bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival benefit in bevacizumab-based therapy in sickle cell trait patients diagnosed with renal medullary carcinoma
Authors: Johnson E. D. , Tannir N. N. , Olejeme K. A. , Logothetis C. J. , Jonasch E.
Published: August 2020

e16096

Background: Renal medullary carcinoma (RMC) is an epithelial malignant tumor arising from collecting duct epithelium. The tumor is almost exclusive to young black patients with the sickle cell hemoglobinopathies, primarily sickle cell trait. This is a rare and highly aggressive tumor that is shown to be most resistant to chemotherapy. In an effort to evaluate treatment outcomes, we retrospectively examined those patients diagnosed with RMC who were treated with and without bevacizumab based regimens. Methods: We reviewed the genitourinary medical oncology database at M. D. Anderson Cancer Center for patient diagnosed between 1999–2008 with histology proven RMC. Vital statistics of birth and death dates were noted. In addition, detailed chemotherapy regimen as well as medical and radiological data were also obtained. Results: All patients had metastatic disease (stage IV) to at least one distant site at presentation. Distant sites included bone, liver or lungs. A sample of five black males 5/9 (53%) were treated with therapy that included a 2 or 3 drug combinations of Adriamycin, Taxol, Gemzar, cisplatin, or Gleevac. Median survival was 12.7 months (3.2–22.2) while median age was 31 year (28–59). Only 4/9 (47%) patients received bevacizumab based therapy in a 2 or 3 drug combinations with Gemzar, Xeloda, cisplatin, or Taxol. In this group, 50% were females, median age of 36 years (33–39) and median survival of 18.5 months (15.5–22.8). Conclusions: Sickle cell trait was confirmed for all in this group diagnosed with RMC. 8/9 of these patients were black and 1/9 South-Asian. The group that received bevacizumab based therapy had a median survival of 5.8 months longer. Future studies, including genetic studies on the tumor types are essential to determining the SNP profiles of renal cell carcinoma in black patients. Furthermore, a prospective multicenter trial should be developed to evaluate the efficacy of bevacizumab based regimens in renal medullary carcinoma in this population.

No significant financial relationships to disclose.
Efficacy and safety of sorafenib in patients with advanced clear-cell renal cell carcinoma (RCC) with diabetes: Results from the phase III TARGET study
Authors: Oudard S. , Eisen T. , Szczylik C. , Siebels M. , Negrier S. , Chevreau C. , Cihon F. , Bukowski R. M. , Escudier B.
Published: August 2020

e16099

Background: Results of the phase III TARGET trial, a randomized, double-blind, placebo-controlled study of sorafenib (SOR) treatment in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective and safe for pts with advanced RCC, leading to the approval of SOR for the treatment of advanced RCC. Diabetes can be associated with increased morbidity during treatment in a variety of malignancies. Therefore, an exploratory subset analysis was performed to evaluate the efficacy and safety of SOR in pts enrolled in TARGET with or without diabetes at baseline. Methods: Pts (N=903) with advanced clear-cell RCC, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or placebo (PBO). End points included OS, PFS, and safety. A planned independently-assessed formal analysis of PFS showed significant benefit for SOR over PBO; consequently, pts assigned to PBO were able to cross over to SOR. Results: Pt demographics were similar for all subsets. Pre- crossover data by subset are shown in the table . The incidence of drug-related adverse events (AEs) across subgroups was consistent with that for the overall population. In pts with vs without diabetes, treatment with SOR was not associated with increased hyperglycemia (1 pt/arm in the without diabetes subgroups only) or hypertension. Conclusions: The safety profile of SOR in pts with diabetes was comparable with that for the overall study population. SOR was well tolerated and AEs were manageable. Trends in improved PFS were observed for SOR regardless of baseline diabetes status; however, the small diabetic subset limits interpretation of a SOR OS benefit in this subpopulation. *Final PFS of overall study population based on independent review from Jan 2005; all other data from May 2005 database [Table: see text]

[Table: see text]
Feasibility and efficacy of gemcitabine and carboplatin neoadjuvant chemotherapy in muscle-invasive bladder cancer
Authors: Koie T. , Yamamoto H. , Okamoto A. , Hatakeyama S. , Momose A. , Iwabuchi I. , Yoneyama T. , Hashimoto Y. , Kamimura N. , Ohyama C. , Saijo Y.
Published: August 2020

e16100

Background: The neoadjuvant M-VAC followed by radical cystectomy for muscle-invasive bladder cancer has improved survival compared to radical cystectomy alone. Nevertheless, M-VAC has been associated with severe toxicity. The objective of this retrospective study was to evaluate the objective response rate, the impact on overall survival, disease-free survival, disease-free survival and toxicity adverse events of gemcitabine and carboplatin (GC) neoadjuvant chemotherapy in patients with locally advanced bladder cancer. Methods: We reviewed the clinical and pathological data of 140 patients who underwent radical cystectomy and bilateral pelvic lymphadenectomy for T2N0M0 to T4aN0M0 bladder cancer at our institution between January 2001 and August 2008. Seventy patients were treated with neoadjuvant GC followed by cystectomy between March 2005 and August 2008 (GC group), and 70 patients were treated with cystectomy alone between January 2001 and May 2007 (cystectomy alone group). In the GC group, the patients received 2 courses of GC therapy consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. The primary endpoint was the objective response rate, and the secondary endpoints were overall survival, cancer-specific survival, disease free survival, and toxicity. Results: Fifteen patients (23.8%) had a complete response and 26 patients (41.3%) had a partial response in the GC group. At a mean follow-up period of 26.7 months, the overall survival was 85.0% in the GC group and 47.8% in the cystectomy alone group (p = 0.003). The cancer-specific survival was 78.4% in the GC group and 44.6% in the cystectomy alone group (p = 0.0018). The disease-free survival was 82.9% in the GC group and 35.7% in the cystectomy alone group (p = 0.0001). Hematologic toxicities were the main adverse events. Grade 3/4 neutropenia occurred in 26 patients (37.1%) and thrombocytopenia in 15 (21.4%). There was no grade 3/4 gastrointestinal toxicity and no renal function abnormalities. Conclusions: Although this is not a randomized study, the GC neoadjuvant therapy followed by radical cystectomy is feasible and may be associated with improved survival among patients with muscle-invasive bladder cancer. A randomized trial is warranted.

