bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer
Authors: Huh W. K. , Straughn J. M. , Cohn D. E. 
Published: August 2020

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]
Influence of residual disease and extreme drug resistance assays on outcome in patients with epithelial ovarian cancer
Authors: Karam A. , Wang Chiang J. , Fung E. , Nossov V. , Karlan B. Y. 
Published: August 2020

5504 Background: Extreme drug resistance (EDR) assays have been used as tools in identifying those agents that are least likely to be of clinical benefit in the treatment of epithelial ovarian cancer (EOC). We sought to examine the effect of obtaining EDR assays on the outcome of patients with EOC in the primary and recurrent setting. Methods: We conducted a retrospective review of demographic, pathologic, EDR assay and outcome data from 377 patients with EOC who had an assay sent at the time of their diagnosis or at recurrence. Univariate followed by multivariate analyses using Cox proportional hazards method were performed to identify and estimate the impact of independent prognostic factors on time to progression (TTP), overall survival (OS) and survival after recurrence (RS). Results: Increasing age was associated with a worse OS and RS (HR = 1.34; 95% CI, 1.14–1.58 and HR = 1.14; 95% CI, 1.00–1.31, for each decade increase in age respectively). Compared with patients with microscopic residual disease, patients who were left with 0.1 to 1.0 cm and >1.0 cm residual disease had an increased risk of recurrence (HR=1.94; 95% CI, 1.33 to 2.84 and HR=3.61; 95% CI; 2.07 to 6.39, respectively) and death (HR = 1.59; 95% CI, 1.03 to 2.45; and HR = 2.14; 95% CI, 1.09 to 4.20, respectively). For patients who recurred, those who did not undergo secondary cytoreductive surgery and patients who were left with >1.0 cm residual had an increased risk of death compared to patients with microscopic residual (HR = 2.13; 95% CI, 1.28 to 3.54; and HR = 2.84; 95% CI, 1.71 to 4.71, respectively). EDR assay results for single agents or combinations did not independently predict patient outcomes. Conclusions: The amount of residual disease continues to be an important prognostic factor, especially when all macroscopic disease is removed both in the primary and recurrent setting. Increasing age is also an independent predictor of OS and RS. EDR assay results do not independently predict or alter the outcomes of patients with EOC who are treated with the current standard of care including optimal cytoreductive surgery followed by platinum and taxane combination chemotherapy in either the primary or recurrent setting. No significant financial relationships to disclose.
Sentinel node (SN) biopsy in patients with vulvar cancer: A Gynecologic Oncology Group (GOG) study
Authors: Levenback C. F. , Tian C. , Coleman R. L. , Gold M. A. , Fowler J. M. , Judson P. L. 
Published: August 2020

5505 Background: Vulvar cancer is a good target for SN strategy because lymphatic drainage is predictable and the morbidity of regional lymphadenectomy is significant. GOG 173 is a validation study of SN biopsy in a multi-institutional setting. Methods: Eligible patients have squamous carcinoma, nonsuspicious lymph nodes and tumor diameter between 2 cm and 6 cm. No surgeon skill verification was required. Use of radiocolloid for SN identification was an optional adjunct to blue dye until 2001 when it became mandatory. All patients underwent completion inguinal femoral lymphadenectomy. The study goal is to enroll 120 patients with nodal metastases to validate the sensitivity of SN > 88% (which would lead to a false negative predictive rate of <5% assuming the node metastases rate is ≤30%). Results: The study was opened in 12/1999 with 510 patients enrolled from 47 institutions (median = 5; range: 1–78 and 25th-75th percent: 3–14) as of 12/2008. 445 patients have data review completed. Of 403 evaluable patients, the median age was 66.9 years and 92.8% were white. 109 patients (27.1%) had lateralized lesions and unilateral groin dissections and 294 (72.9%) had midline involvement and bilateral dissections, resulting in 697 groins evaluated. SN was successfully identified in 78.8% (67/85) of patients using blue dye only and in 96.2% (306/318) using combination of radiolocalization and blue dye. For 294 patients with midline lesion treated by bilateral dissection, 159 (54.1%) had SN identified on both sides,114 (38.8%) on one side, and 21 (7.1%) not identified on either side. SN identification was successful in 373 (92.6%) patients. Nodal metastases were identified in 117 patients (31.4%). Conclusions: The combination of blue dye and radiocolloid appear superior to blue dye alone. Confirmed results for the entire cohort will be reported. No significant financial relationships to disclose.
Effect of six courses of neoadjuvant chemotherapy on pathological complete remission in advanced ovarian cancer
Authors: Zamagni C. , De Iaco P. , Rosati M. , Cacciari N. , Rosati F. , Rubino D. , Martoni A. A. 
Published: August 2020

