Mixed clear cell/endometrioid and clear cell/serous carcinoma of the uterus are clinicopathologically similar to pure clear cell carcinoma: An NRG Oncology/Gynecologic Oncology Group (GOG-210) study of 311 women.

OBJECTIVES: Clear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. METHODS: The term "mixed" was applied to tumors with multiple identifiable components, and "indeterminate" was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. RESULTS: One hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. CONCLUSION: In clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.

Clinical outcome of multidisciplinary treatment of vulvar necrotising fasciitis.

OBJECTIVE: Vulvar necrotising fasciitis (VNF) is a severe soft tissue infection associated with substantial morbidity and high mortality. At Stony Brook Medicine, US, patients with known or suspected VNF are treated by a structured multidisciplinary team consisting of members of the Departments of Emergency Medicine and Medicine, the Divisions of Gynecologic Oncology, Burn and Surgical Intensive Care Units, Infectious Disease and Plastic Surgery, and the nursing, nutrition, physical/occupational therapy and social work services. METHOD: This is a retrospective review of patients presenting to Stony Brook University Hospital with VNF over an 18-month period. RESULTS: A total of 10 patients were treated for VNF during the study period. All patients were treated by the structured multidisciplinary team, including extensive initial surgical debridement by the gynaecologic oncologists. All patients survived to discharge. CONCLUSION: The results of this review demonstrated that prompt diagnosis, rapid implementation of appropriate antibiotic coverage, surgical debridement of necrotic tissue, and comprehensive care delivered by a structured multidisciplinary team contributed to positive clinical outcomes and decreased the risk of death from VNF.

The presence of an endometrioid component does not alter the clinicopathologic profile or survival of patients with uterine serous cancer: A gynecologic oncology group (GOG/NRG) study of 934 women.

OBJECTIVE: While most cases of endometrial cancer can readily be classified as pure endometrioid, pure serous, or another type, others show an apparent mixture of serous and endometrioid components, or indeterminate serous versus endometrioid features. Since serous histology carries a worse prognosis than endometrioid, Gynecologic Oncology Group protocol GOG-8032 was established to examine whether the presence of a non-serous component is a favorable feature in an otherwise serous cancer. METHODS: 934 women with serous cancer were prospectively identified among a larger group enrolled in GOG-0210. Six expert gynecologic pathologists classified each case as pure serous (SER, n=663), mixed serous and endometrioid (SER-EM-M, n=138), or indeterminate serous v. endometrioid (SER-EM-I, n=133) by H&E morphology. Follow-up data from GOG-0210 were analyzed. RESULTS: The subgroups did not differ on BMI, race, ethnicity, lymphovascular invasion, cervical invasion, ovary involvement, peritoneal involvement, omental involvement, FIGO stage, or planned adjuvant treatment. SER-EM-M patients were younger (p=0.0001) and less likely to have nodal involvement (p=0.0287). SER patients were less likely to have myoinvasion (p=0.0002), and more likely to have adnexal involvement (p=0.0108). On univariate analysis, age, serous subtype, race, and components of FIGO staging predicted both progression-free and overall survival. On multiple regression, however, serous subtype (SER, SER-EM-M, or SER-EM-I) did not significantly predict survival. CONCLUSIONS: There were few clinicopathologic differences between cases classified as SER, SER-EM-M, and SER-EM-I. Cases with a mixture of serous and endometrioid morphology, as well as cases with morphology indeterminate for serous v. endometrioid type, had the same survival as pure serous cases. NCT#: NCT00340808.

Which patients on a gynecologic oncology service will require perioperative transfusion? A single-center retrospective cohort study.

The purpose of this study was to determine which patient- or surgery-related factors are predictive of need for perioperative transfusion to avoid obtaining unnecessary pre-operative type and screens (T&S). We conducted an observational retrospective cohort study of 1200 women ≥ 18 years old undergoing gynecologic surgery for benign, possibly benign, or malignant indications on a gynecologic oncology service at a university medical center from 2009-2016. A logistic regression model was used to examine patient-related and surgery-related variables predictive of outcome of transfusion. Independent variables included patient demographics, comorbidities, and surgical indication surgical route, and surgical type. Dependent variable was transfusion outcome (T&S only, conversion to type and cross (T&C), or transfusion). Eight hundred ninety-nine (74.9%) women underwent pre-operative T&S, of which 118 (9.8%) were converted to T&C, and 80 (6.7%) received a transfusion of blood or blood products. Cancer indication, major surgery, and preoperative hematocrit less than 36% were significantly associated with need for transfusion (P = 0.002, P < 0.0001, P < 0.0001, respectively). Patients with a benign indication undergoing minor procedures and with normal preoperative hematocrit are least likely to require transfusion.