No significant financial relationships to disclose.
Decreased toxicity schedule of suitinib in renal cell cancer: 2 weeks on/1 week off
Authors: Gyergyay F. , Nagyványi K. , Bodrogi I.
Published: August 2020

e16113

Background: Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET approved for treatment of metastatic renal cell cancer (mRCC). Pharmacokinetics and pharmacodynamics suggest that dose reduction might decrease the plasma concentration of SU and its major metabolite to an ineffective level. Methods: Pts with mRCC, measurable disease, ECOG PS 0–2 received SU 50 mg po daily 4 weeks on/2 weeks off. Results: Of 36 pts, median age 59.5 yrs (range 42–83), M/F (26:10), ECOG: 0 (21); 1 (9); 2 (6); prior nephrectomy (35),prior radiation therapy (28), prior cytokine therapy: IFNα (25), IL-2+IFNα (9) none (2); pts with 1 metastatic organ (24); 2 metastatic sites (7); ≥ 3 sites (5); Sites of metastases: Lung (27), Bone (11), Liver (3); MSCC risk factors: 0 (20), 1–2 (14); ≥3 (2). Objective response occurred: PR (13) 42%; CR (2) 5%; SD (9) 25%. Number of cycles (6 weeks cycles) given was: 162 (2–15).Main side effects were: fatigue 42% (Gr≥3: 17%), diarrhoea 42% (Gr≥3: 25%), nausea 31% (Gr≥3: 6%), stomatitis 10%, anorexia 10%, weight-loss 20% (Gr≥3: 11%), hand-foot syndrome 39% (Gr≥3: 17%), hypertension 28%, anemia 25%, neutropenia 8%, thrombopenia 11%, hypothyroidism 11%. Five cases of dose reduction and two cases of treatment discontinuation occurred due to toxicity. During the second part of the study if serious toxicity had been reported, instead of dose reduction, two weeks on and one week off schedule (50mg daily) had been offered to pts. 14 pts (79 cycles) were treated according to the schedule. Short term side effects decreased significantly: fatigue 28%, diarrhea 14%, nausea 14%, stomatitis 7%, anorexia 7%, weight-loss 7%, hand-foot syndrome 14%, hypertension 7%, anemia 14%, hypothyroidism 11%. Conclusions: Further prospective studies are needed to confirm the better tolerance of the SU, without decreasing the dose intensity of the treatment.

No significant financial relationships to disclose.
Long-term use of sorafenib (SOR) in metastatic renal cell carcinoma (mRCC) previously treated with systemic therapy
Authors: Battaglia M. , Gernone A.
Published: August 2020

e16123

Background: The recent development of new targeted agents for the treatment of advanced RCC has definitely changed the approach and the outcome of this disease. Among them, SOR, has proved to be highly active in the treatment of mRCC. The aim of this study was to assess the activity and the safety of SOR in pts with mRCC relapsed after prior systemic therapy. Methods: Between 2/2007 and 10/2008, 22 pts with mRCC relapsed after 1–2 prior lines of chemotherapy (gemcitabine, vinorelbine, 5-FU) have been treated with SOR orally administered at the dose of 400mg b.i.d. continuous dosing. They were18 males and 4 females, with a median age 67 years, an ECOG PS 0–2, and the majority (96%) had undergone prior nephrectomy. Patients were assessed for activity every three months (mos.) by CT. The primary endpoints were response rate (RR) evaluated by RECIST criteria and time to progression (TTP). Results: To date, 20 pts are evaluable for response: of them, 13 (59%) achieved a partial response (PR) after 3 mos. of therapy whose median duration was 13 mos. (range, 7–18), while 7 (31%) remained with stable disease (SD) with a median length of 14 mos. (range, 5–17). No complete responses have been observed. Among those who progressed (2 pts), the median time to disease progression was 7 mos. At a median length of time of 15 mos., 18 pts. are continuing the therapy with SOR and in all of them the benefit achieved remained unchanged. Two pts discontinued the treatment because of the onset of side effects, while in 4 pts dose reductions were required. Grade 3/4 toxicities were: hypertension in 3 pts (13%), hand-foot skin reactions in 5 (22%), rash/desquamation in 4 (18%), diarrhoea in 2 (9%), fatigue in 6 (27%), bleeding in 2 (9%). Conclusions: These data confirm other experiences showing the efficacy of SOR in previously treated patients with mRCC. However, notwithstanding the rather small sample size of pts., the overall clinical benefit rate (PR+SD) turned out particularly high (> 90%): chiefly, the evidence of a long lasting disease control both for patients achieving partial response and for those with stable disease makes SOR a very useful treatment for patients with mRCC.

