bluuebunny/crossref_metadata_2025 huggingface dataset:
Surveillance for stage I testicular seminoma: Retrospective analysis of prognostic factors for relapse at a single institution in Japan
Authors: Kakimoto K. , Ono Y. , Meguro N. , Kawashima A. , Kinouchi T. , Usami M.
Published: March 2020

15630

Background: Treatment options for clinical stage I seminoma include adjuvant radiotherapy (RT) as well as surveillance and adjuvant chemotherapy. Although adjuvant RT remains the treatment of choice in most centers, the success of surveillance of patients with stage I nonseminomatous germ cell tumors and the establishment of curative chemotherapy for advanced disease have led to re-examination of the standard treatment approach. Data available from the surveillance and adjuvant RT series suggest that nearly 100% of patients with stage I testicular seminoma are cured, whichever approach is chosen. We report here results of a retrospective analysis of prognostic factors for stage I testicular seminoma. Methods: Between January 1980 and December 2004, surveillance was performed for 61 patients. Tumor characteristics (age at diagnosis, size, elevation of beta hCG level, invasion of the rete testis, vascular invasion, and lymphatic invasion) were examined as factors possibly predictive of relapse. Cause-specific survival rate was calculated using the Kaplan-Meier method. Results: With a median follow-up of 10.5 years (range, 2.35–20.8 years), 7 relapses were observed, with an actuarial 5- year relapse-free rate (RFR) of 89.2%. On univariate analysis, only tumor size (RFR: <8cm, 96%; =8cm, 76%; p=0.029) was predictive of relapse. Age at diagnosis (RFR: <36, 89%; =36, 91%), elevation of beta hCG level (RFR: 93% [normal] v 91% [elevated]), invasion of the rete testis (RFR:92% [absent] v 90% [present]), vascular invasion (RFR:89% [absent] v 86% [present]), and lymphatic invasion (RFR: 89% [absent] v 78% [present]) were not predictive of relapse. The overall relapse rate was 11.5%. Overall 5-year survival rate was 97%. Conclusions: Size of primary tumor was found to be predictive of relapse in patients with stage I seminoma managed with surveillance, on analysis at a single institution in Japan.

No significant financial relationships to disclose.
Sunitinib malate is active and synergistic with cisplatin against human urothelial carcinoma in a preclinical model
Authors: Sonpavde G. , Jian W. , Lerner S. P.
Published: March 2020

15632

Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. Angiogenesis and plasma VEGF correlate with poor outcomes in human urothelial carcinoma. We designed a preclinical study to examine the efficacy of sunitinib malate alone and in combination with cisplatin against human urothelial carcinoma in vitro and in a murine xenograft model. Methods: The IC50 for sunitinib malate and cisplatin was determined separately against two human urothelial carcinoma cell lines (TCC-SUP and 5637). Sunitinib malate and cisplatin were also applied concurrently to determine activity of the combination. Immunohistochemical staining was performed to detect expression of VEGFR2 on the cell lines, and to measure modulation of this pathway by sunitinib by measuring phosphorylated (p)VEGFR2. Anti-tumor activity of sunitinib malate alone and in combination with cisplatin was determined in a murine xenograft model bearing 5,637 cells. Results: Both human urothelial carcinoma cell lines were found to express VEGFR2. Sunitinib malate displayed significant activity against both urothelial carcinoma cell lines in vitro at low nanomolar concentrations. Furthermore, sunitinib malate in combination with cisplatin was synergistic in vitro. We observed primarily cytostatic activity for sunitinib malate at both 20 mg/kg and 40 mg/kg orally once daily against a murine xenograft model bearing subcutaneous 5,637 cell tumors during 4 weeks of treatment. Anti-tumor activity of sunitinib malate in combination with cisplatin and correlative studies are being evaluated in the murine xenograft model. Conclusion: Sunitinib malate has anti-tumor activity against human urothelial carcinoma as a single agent and is synergistic in combination with cisplatin in vitro. Sunitinib also has significant efficacy in a murine xenograft model of human urothelial carcinoma. These results warrant further exploration of sunitinib malate as a single agent and in combination with cisplatin chemotherapy in human urothelial carcinoma.