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer.

OBJECTIVES: The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. METHODS: Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. RESULTS: Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53-3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10-7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04-4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. CONCLUSIONS: A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.

Surgical outcomes among elderly women with endometrial cancer treated by laparoscopic hysterectomy: a NRG/Gynecologic Oncology Group study.

OBJECTIVE: Tolerance of and complications caused by minimally invasive hysterectomy and staging in the older endometrial cancer population is largely unknown despite the fact that this is the most rapidly growing age group in the United States. The objective of this retrospective review was to compare operative morbidity by age in patients on the Gynecologic Oncology Group Laparoscopic Surgery or Standard Surgery in Treating Patients With Endometrial Cancer or Cancer of the Uterus (LAP2) trial. STUDY DESIGN: This is a retrospective analysis of patients from Gynecologic Oncology Group LAP2, a trial that included clinically early-stage uterine cancer patients randomized to laparotomy vs laparoscopy for surgical staging. Differences in the rates and types of intraoperative and perioperative complications were compared by age. Specifically complications between patients <60 vs ≥60 years old were compared caused by toxicity analysis showing a sharp increase in toxicity starting at age 60 years in the laparotomy group. RESULTS: LAP2 included 1477 patients ≥60 years old. As expected, with increasing age there was worsening performance status and disease characteristics including higher rates of serous histology, high-stage disease, and lymphovascular space invasion. There was no significant difference in lymph node dissection rate by age for the entire population or within the laparotomy or laparoscopy groups. Toxicity analysis showed a sharp increase in toxicity seen in patients ≥60 years old in the laparotomy group. Further analysis showed that when comparing laparotomy with laparoscopy in patients <60 years old vs ≥60 years old and controlling for race, body mass index, stage, grade, and performance status, patients <60 years old undergoing laparotomy had more hospital stays >2 days (odds ratio, 17.48; 95% confidence interval, 11.71-27.00, P < .001) compared with patients <60 years old undergoing laparoscopy. However, when comparing laparotomy with laparoscopy in patients ≥60 years old, in addition to hospital stay >2 days (odds ratio, 12.77; 95% confidence interval, 8.74-19.32, P < .001), there were higher rates of the following postoperative complications: antibiotic administration (odds ratio, 1.63; 95% confidence interval, 1.24-2.14, P < .001), ileus (odds ratio, 2.16; 95% confidence interval, 1.42-3.31, P <0.001), pneumonias (odds ratio, 2.36; 95% confidence interval, 1.01-5.66, P = .048), deep vein thromboses (odds ratio, 2.87; 95% confidence interval, 1.08-8.03, P = .035), and arrhythmias (odds ratio, 3.21; 95% confidence interval, 1.60-6.65, P = .001) in the laparotomy group. CONCLUSION: Laparoscopic staging for uterine cancer is associated with decreased morbidity in the immediate postoperative period in patients ≥60 years old. These results allow for more accurate preoperative counseling. A minimally invasive approach to uterine cancer staging may decrease morbidity that could affect long-term survival.

Receipt of adjuvant endometrial cancer treatment according to race: an NRG Oncology/Gynecologic Oncology Group 210 Study.