5513 Background: The role and the duration of NACT in ovarian cancer are debated. A randomized trial comparing upfront surgery versus 3 courses of NACT (Vergote 2008) demonstrated similar survival, but less morbidity in favor of NACT. However, pathological complete remissions (pCR) were rare and 68% of pts still had lesions greater than 2 cm after 3 courses of NACT. The rate of pCR correlates with a better survival in other tumors, such as breast cancer, and its rate is higher after 6–8 courses of NACT. We conducted this study to verify the incidence of optimal pathological remission after 6 courses of NACT. Methods: Eligible pts had stage IIIC-IV EOC unsuitable for optimal upfront surgery and were treated with 6 cycles of carboplatin AUC 5 and paclitaxel 175 mg/sm, every 3 weeks before surgery. We considered as optimal pathological responders: 1) the pts with absence of cancer cells in surgical specimens, and 2) the pts with no macroscopic residual after surgery and with only small clusters or individual cancer cells in surgical specimens. All the other cases were considered as pathological nonresponders, even if a relevant shrinkage of tumor burden and an optimal surgical debulking were obtained. Results: 35 stage IIIC/IV pts were enrolled; 33 (94%) completed 6 courses of NACT. We observed 18 (51%) pathological responders, and 17 pathological nonresponders (as defined above). Overall, in 20 (57%) pts the goal of no residual tumor after surgery was achieved. After a median follow-up of 21 mo.s, 21 pts progressed (median PFS 15 mo.s) and 10 pts died. As expected, pts with tumor residual after surgery less than 1 cm survived significantly longer than patients with a greater residual (p .0005). The median overall survival was longer in pathological responders (median not reached) vs nonresponders (19.8 mo.s) (p.03). Conclusions: In our study an optimal pathological response occurred in 51% of cases after 6 cycles of carboplatin-paclitaxel, doubling the results described in the literature with 3 courses of NACT. Given that an optimal pathological response correlates with a longer survival compared to a sub-optimal one, a randomized study of 6 vs 3 courses of NACT in order to verify if the increase in pathological response rate will translate into a survival benefit is warranted. No significant financial relationships to disclose.
Paclitaxel (T), ifosfamide (I), and carboplatin (Cb) (TICb) combination chemotherapy in advanced uterine and adnexal malignant mixed mullerian tumors (MMMTs)
Authors: Kosmas C. , Mylonakis N. , Tsakonas G. , Vorgias G. , Pantelis N. , Politis P. , Kalinoglou N. , Tsavaris N. , Akrivos T. , Karabelis A. 
Published: August 2020

5517 Background: Malignant mixed mullerian tumors (MMMTs) of the uterus and adnexa represent aggressive gynecologic malignancies with a high rate of locoregional and distant failure. For that reason we evaluated the TICb combination in patients with advanced MMMTs. Methods: Patients with advanced MMMTs [stages III-IV and relapses after surgery (Sx)±RT], WHO-PS 0–2, no prior chemotherapy, unimpaired hematopoietic/organ function were eligible. Chemotherapy was administered as follows; T: 175 mg/m2 d1, I: 2.0 g/m2/d-d1+2, and Cb at a target AUC = 5 (according to creatinine clearance based on Calvert's formula) on d2 after I. G-CSF was administered from day 3–7. Results: Thirty-two patients with MMMTs of the uterus (n = 28), tubes (n = 2), or ovary (n = 2) have entered so far and all are evaluable for response and toxicity: median age = 61 (45–72), PS = 1 (0–1), stages; III = 18 (56%), IV = 14 (44%), histologies were; with homologous sarcoma component: 21, with heterologous component: 11. Prior treatment for locoregional disease included Sx: 23, Sx+RT: 9. Disease sites at diagnosis included: pelvic disease 12; pelvic/paraortic lymph nodes 14; peritoneal implants 16; liver 4; lung nodules 9; bone metastases 1; malignant pleural effusion 4. Responses were as follows: 21/32 (66%) evaluable patients responded, with 9 complete responses (CR) and 12 partial responses (PR), while 8 had stable disease (SD), and 3 developed progressive disease (PD). The median response duration was 8 mo (4–28), median time-to-progression (TTP) 12.5mo (4–26), while median overall survival (OS) has not been reached yet since most patients receive second-line therapy. Grade (Gr) 3/4 toxicities included: neutropenia 18/32 (56%)-with 11 developing Gr4 (≤7 days) and 19% of patients at least one episode of febrile neutropenia managed successfully by broad spectrum antibiotics, thrombocytopenia Gr3: 5/32 (16%) and Gr4 3/32 (9%), no Gr3 neuropathy, Gr1 CNS toxicity in 1, no renal toxicity, 15 Gr2 myalgias, and 4 Gr3 vomiting. Conclusions: In the present study, it appears that the TICb combination, yielded important activity with acceptable toxicity in females with advanced MMMTs. No significant financial relationships to disclose.
A randomized phase II study: Pazopanib (P) versus lapatinib (L) versus combination of pazopanib/lapatinib (L+P) in advanced and recurrent cervical cancer (CC)
Authors: Monk B. , Mas L. , Zarba J. J. , Oaknin A. , Tarpin C. , Termrungruanglert W. , Alber J. A. , Ding J. , Stutts N. W. , Pandite L. N. 
Published: August 2020