No significant financial relationships to disclose.
Use of an inhibitor of differentiation-1 (Id1) expression (exp) to discriminate good prognosis (GP) from poor prognosis (PP) prostate cancer (PCa)
Authors: Calvo A. , Ponz-Sarvisé M. , Rosell D. , Redrado M. , Nguewa P. A. , García-Foncillas J. , Abella L. , Panizo A. , Gil- Bazo I.
Published: August 2020

e16128

Background: In the PSA era a significant proportion of PCa patients (pts) at onset have potential indolent tumors that will not impact their life expectancy or quality of life. Most of them will be radically treated and suffer its consequences. Thus, PCa overtreatment is a great concern among clinicians. Pre-treatment molecular factors may help differentiate indolent from aggressive PCa. Id1, involved in cell differentiation and angiogenesis, has recently showed to mediate lung metastasis (mts) from breast cancer. Its role in PCa endothelial (end) cells is well established but its exp and role in PCa cells is controversial. Using a new monoclonal antibody (MoAb) (195–14) for immunohistochemistry (IHC), Id1 exp is limited to some PP breast and bladder tumors. Whether Id1 exp is relevant in PCa prognosis is unknown. We tested 195–14 in PP and GP PCa samples and matched mts where available. Methods: 52 PCa pts were studied, 20 GP + 32 PP. All formalin-fixed and paraffin-embedded primary biopsies and matched mts of 16 of them were stained for tumor and end cell Id1 exp. 195–14 (1:500), (Biocheck), was used for IHC. Results: GP group: median age 65, all pts T2N0M0, median Gleason score 6 (6–9), median PSA at onset 5,5 ng/ml. After a median follow-up of 38 months (ms) 1 pt showed radiological and PSA progression (P); other PSA P. All but one remain alive. PP group: median age was 70, T3-T4 (70%), Gleason 8–10 (61%), median PSA at onset 58 ng/ml, 2 or more mts locations (79%), 94% showed P to docetaxel, median time-to- progression and overall survival after chemotherapy were 18 weeks and 7 ms. Among PP, 39% of primary PCa and 38% of mts showed Id1 tumor cell exp and 79% of primary tumors and 81% of mts showed end Id1 exp. In the GP group 0% showed Id1 tumor cell exp, and 50% showed end Id1 exp. The unexpected Id1 exp difference in tumor cells in PP compared to GP pts predicted clinical outcome. Consistently with other reports end Id1 exp is high in both groups. PP showed higher levels. Conclusions: Id1 exp discriminated GP from PP in our PCa cohort. These novel results highlight Id1 as a prognostic marker in PCa. Whether Id1 exp in the diagnostic biopsy can impact PCa therapeutic decision-making needs further investigation.

No significant financial relationships to disclose.
Combined modality treatment for organ preservation in patients with invasive bladder cancer
Authors: Carrizo M. N. , Sade J. P. , Costanzo M. V. , Chacon M. , Chacon C. , Orlando M. , Chacon R. D.
Published: August 2020

e16129

Purpose: To evaluate long term results of chemoradiation and organ preservation in invasive T2-T4a bladder carcinoma in a single institution with prolonged follow up. Methods: Sixty one patients with clinical stage II and III (T3N0) muscle invasive bladder carcinoma were treated between February 1991 and December 2007. Forty four received sequential treatment (chemo followed by radiation) and seventeen concurrent treatments. Chemotherapy was platinum based in all patients, fifth teen with Carboplatin. All underwent maximal citoreduction with TUR .First 20 patients received pelvic radiation (1991–1993),while the other 41 three-dimensional radiotherapy (median dose 60 Gy). Male/female 55/6: median age 64 (range 46–80); transitional type 58 and mixed-epidermoid 6. Grade II: 3, grade III: 48 and grade IV: 10. Clinical stage II:50 and III:11. Mean follow up 63 months. Results: The 5 year overall survival rate was 57%. Forty patients remained NED, with eight deaths due to second primary or cardiovascular disease. Twenty pts were treated more than 5 years ago, 16(80%) are alive, 14 NED,2 pts relapsed after 5 years. Of all predictive factors analyzed only clinical stage reached statistical significance for relapse (p=0.0029), and borderline significance for overall survival (p=0.064). Toxicity: Grade 3–4: 7%, with 3% of febrile neutropenia. No patient required cystectomy because of bladder morbidity. Conclusions: Trimodality treatment in selected patients offers rates of event free survival and overall survival similar to those reported for surgery with acceptable toxicity and no treatment related cystectomy. Relapse after 5 year is very uncommon. In this small group of patient results were similar with concurrent and sequential treatment. At present we treat our patients with concurrent chemoradiation with tridimensional technique.

No significant financial relationships to disclose.
Pancreatic metastasis from renal cell carcinoma: Presentation, recurrence, survival, and response to antiangiogenic therapy
Authors: Albouy B. , Billemont B. , Massard C. , Gross-Goupil M. , Rixe O. , Escudier B.
Published: August 2020