No significant financial relationships to disclose.
An analysis quantifies prostate brachytherapy swelling using peripheral seeds as fiducial reference points
Authors: Minehan K. J. , Groshek D. , McNamara K. , Mitchell E. , Emme M. , Price M. , Davis B.
Published: March 2020

15639

Background: Permanent prostate brachytherapy (PPB) assesses implant quality but may suffer significant variability due to: 1) Prostate edema may occur during the procedure which usually subsides within several months, and 2) interobserver variability of CT- derived prostate volumes. An analysis is described, which uses the seeds as prostate fiducials to produce an implant reference volume (IRV). The ratio of the IRV volumes at day 0 and day 33 provides a unique way to quantify prostate edema; thus reducing this factor as a source of variability. Methods: Thirteen low risk prostate cancer patients, (Stage ≤ T2, PSA<13.9, Gleason Score ≤7) were implanted with 125Iodine seeds (77% stranded; prescription dose of 145 Gy). PPB was completed for each patient on day 0 and 33 ±3 days following the implant. The IRV was defined as the volume obtained by contouring the outer most peripheral seeds, circumferentially, on each axial image, resulting in a 3D volume. Contouring was performed by three separate investigators (KJM, DCG, EKM), who were blinded with respect to patient identification. The IRV's were compared both by investigator and by time of PPB (day 0 vs. day 33). The radiation dose encompassing 90% (D90) of the IRV and Prostate (PST) was calculated and compared . Results: The IRVs contoured were reproducible between the investigators with a maximum mean difference of .56 (SD .33) cc. There was no statistical difference between any of the investigators contoured volume (minimum Spearman correlation was 0.978). The average IRV was significantly larger on day 0 (Avg. 52.7;SD 19.7 cc) compared to day 33 (Avg. 44.6; SD 19.1 cc) (p<0.001). The day 0 IRV was an average of 1.18 times larger than the Day 33 PRV. There was no difference between either the day 0 D90PST (Avg.149.1; SD18.7 cGy) vs the day 0 D90IRV (Avg.149.8, SD 27.5 cGy) (p=.442) nor between the day 33 D90PST (Avg.163.7; SD22.7 cGy) vs the day 33 D90IRV (Avg.166.6, SD 30.3 cGy) (p=.257). Both the D90IRV and D90PST were significantly different at day 0 vs 33 (p=.0003, p=<.0001 respectively). Conclusions: The IRV analysis demonstrates no significant interobserver variability, provides accurate quantification of prostate swelling after PPB, and is an accurate objective surrogate analysis for PSI quality.

No significant financial relationships to disclose.
First-line phase II trial of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma unsuitable for cytokine treatment
Authors: Maroto-Rey P. , Bellmunt J. , Trigo J. M. , Guillem V. , López-Martín J. A. , Carles J. , Antón-Torres A. , Urruticoechea L.
Published: March 2020

15640

Background: Sorafenib (BAY 43–9006) is a serine/threonine and receptor tyrosine kinase inhibitor that prevents tumor cell proliferation and angiogenesis. The objective of this open-label, phase II trial was to determine median progression-free survival (PFS) following sorafenib therapy in patients with renal cell carcinoma (RCC) unsuitable for cytokine treatment. Methods: Eligible patients had cytologically or histologically confirmed clear cell RCC; Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1; adequate renal, liver and medullar function; no active central nervous system metastases; had received no previous treatment with antiangiogenic agents; and had at least one evaluable lesion. Sorafenib was given as first-line treatment in patients unsuitable for cytokine therapy, defined as being intolerant to or ineligible for immunotherapy. Treatment consisted of oral sorafenib 400mg twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint was PFS; secondary endpoints were response rate according to Response Evaluation Criteria in Solid Tumors, tolerability and overall survival. Results: Twenty-six patients were enrolled between March and July 2006 (median age: 68.5 years [48–82]; male/female: 17/9, ECOG Performance Status 0: 11 patients; prior nephrectomy: 19 patients). The main metastatic locations were lung and bone, 14 patients had = 2 metastatic lesions, and 2 patients had abnormal lactate dehydrogenase levels. As of 31 December 2006, with a median follow-up of 6.4 months, the median PFS had not been reached. In 19 patients evaluable for response, the overall clinical benefit rate was 68.4% (1 complete response; 1 partial response; 11 stable disease). Six patients experienced serious adverse events, only one of which was related to treatment. Conclusions: Sorafenib first-line therapy is a tolerable alternative for patients unsuitable for cytokine treatment. Final PFS data will be available in June 2007.