5520 Background: P and L are oral tyrosine kinase inhibitors. P targets VEGFR, PDGFR, and c-Kit. L targets EGFR and HER2 in CC, EGFR overexpression and markers of angiogenesis correlate with poor outcome; the prognostic value of HER2 overexpression remains unclear. Methods: Patients (pts) with measurable stage IVB, persistent or recurrent squamous or adenocarcinoma of the cervix not amenable to curative therapy; 0–1 prior regimens in the metastatic setting; ECOG PS 0–1; were randomized 1:1:1 to each of 3 treatment groups; not prescreened for EGFR or HER2 status. Treatment consisted of P 800mg QD; L 1,500 mg QD; L+P: P 400 mg + L 1,000 mg QD; the doses were escalated to P 800 mg + L 1,500 mg after 20 pts treated at 400 mg + 1,000 mg. Therapy continued until progression (PD), withdrawal due to adverse events (AEs), or withdrawal of consent. Primary endpoint was progression free survival (PFS); secondary overall survival (OS), tumor response (RR), safety. The study had 85% power to detect 80% improvement in PFS. A hierarchical testing procedure was applied comparing L+P vs L followed by L+P vs P and P vs L. The futility boundary was crossed for L + P vs L at the planned interim analysis and this arm was discontinued. Only the comparison of P vs L at the final analysis is reported. Results: Total N = 235 pts: 152 in the monotherapy arms: P (78); L (74). Baseline characteristics were balanced: median age 49 yrs (23–81). Stage IVB: 5%; recurrent 62%; persistent 34%. 86% had prior radiotherapy (45% with chemotherapy); 42% had prior chemotherapy for recurrent/persistent disease. P improved PFS (HR = 0.66; 90% CI 0.48, 0.91 p = 0.013) and OS (HR = 0.67; 90% CI 0.46, 0.99 p = 0.045; median OS for P is 50.7 wks; L is 39.1 wks) with RR for P of 9% and L 5%. Most common AEs (%) P/L were diarrhea (54/58), nausea (36/33), anorexia (28/32), vomiting (20/24); the most common Gr 3 AE was diarrhea (11/13); Gr 4 for any individual AE was ≤ 1%; 1 Gr 5 event of cachexia unrelated to L. Conclusions: PFS and OS were significantly prolonged with P compared to L. P and L both demonstrated a favorable toxicity profile in pts with advanced and recurrent CC. This study demonstrates the potential benefit of P in CC. Further exploration is indicated. [Table: see text]
Somatic BRCA status in ovarian tumors
Authors: Hennessy B. , Timms K. , Carey M. S. , Gutin A. , Broaddus R. , Gonzalez-Angulo A. , Lanchbury J. , Lu K. , Mills G. B. 
Published: August 2020

