of this study was to assess the role of frozen section (FS) in identifying an absence of lymph nodes during sentinel lymph node (SLN) biopsy for apparent early-stage endometrial cancer (EC). METHODS: Consecutive apparent early-stage EC patients who had SLNs removed after cervical injection with indocyanine green (ICG) from 1 June 2014 to 30 June 2016 were analyzed. An empty node (EN) was defined as an SLN specimen without evidence of lymph node(s). The association of tumor and patient characteristics with an EN was evaluated, and trend analysis to compare the rate of ENs over calendar quarters was performed. A decision-tree model was then created to compare the use of FS versus no FS for SLN evaluation in the hypothetical cohort affected by early-stage EC in the US each year. RESULTS: Over the study period, 300 patients met the inclusion criteria. FS revealed ENs in 24 (8%) patients. No association between patient demographic characteristics (age, body mass index, prior abdominopelvic surgery, international federation of gynecology and obstetrics (FIGO) stage, histology, myometrial invasion, cervical stromal invasion) and presence of ENs was observed. The rate of ENs at FS did not change over time (p = 0.68). The hypothetical analysis showed a 4.3% decrease of inappropriately staged patients with the use of FS on the SLN (95% confidence interval 4.1-4.5). CONCLUSIONS: ENs during SLN biopsy for EC staging is not a rare event and can be easily detected with FS. The implementation of FS of SLN might reduce inadequate staging of EC. Individual institutions may want to examine their own EN rates and determine if this would assist them in their SLN practices for EC.

Factors that influence survival in high-grade serous ovarian cancer: A complex relationship between molecular subtype, disease dissemination, and operability.

OBJECTIVE: To investigate the relationship between molecular subtype, intraperitoneal (IP) disease dissemination patterns, resectability, and overall survival (OS) in advanced high-grade serous ovarian cancer (HGSOC). METHODS: Patients undergoing primary surgery for stage III-IV HGSOC at Mayo Clinic from 1994 to 2011 were categorized into three IP disease dissemination patterns: upper abdominal or miliary; lower abdominal; and pelvic. Residual disease was defined as 0 (RD0), 0.1-0.5, 0.6-1.0, or >1 cm. Molecular subtypes were derived from Agilent 4x44k tumor mRNA expression profiles and categorized as mesenchymal (MES) or non-mesenchymal (non-MES). RESULTS: Operative and molecular data was available for 334 patients. Median OS was shorter in patients with MES compared to non-MES subtypes (34.2 vs 44.6 months; P = 0.009). Patients with MES subtype were more likely to have upper abdominal/miliary disease compared to non-MES subtype (90% vs. 72%, P < 0.001). For patients with upper abdominal/miliary disease, complete resection (RD0) was less common in MES compared to non-MES subtypes (11% vs. 27%, P = 0.004). On multivariable analysis, RD was the only factor associated with OS (P < 0.001). In patients with upper abdominal/miliary disease, though less commonly achieved, RD0 improved survival irrespective of molecular subtype (median OS of 69.2 and 57.9 months for MES and non-MES subtype). CONCLUSIONS: Our results support a paradigm in which molecular subtype is an important driver of dissemination pattern; this in turn impacts resectability and ultimately survival. Consequently mesenchymal subtype is associated with much lower rates of complete resection, though RD0 remains the most important independent predictor of survival.

Intraperitoneal disease dissemination patterns are associated with residual disease, extent of surgery, and molecular subtypes in advanced ovarian cancer.

OBJECTIVE: To investigate the association between intraperitoneal (IP) disease dissemination patterns, residual disease (RD), surgical complexity, and molecular subtypes in advanced high-grade serous ovarian cancer (HGSOC). METHODS: 741 patients with operable stage III-IV HGSOC undergoing primary debulking surgery at Mayo Clinic from 1994 to 2011 were categorized into four mutually exclusive IP disease dissemination patterns: upper abdominal (60%), miliary (16%), lower abdominal (15%), and pelvic (9%). Surgical complexity was classified as high, intermediate, or low; RD status was defined as 0, 0.1-0.5, 0.6-1.0, or >1cm; molecular subtype assignments were derived from expression profiling of tumors from 334 patients. RESULTS: Patients with either miliary or upper abdominal dissemination patterns were less likely to achieve RD0 compared to patients with pelvic and lower abdominal dissemination patterns (25% vs. 9% and 62%, each P<0.001) despite higher surgical complexity (39% vs. 6% and 20%, each P<0.001). Among the subset with molecular subtype data, patients with mesenchymal subtype of tumors were more likely to have upper abdominal or miliary dissemination patterns compared to patients with differentiated, proliferative, or immunoreactive subtypes (90% vs. 77%, 70%, 69%, respectively, P<0.05). CONCLUSIONS: IP disease dissemination patterns are associated with RD, surgical complexity, and tumor molecular subtypes. Patients with upper abdominal or miliary dissemination patterns are more likely to have mesenchymal HGSOC and in turn achieve lower rates of complete resection. This provides a plausible model for how the biologic behavior of molecular subtypes is manifest in disease and oncologic outcomes.