e16137

Background: Pancreas represents an uncommon site of metastasis in renal cell carcinoma (RCC). The natural history of pancreatic metastases is largely unknown, and efficacy of targeted agents has never been assessed. We examined the outcome in a series of RCC patients (pts) with pancreatic metastases, treated by either surgery or antiangiogenic therapy. Methods: We reviewed the charts of RCC pts treated for pancreatic metastases, between 2001 and 2008, in Institut Gustave Roussy and Pitié-Salpetrière Hospital. Data base was reviewed to determine presentation, clinical symptoms, pancreatic metastases treatment, use of systemic therapy, disease-free survival (DFS) or progression-free survival (PFS) and overall survival (OS) after treatment. Results: A total of 40 pts with pancreatic metastases from RCC have been analyzed. Median age was 63 years (range: 48–81), sex ratio M/F was 29/11, and metastases occurred initially (synchroneous) in 9 pts, while they were metachronous in 31 pts. Most of the metastases were asymptomatic (87%), detected on routine CT scans, while only 12% were symptomatic (pain, cholestasis). Surgical resection of pancreatic metastases was performed in 8 (20%) patients, and DFS and OS were 45 and 66 months. In patients with multiple metastatic sites (lung : 20 (50%); liver : 8 (20%); thyroid : 3(7%)), therapeutic approaches have included antiangiogenic therapies (75%): sorafenib (20 pts), sunitinib (7 pts), bevacizumab (2 pts), Torisel (1 pt). Best response was partial response in 30% of pts and stable disease in 50% of pts. Median PFS and OS were 21 months and 30 months. Conclusions: Patients with RCC pancreatic metastases seem to have a longer survival than the usual metastatic RCC pts. Surgical resection must be discussed in pauci-metastatic disease, as it can be associated with prolonged survival. Antiangiogenic therapies are active in these patients with high response rate and prolonged survival.

No significant financial relationships to disclose.
Multiple primary tumors in patients with carcinosarcoma of bladder: A coincidence or an etiological association? A study of 221 carcinosarcoma of bladder cases
Authors: Wang J. , Wang F.
Published: August 2020

e16138

Background: Carcinosarcoma of the bladder are rare; As a result, few studies of carcinosarcoma of the bladder have included sufficient number of patients to define their natural history and to determine the factors that impact survival. The objective of this study was to examine the epidemiology, natural history, and prognostic factors that affect the survival for carcinosarcoma of the bladder by using population-based registries. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program database (1973–2004) was used to identify cases of carcinosarcoma of the bladder by tumor site and histology codes. The association between clinical and demographic characteristics and survival of carcinosarcoma of the bladder was examined. Results: A total of 221 cases of histology confirmed carcinosarcoma of the bladder were identified, this account for approximately 0.11% of primary bladder tumors during same period. By using linked population files, we calculated the incidence of carcinosarcoma of the bladder as a rate 0.22 per 100,000 per year, age-adjusted to year 2000 U.S. standard population. Median age of all patients were 75 years (range 41–96). In about 40% of study population, more than one or multiple primary were also indentified. Majority of (212, 95.9 %) patients received cancer directed surgery. For survival analyses, we excluded the cases that were identified at autopsy or on the basis of death certificates only and the patients have more than one primary. Total 132 patients were included in survival analysis. The median overall survival for all cases was 9 months (range 6–12 months). In multivariate analysis, only tumor stage was found to be significant prognostic factors for disease-specific survival. Conclusions: Carcinosarcoma of the bladder are rare tumors that are challenging, the survival is poor even in patients underwent surgical resection. Better therapy is needed to improve patient's outcome. A significant fraction of carcinosarcoma patients are actually affected by multiple primary tumors, the potential association between carcinosarcoma and other neoplasms remain to be investigated.

No significant financial relationships to disclose.
Unraveling the metabolome in prostate tumorigenesis: Effects by an oncogenic isopeptidase
Authors: Priolo C. , Loda M.
Published: August 2020

e16148

Background: Cancer cells undergo fundamental changes in their metabolism, including a higher rate of glycolysis and an increase in de novo fatty acid synthesis. The high incorporation of glucose into tumor cells has already been exploited in cancer diagnostics with the generation of the FDG-PET scan technology. However, some tumors including those arising in the prostate are less prone to FDG-PET imaging and could benefit from other imaging techniques based on alternative metabolic features. We asked whether prostate epithelial cell transformation driven by specific oncogenes results in a typical metabolic profiling, whose characterization may be useful to improve diagnostics and to address new therapeutics. Methods: Normal prostate epithelial cells (RWPE-1 and PrEC) were transformed by overexpressing known oncogenes, such as the protein kinase AKT1 and the de-ubiquitinating enzyme (isopeptidase) USP2a. These cells were then subjected to mass spectrometry-based metabolomics, gene expression analysis, oxygen consumption and glucose uptake assays. Multiple bioinformatic tools were utilized for data mining and pathway visualization. Results: We integrated data from different high-throughput technologies to map metabolic changes induced during prostate tumorigenesis by genes that are often altered in prostate cancer. A different metabolic profiling was found in association to each specific oncogene. In fact, extremely significant alterations were found in the glycolytic pathways in the case of AKT-driven transformation, whereas changes in the lipid metabolism and in some aminoacids were prevalent in USP2a-overexpressing cells. Complementary assays including oxygen consumption and glucose uptake measurement confirmed the global metabolic analysis. Conclusions: These results suggest that tumors showing different genetic alterations may be characterized by a different metabolic profiling, whose assessment can potentially improve diagnostics and individualized treatment. Metabolic profiling analysis of human prostate tumors is currently ongoing.