5528 Background: The combined prevalence of BRCA1/2 mutations in germline DNA derived from a population of invasive ovarian cancer patients is up to 15.3%. PARP inhibitor trials are ongoing in patients who carry germline BRCA1/2 mutations. It is important to know whether somatic (non-germline) BRCA changes are present in ovarian tumors, given the predicted sensitivity of BRCA mutation-carrying tumors to PARP inhibitors and other DNA damaging agents. However, a large cohort of ovarian tumor tissues has not been studied to determine the frequency of BRCA deficiency due to additional somatic changes. Methods: BRCA1/2 exons/flanking regions were sequenced in 235 high-grade ovarian cancers and 38 ovarian cancer cell lines. In 112 tumors, we also performed gene expression analysis and copy number arrays with ultradense probe tiling throughout both BRCA genes. Results: For BRCA1, 31 tumors (13.2%) harbored mutations: 23 known deleterious mutations, 1 suspected deleterious mutation, 3 novel indels, 1 novel mis-sense and 3 novel nonsense mutations. For BRCA2, 12/178 sequenced tumors (6.7%) harbored mutations: 8 known deleterious mutations, 1 suspected deleterious mutation and 3 novel indels. Only 3 BRCA1 mutations were detected in 2 cell lines, two known deleterious and 1 a novel 29 base pair deletion. One cell line thus appears to have both a germline and a somatic mutation. BRCA mutation status was associated with a trend to improved progression-free survival (PFS) in univariate analysis (p = 0.17). However, BRCA deficiency (defined by BRCA1/2 gene expression loss (4 tumors) and homozygous deletion (1 tumor) in addition to mutations) was associated with improved PFS in univariate (p = 0.04) and multivariate (p = 0.03) analyses. Conclusions: The frequency of BRCA1/2 mutations in ovarian tumors detected by sequencing regardless of family history is ≈20%, higher than the expected prevalence of germline mutations. In both BRCA1/2 genes, almost 25% of mutations in tumor tissue were novel and not previously seen in germline DNA. We are now sequencing corresponding germline DNA to determine the exact number of these novel mutations that are somatic. Direct analysis of ovarian tumor tissue is likely to expand the number of women with BRCA-deficient tumors beyond that detectable by germline sequencing. [Table: see text]
Detection of chromosomal anomalies in uterine endometrial carcinoma using fluorescence in situ hybridization (UteroFISH)
Authors: Qian J. , Weber D. , Cochran R. , Hossain D. , Bostwick D. G. 
Published: August 2020

5533 Background: Endometrial cancer is the most common pelvic gynecological malignancy. The diagnosis of well-differentiated endometrial adenocarcinoma, atypical hyperplasia, and marked hyperplasia is often challenging. We sought to investigate the utility of chromosomal anomalies for the detection of uterine endometrial carcinoma using multitarget fluorescence in situ hybridization (FISH). Methods: Samples were collected by endometrial brush and processed by liquid-based thin-layer cytological preparation protocol. For study, we collected cytology slides from consecutive cases to include 50 benign, 50 hyperplasia without atypia, 50 atypical hyperplasia, and 50 endometrial cancers. Each was hybridized using fluorescence labeled DNA probes to chromosomes 1, 8, and 10 (UteroFISH). The FISH signals were enumerated in 100 cells per case, and the chromosomal anomalies were correlated with pathologic findings, including histologic diagnoses on endometrial tissue samples. Results: Numeric chromosomal anomalies were found in 0% (0/50) of benign, 20% (10/50) of hyperplasia, 76% of atypical hyperplasia (38/50), and 86% (43/50) of carcinoma specimens. The mean percentage of cells with chromosomal changes was 54% in cancer specimens, significantly higher than that in hyperplasia without atypia (13%, p< 0.0001) and atypical hyperplasia (34%, p< 0.0001). The most frequent chromosomal anomaly was gain of chromosome 1. FISH anomalies had an overall sensitivity of 81% and specificity of 90% for the detection of atypical hyperplasia and/or endometrial carcinoma. There was no association with grade of endometrial carcinoma. Conclusions: Multi-target UteroFISH appeared to be useful for the differential diagnosis of reactive hyperplasia, atypical hyperplasia, and endometrial adenocarcinoma, with a high level of sensitivity and specificity. Endometrial hyperplasia with FISH-detected chromosomal anomalies may require close clinical follow-up. No significant financial relationships to disclose.
Heparanase expression and angiogenesis in endometrial cancer: Analyses of RT-PCR and immunohistochemistry
Authors: Aoki Y. , Inamine M. , Hirakawa M. , Kudaka W. , Nagai Y. 
Published: August 2020