Risk factors for the development of uterine cancer in breast cancer survivors: an army of women study.

BACKGROUND: Our study compares breast cancer survivors without a secondary diagnosis of uterine cancer (BC) to breast cancer survivors with a diagnosis of uterine cancer (BUC) to determine clinical characteristics that increase the odds of developing uterine cancer. METHODS: A total of 7,228 breast cancer survivors were surveyed. A case-control study was performed with 173 BUC patients matched by age and race in a 1:5 ratio to 865 BC patients. Multivariable logistic regression examined which factors influence the odds of developing uterine cancer. RESULTS: A total of 5,980 (82.3 %) women did not have a previous hysterectomy at the time of breast cancer diagnosis, of which 173 (2.9 %) subsequently developed uterine cancer. There was no significant difference in body mass index (BMI) (34.4 vs. 34.1, p = 0.388) or age (52.3 vs. 52.3 years, p = 0.999) between the two groups. Increased odds for developing uterine cancer were found in patients with a personal history of hypertension [odds ratio (OR) = 1.62, 95 % confidence interval (CI) 1.45-2.70, p < 0.001], gallbladder disease (OR = 1.30, 95 % CI 1.14-1.55, p = 0.005), and thyroid disease (OR = 1.55, 95 % CI 1.37-1.69, p < 0.001). More than 80 % of women in both groups expressed a desire for a blood test to estimate the risk of uterine cancer (80.4 % BUC vs. 91.2 % BC, p < 0.001). CONCLUSIONS: Hypertension, gallbladder disease, and thyroid disease in breast cancer survivors increase the odds of developing uterine cancer. Breast cancer survivors also express significant interest in potential serum tests to assess the risk of developing uterine cancer.

Identifying the Rate-Limiting Step in Total Laparoscopic Hysterectomy in a Training Hospital.

STUDY OBJECTIVE: To identify the lengthiest step of total laparoscopic hysterectomy (TLH) in a teaching hospital and to determine which clinical factors affect the duration of this step. SETTING: The University of Louisville Hospital. DESIGN: Single institution retrospective case series. METHODS AND MAIN RESULTS: This is a retrospective chart and video review that included 135 benign, elective TLHs performed at The University of Louisville. TLH was divided into 5 steps: (1) insertion of laparoscopic ports and adhesiolysis to restore normal anatomy; (2) identification of the ureter and resection of adnexal structures to transection of the round ligament; (3) transection of the round ligament to transection of the uterine artery; (4) lateralization of the uterine vessel pedicle to completion of colpotomy; and (5) completion of vaginal cuff closure. The random intercept and slope model was used to identify the lengthiest step of TLH, and the backward elimination procedure was used to evaluate which clinical factors affected this step. Mean ± SD total length of TLH was 81 ± 30 min. The lengthiest step was colpotomy, with a mean duration of 24 ± 13 min. Uterine weight significantly increased the length of time required for colpotomy (p = .001). The primary energy source (ultrasonic scalpel vs monopolar hook) used to perform colpotomy did not influence the length of time (p = .539 vs p = .583). Uterine weight (p < .001) and adhesiolysis (p = .003) significantly increased the total time of TLH. CONCLUSIONS: At a teaching institution where surgeries are performed by residents and fellows, colpotomy is the lengthiest step of TLH and is influenced by uterine weight. This finding may reflect the training levels of the surgeons performing these cases and the learning curve associated with a challenging surgical skill. Further research should focus on simulation models and/or tools for colpotomy that may result in greater efficiency in the operating room.

The CTo-aBCDE score: A new predictor of success in chronic total occlusions.