No significant financial relationships to disclose.
Survival and association with time to treatment change in patients with metastatic renal cell carcinoma
Authors: Liu Z. , Burke J. , Zheng J. , Johnson J.
Published: August 2020

e16160

Background: Metastatic renal cell carcinoma (MRCC) is associated with high mortality rates. The objectives of this study are to examine survival rates among patients using targeted therapies (Sunitinib, Sorafenib) for MRCC and the association of time to treatment change with survival. Methods: Administrative claims data from a large, US managed care plan were used to identify commercially insured and Medicare patients with newly diagnosed MRCC from 01/01/03–12/31/07 and continuous enrollment for 12 months prior to and at least 90 days after MRCC diagnosis. Survival from earliest evidence of targeted therapy (TT) was assessed through 9/16/2008. Treatment change was defined as stopping TT, switching TT or the addition of other treatments for MRCC. Results: 253 patients were identified with newly diagnosed MRCC (average age: 60.5 years; 71.5% male) who also received TT. Mean (median) survival time from initiation of therapy was 533 (507) days. A majority of those on TT (n = 205, 81.0%) experienced treatment change within 6 months after initiating the therapy; two-thirds within 30 days of therapy initiation. Unadjusted survival rates increased significantly with longer time to change in treatment (p=0.0075), with a mean survival time of 437 days for those with treatment change within 30 days and 724 days among those with treatment change 5–6 months post therapy initiation. Conclusions: Early treatment changes are associated with shorter survival times. High rates of early treatment changes indicate inadequacies in currently available targeted therapies for MRCC patients.

No significant financial relationships to disclose.
Predictive value of serum CA125 levels in women with persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) treated with bevacizumab (Bev) on a Gynecologic Oncology Group (GOG) phase II trial
Authors: Randall-Whitis L. , Burger R. A. , Sill M. , Monk B. J. , Buening CCRC B. , Sorosky J. I.
Published: August 2020

e16505

Background: The clinical utility of serum CA125 in patients (pts) with EOC/PPC treated with biologic agents is unknown. The primary objective of this study was to determine the proportion of pts treated with bevacizumab on a phase II clinical trial with stable disease by RECIST who demonstrated disease progression (pgrn) as assessed by modified GCIG CA125 criteria. Methods: Sixty-two pts with measurable recurrent or persistent EOC/PPC were treated with bevacizumab 15 mg/kg Q 21 days on a phase II clinical trial. Primary endpoints of the clinical trial were progression-free (PF) survival at 6 months and response assessed by RECIST criteria. Pts were removed from therapy/evaluation for disease prgn by RECIST, toxicity, or by subject request. Serum CA125 was collected at entry and prior to each cycle but levels were only used to define a complete response which required CA125 normalization (≤35). Modified GCIG criteria were retrospectively applied to these CA125 values to determine time to progression from date of entry to either the first time CA125>70 for pts whose CA125 normalized on treatment or was greater than 2X the nadir value for pts whose CA125 did not normalize. Censored cases provided time until the date of last CA125 measurement. Results: The median PFS by RECIST was 4.7 mos. Of those patients who had prgn by CA125, the median residual time to prgn by RECIST was 1.4 mos. In all, twenty-five (40.3%) pts survived PF for 6 mos. by RECIST and 16 (25.8%) by CA125. Ten pts who survived PF for at least 6 mos. by RECIST indicated treatment failure before 6 mos. by CA125, or 40% of the 25 positive outcomes. Eight pts continued to receive treatment for at least 4 mos. after prgn by CA125, with one continuing therapy for more than 3 years. Conclusions: Serum CA125 levels were a useful marker of progression in some pts treated on this trial; however, some pts received clinical benefit from continued therapy in spite of indications of disease prgn by CA125. Consideration should be given before discontinuing bevacizumab therapy based on CA125 progression alone.

No significant financial relationships to disclose.
Expression and signaling of Toll-like receptor 4 (TLR4) and MyD88 in ovarian carcinoma cells
Authors: Szajnik M. E. , Szczepanski M. J. , Czystowska M. , Elishaev E. , Mandapathil M. , Nowak-Markwitz E. , Spaczynski M. , Whiteside T. L.
Published: August 2020

e16508

Background: TLR4, expressed by the cells of the immune system play a role in the protection of the host against pathogens. TLRs are also expressed on human cancer cells, but their role in tumor growth is unknown. The aim of this study was to correlate the presence of TLR4 and MyD88 expression with clinicopathologic outcome in patients with ovarian cancer and to analyze the consequences of signaling via the TLR4/MyD88 pathway in ovarian cancer cell lines. Methods: Tumor specimens from 41 patients with ovarian carcinoma were evaluated for TLR4 and MyD88 by immunohistochemistry and correlated with clinical and pathologic disease features. TLR4/MyD88 expression in OVCAR3, SKOV3, and A2780 was determined using RT-PCR, WB, and immunohistochemistry. NF-kB translocation to nucleus was measured by confocal microscopy. Culture supernatants were tested for levels of cytokines in Luminex-based assays. Proliferation of cancer cells was measured in the CFSE assays. Their sensitivity to paclitaxel (PLX) was measured by Annexin V binding. Western Blot analysis was used to measure activation of the PI3K/Akt, IRAK 1, IRAK 4, and TRIF. Results: In ovarian cancer patients TLR4 and MyD88 expression by the tumor was observed in 100% and 83% of tissues, respectively. The expression of MyD88 was associated with shorter progression-free survival (42 vs 31 months, p < 0.05). Ex vivo studies showed that TLR4 was expressed on OVCAR3, SKOV3, and A2780 cell lines, while A2780 did not expressed MyD88. In MyD88+ tumor cells, LPS increased proliferation (PI 17 vs 8, p < 0.05), activated NF-kB pathway and promoted cytokine production (IL-8, IL-6, RANTES, VEGF and MCP-1). LPS and PLX binding to TLR4 on MyD88+ cells induced activation of PI3K/Akt, IRAK4, and IRAK1, but decreased expression of pro-apoptotic TRIF. In contrast, in MyD88(-) cells LPS did not induce proliferation and neither LPS nor PLX induced secretion of pro-inflammatory cytokines. Further, no changes were noted in IRAK1 expression, but strong signal was observed for TRIF. TLR4+/MyD88+ tumor cells showed grater resistance to PLX. Conclusions: Our ex vivo studies elucidate the molecular mechanisms involved in TLR4/MyD88 signaling. Ligation via TLR4 leads to tumor growth, release of proinflammatory cytokines and induction of resistance to PLX-induced apoptosis.