BACKGROUND: Black women with endometrial cancer are more likely to die of their disease compared with white women with endometrial cancer. These survival disparities persist even when disproportionately worse tumor characteristics among black women are accounted. Receipt of less complete adjuvant treatment among black patients with endometrial cancer could contribute to this disparity. OBJECTIVE: We assessed the hypothesis that black women with endometrial cancer are less likely than their white counterparts to receive adjuvant treatment within subgroups defined by tumor characteristics in the NRG Oncology/Gynecology Oncology Group 210 Study. STUDY DESIGN: Our analysis included 615 black and 4283 white women with endometrial cancer who underwent hysterectomy. Women completed a questionnaire that assessed race and endometrial cancer risk factors. Tumor characteristics were available from pathology reports and central review. We categorized women as low-, intermediate-, or high-risk based on the European Society for Medical Oncology definition. Adjuvant treatment was documented during postoperative visits and was categorized as no adjuvant treatment (54.3%), radiotherapy only (16.5%), chemotherapy only (15.2%), and radiotherapy plus chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios and 95% confidence intervals for multivariable-adjusted associations between race and adjuvant treatment in the overall study population and stratified by tumor subtype, stage, or European Society for Medical Oncology risk category. RESULTS: Overall, black women were more likely to have received chemotherapy only (odds ratio, 1.40; 95% confidence interval, 1.04-1.86) or radiotherapy plus chemotherapy (odds ratio, 2.01; 95% confidence interval, 1.54-2.62) compared with white women in multivariable-adjusted models. No racial difference in the receipt of radiotherapy only was observed. In tumor subtype-stratified models, black women had higher odds of receiving radiotherapy plus chemotherapy than white women when diagnosed with low-grade endometrioid (odds ratio, 2.04; 95% confidence interval, 1.06-3.93) or serous tumors (odds ratio, 1.81; 95% confidence interval, 1.07-3.08). Race was not associated with adjuvant treatment among women who had been diagnosed with other tumor subtypes. In stage-stratified models, we observed no racial differences in the receipt of adjuvant treatment. In models that were stratified by European Society for Medical Oncology risk group, black women with high-risk cancer were more likely to receive radiotherapy plus chemotherapy compared with white women (odds ratio, 1.41; 95% confidence interval, 1.03-1.94). CONCLUSION: Contrary to our hypothesis, we observed higher odds of specific adjuvant treatment regimens among black women as compared with white women within specific subgroups of endometrial cancer characteristics.

Synuclein-γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.

iCTC drug resistance (CDR) Testing ex vivo for evaluation of available therapies to treat patients with epithelial ovarian cancer.

GOALS: Management of epithelial ovarian cancer (EOC) could use serial measurements of invasive circulating tumor cells (iCTCs) for monitoring therapeutic response and early detection of disease progression/recurrence. Goals of this study are to develop an iCTC drug resistance (CDR) assay and to evaluate clinical significance of patient-derived, cultured iCTCs in selecting available therapies. METHODS: The CDR assay using Taxol-Carboplatin and eight other EOC drugs at the concentration used for patients was performed. Blood was donated by six patients before primary Taxol-Carboplatin chemotherapy, one recurrent patient, six patients during and after their course of chemotherapy, and two patients with benign disease for procedure control. CDR score above and below 100 indicates sensitivity and resistance, respectively, to that drug. RESULTS: Five of six pre-therapy samples had >20 iCTCs/>111 CDR for Taxol-Carboplatin sensitivity, and one had 40 iCTCs/23 CDR for resistance. The recurrent sample had 58 iCTCs/5 CDR for resistance. Four of six post-therapy patients had iCTCs decreased to 0/>153 CDR indicating sensitivity, while two patients had >45 iCTCs/<85 CDR indicating resistance. The patients' treatment history and follow-up confirmed that patients were in response or remission when iCTCs were sensitive to Taxol-Carboplatin, and patients were in relapse or recurrence when iCTCs were resistant to Taxol-Carboplatin. CONCLUSION: Further investigation on the CDR assay is warranted to examine its use in selecting drugs before treating a patient.

FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. METHODS: Tumors were collected as part of the GOG 210 clinical trial "Molecular Staging of Endometrial Cancer" where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. RESULTS: Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p=0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p<0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177-3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096-3.696). CONCLUSION: In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted.

Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol.

OBJECTIVE: To report clinical and pathologic relationships with disease spread in endometrial cancer patients. METHODS: Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003-2007, open eligibility enrollment was conducted, and from 2007-2011, eligibility was restricted to enrich underrepresented patients or those at high risk. RESULTS: This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease. CONCLUSIONS: This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.

Analysis of normal and dysplastic glenohumeral morphology at magnetic resonance imaging in children with neonatal brachial plexus palsy.

BACKGROUND: Glenoid version and percentage of the humeral head anterior to the scapular line are commonly used 2-D measures to assess deformity of the glenohumeral joint of children with neonatal brachial plexus palsy. OBJECTIVE: To assess whether glenoid version and percentage of the humeral head anterior to the scapular line would be altered by standardizing the measurements to the orientation of the scapula. MATERIALS AND METHODS: Twenty-one bilateral magnetic resonance imaging (MRI) scans were evaluated by four reviewers. Measurements were performed on the axial image slices and again after applying 3-D reformatting. RESULTS: Three-dimensional reformatting led to intrapatient corrections up to 25° for version and -30% for percentage of the humeral head anterior to the scapular line. The mean difference on the involved side between clinical and anatomical version across all subjects from all reviewers was 2.2° ± 3.9° (range: -4.5° to 11.5°). The mean difference in the percentage of the humeral head anterior to the scapular line after reformatting was -1.8% (range: -15.9% to 5.2%). CONCLUSION: Measurements can differ greatly for the same child depending on technical factors of image acquisition and presentation in the clinical setting. With this study, we present a clinically accessible protocol to correct for scapular orientation from MRI data of children with neonatal brachial plexus palsy.

Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: An NRG Oncology/Gynecologic Oncology Group ancillary analysis.

OBJECTIVES: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. METHODS: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. CONCLUSIONS: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach.

Treatment monitoring of patients with epithelial ovarian cancer using invasive circulating tumor cells (iCTCs).

GOALS: Contemporary management of epithelial ovarian cancer (EOC) uses biomarkers to monitor response to therapy. This study evaluates the role of invasive circulating tumor cells (iCTCs) in monitoring EOC treatment in comparison with serum cancer antigen 125 (CA125). METHODS: Molecular and microscopic analyses were used to identify seprase and CD44 as tumor progenitor (TP) markers. The iCTC flow cytometry assay was optimized using blood donated by 64 healthy donors, 49 patients with benign abdominal diseases and 123 EOC patients. Serial changes in iCTCs and CA125 were measured in 129 blood and 169 serum samples, respectively, from 31 EOC patients to assess their concordance during therapy and their relationship with risk of progressive disease (PD). RESULTS: The assay had 97% specificity and 83% sensitivity for detecting iCTCs in blood of EOC patients. iCTCs were detected in each monitoring patient (31/31, 100%) and in 110 of the 129 blood samples (85.3%). The concordance between changes in iCTCs/CA125 levels and changes in the intervals associated with no evidence of disease (NED) were markedly stronger (specificity: CA125 93.8%; iCTCs 90.6%), whereas increases in iCTCs (79.5%) were more sensitive than increases in CA125 (67.6%) to predict PD or relapse. Among the six patients who had greater than 6 measurements, iCTCs but not CA125 antedated changes in clinical status from PD to NED during and after chemotherapy and predated relapse. CONCLUSION: Serial measurements of iCTCs could predict therapeutic responsiveness in 31 EOC patients who underwent standard taxol/carboplatin therapy.

Glenoid version by CT scan: an analysis of clinical measurement error and introduction of a protocol to reduce variability.

OBJECTIVE: Recent studies have challenged the accuracy of conventional measurements of glenoid version. Variability in the orientation of the scapula from individual anatomical differences and patient positioning, combined with differences in observer measurement practices, have been identified as sources of variability. The purpose of this study was to explore the utility and reliability of clinically available software that allows manipulation of three-dimensional images in order to bridge the variance between clinical and anatomic version in a clinical setting. MATERIALS AND METHODS: Twenty CT scans of normal glenoids of patients who had proximal humerus fractures were measured for version. Four reviewers first measured version in a conventional manner (clinical version), measurements were made again (anatomic version) after employing a protocol for reformatting the CT data to align the coronal and sagittal planes with the superior-inferior axis of the glenoid, and the scapular body, respectively. RESULTS: The average value of clinical retroversion for all reviewers and all subjects was -1.4° (range, -16° to 21°), as compared to -3.2° (range, -21° to 6°) when measured from reformatted images. The mean difference between anatomical and clinical version was 1.9° ± 5.6° but ranged on individual measurements from -13° to 26°. In no instance did all four observers choose the same image slice from the sequence of images. CONCLUSIONS: This study confirmed the variation in glenoid version dependent on scapular orientation previously identified in other studies using scapular models, and presents a clinically accessible protocol to correct for scapular orientation from the patient's CT data.

Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer.