INTRODUCTION: Patient selection for percutaneous coronary intervention (PCI) in chronic total occlusions (CTOs) is crucial to procedural success. Our aim was to identify independent predictors of success in CTO PCI in order to create an accurate score. METHODS: In a single-center observational registry of CTO PCI, demographic and clinical data and anatomical characteristics of coronary lesions were recorded. Linear and logistic regression analysis were used to identify predictors of success. A score to predict success was created and its accuracy was measured by receiver operating curve analysis. RESULTS: A total of 377 interventions were performed (334 patients, age 68±11 years, 75% male). The success rate was 65% per patient and 60% per procedure. Predictors of success in univariate analysis were absence of active smoking (OR 2.02, 95% CI 1.243-3.29; p=0.005), presence of tapered stump (OR 5.2, 95% CI 2.7-10.2; p<0.001), absence of tortuosity (OR 6.44; 95% CI 3.02-13.75; p<0.001), absence of bifurcation (OR 1.95; 95% CI 1.08-3.51; p=0.026), absence of calcification (OR 3.1; 95% CI 3.10-5.41; p<0.001), LAD as target vessel (OR 1.9, 95% CI 1.0-3.5; p=0.048), and CTO length <20 mm (OR 3.00, 95% CI 1.69-5.3; p<0.001). Only anatomical factors were independent predictors of success, and an anatomical score (0-11 points) with high accuracy (area under the curve 0.831) was subsequently created. A score <3 was associated with low probability of success (15%), 3-8 with intermediate probability (55%), and >8 with high probability (95%). CONCLUSION: In our sample only anatomical characteristics were predictors of success. The creation of a score to predict success, with good accuracy, may enable selection of cases that can be treated by any operator, those in which a dedicated operator will be desirable, and those with an extremely low probability of success, which should be considered individually for conservative management, surgical revascularization or PCI by a team experienced in CTO.

Minimally Invasive Hysterectomy and Bariatric Surgery to Improve Endometrial Cancer Survivorship.

BACKGROUND: Surgery is curative for the majority of early-stage endometrial cancers. Postoperatively, patients are actually at much higher risk of mortality from obesity-related comorbidities unless they have sustained weight loss. CASE: A 54-year-old woman with class III obesity, type II diabetes mellitus complicated by neuropathy and retinopathy, hypertension, sleep apnea, and fatty liver disease was diagnosed with grade 1 endometrioid uterine cancer. She underwent dual surgery with laparoscopic bariatric surgery and robotic-assisted laparoscopic hysterectomy. The perioperative period was uncomplicated, and final pathology was consistent with a stage IA grade 1 endometrial cancer. In 12 months, the patient lost 41.3 kg and required less insulin, metformin, and antihypertensive medication. CONCLUSION: Combined minimally invasive hysterectomy and bariatric surgery for obese women with endometrial cancer can promote sustained weight loss and improve survivorship.

Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A.

OBJECTIVES: Inhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models. METHODS: PAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis. RESULTS: The addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive. CONCLUSIONS: The addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic.

Comparative analysis of fractional flow reserve and instantaneous wave-free ratio: Results of a five-year registry. / Análise comparativa do fractional flow reserve (FFR) e do instantaneous wave­free ratio (iFR): resultados de um registo de 5 anos.

INTRODUCTION AND OBJECTIVE: Assessment of coronary lesions by the instantaneous wave free ratio (iFR) has generated significant debate. We aimed to assess the diagnostic performance of iFR and its impact on the decision to use fractional flow reserve (FFR) and on procedural characteristics. METHODS: In this single-center registry of patients undergoing functional assessment of coronary lesions, FFR was used as a reference for assessing the diagnostic performance of iFR. An iFR value <0.86 was considered positive and a value >0.93 was considered negative. RESULTS: Functional testing was undertaken of 402 lesions, of which 154 were assessed with both techniques, 222 with FFR only, and 26 with iFR only. Using a cut-off of ≤0.80 for iFR, the area under the curve was 0.73 (95% CI 0.65-0.81), with an optimal value of ≤0.91. FFR was undertaken in 93 out of 94 lesions with an inconclusive iFR and was performed in 69.1% of the remaining iFR-tested lesions. Concordance between iFR and FFR was 87% (chi-square=22.43; p<0.001). Notwithstanding, there were four out of 13 cases (30.7%) of positive iFR with negative FFR and three out of 42 (7.1%) cases of negative iFR and positive FFR. This difference was significant (p=0.026). iFR had no impact on procedure time, fluoroscopy time or radiation dose. CONCLUSION: iFR had a reasonable diagnostic performance. Operators often chose to perform FFR despite conclusive iFR results. iFR and FFR were highly concordant, but a non-negligible proportion of lesions classified as ischemic by iFR were classified as non-ischemic by FFR. iFR had no impact on procedural characteristics.

Anomalous origin of the circumflex coronary artery--two case reports.