No significant financial relationships to disclose.
Survival with surgical versus medical treatment of patients with bowel obstruction secondary to ovarian cancer recurrence: A 15-year experience
Authors: Al-Niaimi A. , Manuelli B. , Safdar N. , Chappell R. , Seo S. , Kushner D. , Connor J. , Hartenbach E.
Published: August 2020

e16515

Background: To compare the impact of surgical versus medical management on the survival of patients presenting with small bowel obstruction (SBO) secondary to recurrent ovarian cancer. Methods: The Institutional Review Board approved a retrospective chart review of all patients with SBO due to recurrent ovarian cancer at the University of Wisconsin Hospital between January 1, 1992, and December 31, 2007. The data abstracted from patient charts included demographics, primary cancer characteristics, detailed clinical information at the time of SBO, management strategy, and outcome. Univariate analysis was performed with Cox proportional hazard model and Kaplan-Meier curves were generated for survival. Results: 71 patients met our search criteria, 6 were excluded because of a paucity of medical information. Of the 65 patients in our study, the median age was 53 years. 86% of the patients had stage III/IV ovarian cancer, while 14% had stage I/II. The median time from tumor recurrence to bowel obstruction was 17 months. 41% of patients presented with high grade bowel obstruction while 69% were low grade. 36 (55%) of patients underwent surgery for management of bowel obstruction and the remaining 29 (45%) were managed conservatively with various medical approaches. Two-year survival for the surgically managed patients was 38% compared to 18% for those who received medical treatment (p = 0.07). There was no difference in survival for patients based on histology (p = 0.38), grade (p = 0.077), grade of SBO (p = 0.56). Patients with stage I/II had a median survival of 50 months versus stage III/IV at 3.5 months (p = 0.01). Median survival for patients without ascites at time of SBO was 9.5 months while those with ascites was 3 months (p = 0.0004). Patients without abdominal or pelvic mass on CT had a median survival of 60 months; patients with any mass noted had a median survival of 3.6 months; patients with liver and lung metastases was 3 months (p = 0.001). Conclusions: In patients with bowel obstruction due to ovarian cancer recurrence; early stage at diagnosis, the absence of ascites, and lack of abdominal/pelvic mass or distant metastases significantly lengthens survival. There is a trend towards the superiority of surgical management in these patients.

No significant financial relationships to disclose.
Quality of care in advanced ovarian cancer: How important is provider specialty?
Authors: Mercado C. , Zingmond D. , Karlan B. Y. , Sekaris E. , Gross J. , Maggard-Gibbons M. , Tomlinson J. S. , Ko C. Y.
Published: August 2020

e16519

Background: Ovarian cancer is one of the most aggressive and deadly cancers in women. While the mainstay of therapy is surgery, ovarian cancer surgical procedures are performed by surgeons with different specialty training, including gynecology, gynecologic oncology, general surgery, and others. We examine the degree to which surgeon specialty impacts survival and other quality of life-related outcomes in advanced ovarian cancer patients. Methods: Analyses of Stage 3c/4 ovarian cancer patients were performed from 4 states (California, Washington, New York, Florida). Four databases were linked for each state: cancer registry, inpatient-hospital discharge, AMA masterfile, and 2000 U.S. Census SF4 File. Multivariate modeling was performed to identify predictors of survival as well as proxy quality of life-related outcomes, as measured by creation of a fecal ostomy. Hospital case volume was defined as low volume (LV) [0–4 cases], middle volume (MV) [5–9], high volume (HV) [10–19], and very high volume (VHV) [20+]. Results: 60,405 ovarian cancer patients were identified; 53% were Stage 3c/4. Mean age was 64 years. Patients had lower hazard of death when treated in higher volume hospitals as compared to LV [HV (Hazard Ratio) HR = 0.89, p < 0.0001; VHV HR = 0.79, p < 0.001]. Patients treated by gynecologists/gynecologic-oncologists had lower hazard of death (HR = 0.61, p < 0.0001) as compared to other surgeons (non-gynecologist), controlling for hospital type, case volume, comorbidity, and demographics. Also, patients treated by a trained gynecologist had the lowest chance of having an ostomy performed as compared to those of other specialties (HR = 0.22, p < 0.0001). Factors associated with receiving treatment from a non-gynecologist included low volume, rural patient residence, poverty, and high comorbidity. Conclusions: Stage 3c/4 ovarian cancer patients have better survival when treated by gynecology-trained surgeons. Our data suggest that gynecology-trained specialists optimize quality of life-related outcomes, specifically minimizing the creation of a fecal ostomy. Surgeon specialty was more important than procedure volume for these outcomes. Referral to gynecology-trained surgeons would improve survival and quality of life outcomes in advanced ovarian cancer patients.