5535 Background: The human heparanase has been shown to function in tumor progression, metastatic spread, and tumor angiogenesis. The aim of the present study was to assess heparanase expression in endometrial cancer in correlation with neovascularization and clinicopathological factors.Methods: Fifty-two endometrial cancers were obtained from previously untreated patients (median age, 56 years; range, 35–80 years). The expression of heparanase mRNA was evaluated using a semi-quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical staining (IHC) with anti-heparanase polyclonal antibody. This antibody was raised by immunizing a rabbit with a peptide containing the amino acid residues from 238 to 250 of the Heparanase. Tumor angiogenesis was assessed using microvessel counting. The Mann-Whitney U test, one factor ANOVA test, and Spearman's test were used to determine the relationship between heparanase expression, microvessel density, and clinicopathological parameters. Results: The expression of heparanase mRNA was detected in 26 of 52 (50%) endometrial cancers, and was significantly correlated with FIGO stage IIIc (p = 0.0075), the presence of lymph-vascular space involvement (LVSI) (p = 0.0041), lymph node metastasis (LNM) (p = 0.0049), and histological tumor grade (p = 0.003). IHC showed that the heparanase was expressed in 23 of 52 (44.2%) endometrial cancers, which was significantly related to LVSI (p = 0.0028), depth of myometrial invasion (p = 0.0026), and histological tumor grade (p = 0.0135). Microvessel density was also associated with FIGO stage IIIc (p = 0.027), LVSI (p = 0.001), LNM (p = 0.038), ovarian metastasis (p = 0.03) and histological tumor grade (p = 0.003). Moreover, we found a strong positive correlation between heparanase expression and microvessel density (r2 = 0.475, p = 0.0001). Conclusions: These results suggest that the expression of heparanase can promote tumor angiogenesis and develop metastasis in endometrial cancer. No significant financial relationships to disclose.
Effect of introduction of paclitaxel on survival among women with stage III and IV ovarian cancer
Authors: Dawood S. S. , Albaracin C. , Gonzalez-Angulo A. , Markman M. , Hennessy B. 
Published: August 2020

5536 Background: The objective of this study was to evaluate survival over time in relation to FDA approval of paclitaxel (P) for second- and first-line treatment in a population-based cohort of women with stage III and de novo stage IV ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was searched to identify 8,267 and 10,746 women with stage III and stage IV epithelial ovarian cancer diagnosed between 1988–2004. Women were divided according to their year of diagnosis and year of FDA approval of P for second- (1992) and first-line(1998) treatment of ovarian cancer: Group1 (1988–1991; before P approval); Group2 (1992–1997; P approved for second-line); Group3 (1998–2003; P approved for first-line). Overall (OS) and ovarian-cancer-specific survival (OCS) were estimated using Kaplan-Meier product method and compared across groups with log rank statistic. Cox-proportional hazards models were fitted to determine the association of group year of diagnosis and survival after adjusting for patient/tumor characteristics. Results: Median age was 66 years. Median OCS was 44 and 18 months among women with stages III and IV disease, respectively. With stage III disease, 2-year OCS was 64%, 68%, and 70% for groups 1, 2, and 3, respectively (p < 0.0001). With stage IV disease, 2-year OCS was 39%, 41%, and 42% for groups 1, 2, and 3, respectively (p = 0.19). In the multivariable model for stage III disease, women in group 1 (HR = 1.4, 95% CI 1.2–1.5, p < 0.0001) and group 2 (HR = 1.2, 95% CI 1.1–1.3, p = 0.0003) had an increased hazard of ovarian-cancer-specific death vs. group 3. For stage IV disease, women in group 1 (HR = 1.2, 95% CI 1.12–1.3, p < 0.0001) had a significantly increased hazard of ovarian cancer-specific death, but no significant difference in group 2 (HR = 1.0, 95% CI 0.9–1.1, p = 0.88) vs. group 3. Similar trends were observed for OS. Conclusions: The survival of women with stages III and IV ovarian cancer has significantly improved with the introduction of P over the last two decades. However, the incremental improvement in survival with stage IV disease is clinically minimal and indeed not significant in the univariable analysis in the SEER patient cohort analyzed, suggesting a desperate need for new and more active drugs in these patients. No significant financial relationships to disclose.