As shown in many series, congenital coronary artery anomalies are found in 0.6 to 1.5% of patients undergoing coronary angiography. Various types of coronary anomalies have been described, many involving the circumflex artery. The second most common anomaly is of the circumflex arising from the right sinus of Valsalva, while origin in the right coronary artery is also frequent. The most common anomaly is absence of the left main coronary artery, the anterior descending and circumflex arteries originating separately in the left coronary sinus. Such anomalies are usually benign, although earlier and more aggressive atherosclerosis is more likely than in normal coronaries and myocardial ischemia can result. Although rare, this can manifest as sudden death. Conventional coronary angiography may be unable to determine the three-dimensional course of the anomalous vessel. The development of multislice computed tomography and its application to cardiac imaging mean that it is now possible to visualize the coronary arteries non-invasively and to obtain more accurate information on their proximal course. We present two cases of congenital anomaly of the circumflex coronary artery diagnosed with the aid of multislice computed tomography.

Clear cell adenocarcinoma arising in an adenomyoma of the broad ligament.

Extrauterine adenomyomas are extremely rare benign tumors of smooth muscles, endometrial glands, and endometrial stroma. Ectopic endometrial glands can undergo malignant change. The ovary is the most common site of malignant change in endometriosis. Cancer arising in extraovarian endometriosis is a rare event with limited cases in the literature. To the best of our knowledge, we present the first case of a clear cell adenocarcinoma arising from foci of ectopic endometrial tissue in an adenomyoma of the broad ligament. It supports the association between endometriomas and clear cell adenocarcinoma. Therefore, patients with a significant history of endometriosis may benefit from close follow-up or definitive surgery.

Left main coronary artery originating in the right sinus of Valsalva.

A forty-one-year-old male, with no risk factors for coronary artery disease (CAD) and with moderate alcohol intake, was admitted in 1992 to Portalegre Hospital with heart failure due to viral cardiomyopathy. He was re-admitted in 1998 with acute pulmonary edema and was put on mechanical ventilation for 48 hours, and transferred to Pulido Valente Hospital when stable. The physical exam was without abnormalities. ECG showed first degree AV block, left ventricular hypertrophy and 2 mm ST depression in the precordial leads. The echocardiogram revealed left ventricular dilatation and depressed systolic function. Coronary angiography showed single-vessel CAD and coronary artery anomaly. Dobutamine stress echocardiography was halted due to hypertension, making it impossible to evaluate ischemic response. Holter monitoring showed five-complex ventricular tachycardia. The patient was discharged medicated with amiodarone, with indication for cardiac scintigraphy and electrophysiological study.

Tissue Doppler imaging in hypertrophic cardiomyopathy: impact of intraventricular obstruction on longitudinal left ventricular function.

BACKGROUND: In non-obstructive hypertrophic cardiomyopathy, tissue Doppler imaging of the mitral annulus shows severe systolic and diastolic dysfunction, with marked heterogeneity and asynchrony. In obstructive forms, the complexity of pathophysiological interactions makes conventional echocardiographic functional assessment extremely difficult and complex. OBJECTIVE: To study longitudinal left ventricular function with tissue Doppler imaging in the obstructive forms of hypertrophic cardiomyopathy. METHODS: Twenty-six patients with hypertrophic obstructive cardiomyopathy and 23 patients with the non-obstructive form of the disease, matched by age, were studied with pulsed tissue Doppler imaging of the 4 sides of the mitral annulus (septal, lateral, inferior, anterior) in 4 and 2 chamber views. In each wave (systolic-s, rapid filling-e, atrial contraction-a) we analyzed velocities, time intervals and velocity-time integrals, as well as heterogeneity and asynchrony indexes. Data were compared between the different sides in each group, between groups and with conventional Doppler data. RESULTS: In contrast to the non-obstructive forms, patients with intraventricular obstruction showed: Systolic function: similar velocities and integrals, the relations between the different sides of the annulus usually being preserved; longer isovolumic contraction time, time to peak s and PEP/LVET. Diastolic function: similar rapid filling and e/a velocities and integrals, lower atrial contraction velocity and integral, similar number of sides with e/a higher than or equal to 1 on the lateral and inferior side of the annulus; similar diastolic time intervals, except diastolic time. CONCLUSIONS: This study shows that the presence of dynamic intraventricular obstruction and the loading conditions of obstructive forms of hypertrophic cardiomyopathy do not significantly influence most annular tissue Doppler imaging parameters, showing the relative load independence of the technique. So, in obstructive hypertrophic cardiomyopathy patients: 1--Longitudinal systolic function (velocities) is similar to the non-obstructive forms--longitudinal systolic dysfunction. 2--Longitudinal diastolic function (velocities and time intervals) is similar to the non-obstructive forms--longitudinal diastolic dysfunction. 3--Left atrial dysfunction is more severe than in non-obstructive forms. 4--The inferior and lateral sides of the annulus should be those selected in order to identify pseudonormalization of the transmitral flow.