No significant financial relationships to disclose.
Six versus nine cycles of paclitaxel-carboplatin as first-line chemotherapy in patients with newly diagnosed epithelial advanced ovarian cancer
Authors: Nayl B. , Durando X. , Pomel C. , Dubray P. , Mouret-Reynier M. , Le Bouedec G. , Gimbergues P. , Chollet P. , Dauplat J. , Cure H.
Published: August 2020

e16535

Background: A multimodality approach with cytoreductive surgery and six courses of paclitaxel-platinum-based chemotherapy is actually the mainstay of treatment of Advanced Ovarian Cancer (AOC). This study was performed to determine retrospectively the efficacy of three additional cycles of paclitaxel-carboplatin (PC) in patients with AOC who had previously demonstrated chemosensitivity to six courses of this regimen. Methods: From January 2000 to August 2008, 125 epithelial AOC (FIGO stages IIIC and IV) were diagnosed in a single institution. After a cytoreductive surgery, 51 patients received six cycles of PC (PC 6 group), 57 received 9 (PC 9 group), and 17 experienced progressive disease during treatment. The chemotherapeutic regimen consisted of intravenous paclitaxel 175 mg/m2 for a 3-hour infusion period and intravenous carboplatin AUC 5 every 3 weeks. Results: Median age was 62 years in PC6 group and 59.7 years in PC9. According to the FIGO criteria, 72.6% patients were in stage IIIC in group PC6 and 75.4% in group PC9. Except the patients who experienced refractory disease, complete clinical response at the end of chemotherapy was assessed in 71.4% patients in group PC6 and 71.9% in PC9 (p = 0.13). The median time to progression (TTP) was 26.2 months in PC6 and 29 months in PC9 (p = 0.5). The median overall survival (OS) was 106 months and 97 months respectively (p = 0.16). Conclusions: This retrospective study suggests that three cycles of consolidation chemotherapy with paclitaxel and carboplatin might not prolong duration of TTP or OS in AOC patients.

No significant financial relationships to disclose.
iGenomicViewer, a Gynecologic Oncology Group software library for the creation of highly customizable, portable, interactive, and linked visualizations of high throughput genomic data
Authors: Gaile D. P. , Shepherd L. , Liu S. , Darcy K. , Brady M. , Morrison C.
Published: August 2020

e16544

Background: An R software library was created with the goal of creating customizable, platform independent, and portable visualization tools for the annotation, dissemination and interrogation of high dimensioned genomic data. Methods: A set of R functions were created to extend the functionality of the sendplot R library. The functions were applied to BAC aCGH data generated for several GOG studies. Results: The iGenomicViewer function calls created and populated a directory structure which was then ported to a password protected server for interrogation by research team members. The linked html and image output allows users to examine genome wide plots of aberration frequencies and p-values and then drill down to visualizations of regions of interest. Users can interrogate a panel of plots which includes: 1) a heat map of the aCGH data for with tool-tip display of sample and assay specific data (e.g., assay values, sample IDs, and hyperlinks to UCSC browser and sample specific images); 2) a set of interactive annotation tracks which display location of cancer, disease and DNA repair genes; and 3) a plot which displays -log10 p-values and/or aberration frequencies for the BAC assays depicted in the heatmap. For the smallest regions of interest, the panel of plots contains a tiled heatmap which depicts the overlap and gaps in BAC coverage and their alignment with the gene locations represented in the adjacent annotation track. Conclusions: The iGenomicViewer library provides open source software for creation of customizable visualization tools for collaborative research projects involving high dimensioned genomic data.

No significant financial relationships to disclose.
Clinical outcome of resection of liver metastasis in patients with ovarian cancer
Authors: Neumann U. P. , Fotopoulou C. , Neuhaus P. , Sehouli J.
Published: August 2020

e16545

Background: Hepatic resection has become the standard treatment for resectable colorectal liver metastases. However, in patients with ovarian cancer resectable liver metastases are rare and the issue is discussed controversially due to the lack of relevant published data. The aim of this retrospective study was to evaluate the efficacy of hepatic resections in patients with ovarian cancer. Methods: Between 1991 and 2006 a total of 73 women with liver metastases underwent surgery for ovarian cancer. The median age of the patients was 59 years. 18 patients had primary and 55 suffered from recurrent disease. The median follow-up was 7 months (1–145 months). In 40 patients a liver resection was performed. In the remaining 33 patients the disease was unresectable. Additional procedures were: hysterectomy 15.1%, bilateral salpingo-oophorectomy 24.7%, omentectomy 32.9%, colon resection 50.7%, small bowel resection 32.9%, gastric resection 5.5%, and pancreatic resection 9.6%. Results: Residual tumor after surgery was by far the strongest predictor for outcome. Median survival in patients with no residual tumor was 65 months, < 0.5 cm 29 months, 1cm 6 months. This data clearly show that macroscopically complete surgical cytoreductive therapy improves long-term survival in patients with ovarian cancer and liver metastases. Conclusions: We still need to identify factors associated to complete debulking to minimize the number of ineffective operations. Therefore, liver resection should be always discussed if complete resection is achievable and should be part of the multimodal strategy in advanced ovarian cancer.

No significant financial relationships to disclose.
Prognosis and comorbidities in stage III and IV endometrial cancer
Authors: Wright K. , Munro E. , del Carmen M. , Goodman A. K.
Published: August 2020