GOALS: Circulating tumor cells (CTCs) have been introduced as a biomarker in detecting advanced epithelial ovarian cancer (EOC). The goals are to examine the prevalence of the invasive subpopulation of CTCs (iCTCs) in patients at high risk of EOC and to compare this biomarker to serum CA125. METHODS: We used a unique cell adhesion matrix (CAM)-based, functional cell enrichment and identification platform to isolate iCTCs from 129 preoperative patients. We confirmed the identity of iCTCs using positive epithelial (Epi+) markers and negative hematopoietic lineage (HL-) markers. Sensitivity and specificity of the assays were examined and iCTCs/CA125 were correlated with overall survival (OS), progression-free survival (PFS) and clinical parameters. RESULTS: We found a 41.2% sensitivity, 95.1% specificity and 77.8% positive predictive value (PPV) of the iCTC assay in detecting patients with stage I and II EOC malignancy, and a 83% sensitivity and 97.3% PPV in detecting all stages of EOC malignancy. However, a positive CA125 test provided weak evidence to detect stage I and II malignancy (61.6% PPV) and all EOC (92.1% PPV), because of its 76.2% specificity. A significantly stronger concordance in OS and PFS of clinical factors (tumor stage, debulking and platinum sensitivity) was noted for elevated iCTCs than for serum CA125. CONCLUSION: The CAM-initiated CTC enrichment/identification method enabled the detection of early stage EOC. iCTCs were better correlated with worse OS and PFS, more specific and better PPV than CA125 in detecting EOC malignancy in patients at high risk of EOC.

Assessing shoulder motion in children: age limitations to Mallet and ABC Loops.

BACKGROUND: Shoulder ROM and function of the shoulder are difficult to evaluate in young children. There has been no determination of the age at which children can comply with the current assessment tools in use, but doing so would be important, because it gives us more accurate insight into the development and assessment of shoulder functional ROM in young children. QUESTIONS/PURPOSES: We (1) determined whether age would limit the use of two different observational scales used to assess shoulder ROM and function in young children (the Mallet scale and the ABC Loops protocol); and (2) compared the two scales in terms of intra- and interobserver reliabilities. METHODS: Sixty-five able-bodied children (32 boys, 33 girls; mean age, 3.9 years; range, 0.5-7.0 years) were recruited from local preschools and evaluated using the Mallet scale and ABC Loops protocol. Children were assessed on their ability to complete the examinations and time to completion for each measurement protocol. Intra- and interobserver reliability was tested by percentage agreement. Forty-eight children (mean age, 4.4 years; SD, 1.3 years) were able to complete the Mallet and ABC Loops measurement protocols; 17 children (mean age, 2.3 years; SD, 1.1 years) failed to complete either test. RESULTS: Younger children had more difficulty completing the examinations; there was a strong negative correlation between age and failure: probability of failure increased with decreasing age (Pearson r = -0.601, p < 0.001). Children who were able to complete one test were able to complete the other. Interobserver and intraobserver agreement was very high for both scales (in excess of 95% for all comparisons), and with the numbers available, there were no differences between the scales. CONCLUSIONS: The Mallet scale and ABC Loops protocol have high reliability metrics in children younger than 6 years, but very young children (those younger than 3 years) generally will not be able to complete the examinations. The ABC Loops test took longer to perform than the Mallet scale but may more comprehensively evaluate a child's functional capabilities. We therefore state that both assessment tools can be reliably used in children older than 3 years; we believe the ABC Loops gives a more accurate assessment of shoulder ROM.

Geometry of the proximal humeral articular surface in young children: a study to define normal and analyze the dysplasia due to brachial plexus birth palsy.

BACKGROUND: Little is known regarding the morphology of the proximal humerus in growing children. This study reports bilateral magnetic resonance imaging measurements in children with internal rotation contractures from birth palsy, hypothesizing that dysplasia alters normal humeral sphericity and symmetry. METHODS: We studied 25 children with unilateral internal rotation contractures (mean age, 3.7 years) for humeral shape by bilateral magnetic resonance imaging studies at the mid-glenoid level. Local radii of curvature were compared for symmetry and orientation. RESULTS: Neither side showed uniform radii (sphericity), but normal humeri showed symmetry lost in dysplasia. Internal rotation contractures were correlated with flattening of the anterior humeral head (P = .0002). All heads were flatter in the region of articular contact. The skew axis (the largest cross-sectional diameter of the proximal humerus) was collinear with the articular surface centerline in normal humeri, an alignment often lost with dysplasia, resulting in a skew axis angle. The severity of glenoid deformity correlated with progressive posterior displacement of the humeral head center (P < .0003). CONCLUSION: The normal humeral articular surface in the young child is not spherical and is flatter in the middle than at the periphery but is symmetric about its central axis. Internal rotation contractures result in loss of this symmetry with characteristic flattening of the anterior humeral head and development of a skew axis angle. CLINICAL RELEVANCE: Posterior displacement of the humeral head center of rotation beyond 50% of the calculated head radius warrants vigilance and possibly surgical intervention because there is a high likelihood for development of a pseudoglenoid.