e16553

Background: While endometrial cancer may be associated with many comorbid conditions, none have been characterized as changing overall prognosis. The aim of this study was to identify medical conditions or laboratory values, that may serve as prognostic factors in stage III and IV endometrial cancer. Methods: A retrospective chart review identified 112 women with stage III or IV endometrial cancer between years 1993–1998. Information about medical comorbidities and presenting lab values were collected using electronic medical records. Progression free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier survival method and the log rank test. Results: The average age was 64.9 yrs. 79 women (70.5%) had stage III disease and 33 women (29.5%) had stage IV disease. For those with a baseline creatinine <1.2 (n = 91), the PFS and OS were not significantly different from those with a baseline creatinine ≥1.2 (n = 17; p = 0.554 and p = 0.487, respectively). There was a non-significant trend toward worse PFS for the 41 patients with hypertension (HTN) compared to the 62 without (48.0 and 61.2 months, p = 0.191). The overall survival was significantly worse for those with HTN (38.7 months vs. 56.0 months p = 0.046). For those with known coronary artery disease, no significant difference in PFS or OS was found (p = 0.792 and p = 0.312 respectively). Those with diabetes (n = 15) did not have a significantly different PFS compared to those who did not (n = 88; p = 0.728). The OS was worse at 20.1 months for those with diabetes compared to 54.3 months for those without (p = 0.001). Baseline albumin had a significant effect on both PFS and OS. Those with an albumin <3.5 (n = 54) had a PFS of 46.2 months compared to 94.0 months for those with an albumin ≥3.5 (n = 23; p = 0.007), and the OS for those with low albumin was 44.8 months compared to 83.4 months for those with the higher albumin (p = 0.005). Conclusions: These results suggest that past medical history and some baseline laboratory values may be important in considering prognosis. In particular, patients with a history of HTN or diabetes have a worse overall survival. Those with a baseline albumin of <3.5 have a worse PFS and OS.

No significant financial relationships to disclose.
Down-regulation of MDR1 by epigenetic alteration in human epithelial ovarian cancer cells
Authors: Kawakami Y. , Miyamoto K. , Takehara K. , Kumagai M. , Samura O. , Nakamura H. , Mizunoe T. , Yoshida H. , Taniyama K. , Saji F.
Published: August 2020

e16556

Background: Ovarian cancer is one of the most lethal malignancies in women. Despite recent studies of many oncogenes and tumor-suppressor genes concerning about its progression, the details of ovarian cancer biology still remains to be unclear. P-glycoprotein (P-gp) encoded by the MDR1 gene is a membrane protein that can export many kinds of antineoplastic agents from cells, and overexpression of P-gp has been reported to be implicated in treatment failure in cancer. DNA methylation, a major epigenetic process, can affect every step in carcinogenesis as well as genetic alterations. The contribution of such epigenetic alteration to the expression of MDR1 remains largely unexplored in human ovarian cancer. Methods: In this study, we evaluated the DNA methylation status of the MDR1 gene by methylation-specific PCR. Then, the expression of MDR-1 mRNA and protein in primary epithelial ovarian cancer specimens were evaluated by real-time RT-PCR and immunohistochemistry using anti-mouse P-gp F4 monoclonal antibody, respectively. The correlation between these results and clinicopathological features was examined. Results: MDR1 was hypermethylated in 12 of 12 (100%) ovarian cancer cell lines, and 5 of 13 (38%) primary ovarian cancers by methylation-specific PCR analysis. MDR1 mRNA expression was subsequently found to be lost in ovarian cancer cell lines with methylation by both real-time RT-PCR and immunohistochemistry. Thus, MDR1expression was associated with the DNA methylation status of the MDR1 gene. Conclusions: In conclusion, MDR1 was frequently hypermethylated in human ovarian cancers. Our results suggest that epigenetic regulation might play a role in the expression of MDR1 and clinical treatment outcomes in human ovarian cancer.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin in ovarian cancer patients with renal compromise
Authors: Basu C. K. , Mukhopadhyay A. , Pandey R. , Dey S.
Published: August 2020

e16569

Background: Ovarian cancer patients with renal compromise poses problem in choosing chemotherapy for them. Pegylated liposomal doxorubicin (PLD) can be used in such cases. However there is not much data regarding the efficacy and toxicity of PLD. We used PLD in a few renal compromised ovarian and peritoneal cancer patients. Methods: The clinical records of patients with recurrent ovarian and peritoneal cancer patients with high creatinine or low creatinine clearance level who were given PLD at the Netaji Subhas Chandra Bose Cancer Research institute) (NCRI) from July 2005 to July 2008 was reviewed retrospectively to study efficacy and toxicity. Results: Twenty-one patients were identified, which included 16 with epithelial ovarian cancer, 5 with peritoneal cancer. Renal compromise was diagnosed and graded according to creatinine clearance test (CCT) as severe when less than 28 mL/min/1.5 m2, moderate when CCT is 28–55 mL/min/1.5 m2, and mild when CCT is 55–84 mL/min/1.5 m2. Normal value was taken as 85 mL/min/1.5 m2. Patients had distribution as mild: 4 patients, moderate:7 patients, and severe:10 patients. The initial doses of PLD were classified into regular initial dose (40 mg/m2/4 weeks) and lower initial dose (20–30 mg/m2/4 weeks). The median cycle was 5 (range 1–12). We used lower dose for moderate and severe renal disease. The incidence of palmar-plantar erythrodysesthesia 5/21 (23.8%), stomatitis 6/21(28.5%), and hematologic toxicity 3/21(14.2 %). Dose reduction due to toxicities occurred in 19.04 % (4/21) patients. Amongst 21 cases no patient had deterioration of renal function while and after the treatment with PLD. However we had primary treatment with PLD in four cases (2 moderate and 2 severe) while others had platinum based initial treatment. We did not have any complete responder though we had 6 (28.5%) partial responders, 8 (38.1%) stable diseases and 7(33.3%) progressive diseases. Conclusions: Patients with renal compromise who received PLD therapy at an initial dose lower than 40 mg/m2/4 weeks tolerated their treatment well. They required subsequent dose reduction due to mucocutaneous and cardiological toxicities in 19% cases. Treatment response in this population with ovarian and peritoneal cancer was similar to that of patients with normal renal function.

No significant financial relationships to disclose.