No significant financial relationships to disclose.
Comparison of combination treatment with endostatin, soluble neuropilin-1 and thrombospondin-2 to single inhibitors in antiangiogenic therapy of renal cell carcinoma
Authors: Bartsch G. , Eggert K. , Loges S. , Fiedler W. , Laack E. , Hautmann R. , Gschwend J. , Bokemeyer C. , Schuch G.
Published: March 2020

15648

Background: Combinations of cytotoxic drugs lead to increased activity and minimize resistance compared to single agents in tumor therapy. Similarly, antiangiogenic treatment could be improved by combinations targeting different pathways. We investigated a combination of endogenous inhibitors using endostatin (ES), soluble Neuropilin-1 (sNP-1), and thrombospondin-2 (TSP-2) in a model of renal cell carcinoma. Methods: Porcine aortic endothelial cells have been engineered for stable production of angiogenic inhibitors by lipofection and were encapsulated in sodium alginate microbeads. Proliferation of human umbilical vein endothelial cells or Renca renal carcinoma cells was examined after incubation with different microbeads. Similarly, effects of inhibitors on endothelial cell function were tested in tube formation and in vitro wound assays. Microbeads were implanted into SCID mice with subcutaneously growing tumors derived from Renca cells or in mice developing lung metastases after intravenous injection of tumor cells. Results: Factors released from microbeads inhibited endothelial cell function but had no effect on tumor cell proliferation in vitro. In vivo, subcutaneous tumor growth was inhibited similarly by each angiogenic inhibitor alone. After 30 days mean tumor weight was 1.3 g in controls and 0.17, 0.18, 0.18g in ES, sNP-1, and TSP-2 treated mice, respectively. Tumor weight in mice treated with all three inhibitors was further reduced to 0.03g. Histological analyses confirmed antiangiogenic activity by inhibition of microvessel density in treated tumors. In a metastastic model treatment with angiogenic inhibitors induced a significant reduction in size and number of lung metastases with additive effects when factors were used in combination. Conclusions: We conclude that combination therapy targeting multiple angiogenic pathways has synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment.

No significant financial relationships to disclose.
Metronomic chemotherapy for hormone refractory prostate cancer (HRPC)
Authors: Hoshi S. , Numahata K. , Hoshi K. , Suzuki K. , Ono K. , Sugano O. , Ihidoya S. , Saito S. , Arai Y.
Published: March 2020

15649

Background: Low dose continuous chemotherapy (metronomic chemotherapy) is trying to many advanced cancers. Metronomic chemotherapy has important anti-angiogenic activity to tumor vessels. For patients who progressed after docetaxel, no standard options exist. We have experienced complete regression of bone metastases on super scan by low does cisplatin, UFT, diethylstilbestrol, and dexamethasone (CUDD) in a patient with HRPC (Int JCO, 8,118, 2003). Methods: CUDD consisting of weekly 5 mg/body of cisplatin plus 125 mg/body of diethylstilbestrol and daily 300–450 mg of UFT/day plus 0.5–1 mg of dexamethasone were given to 47 HRPC patients, (median and range of age: 66 and 52–72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 10 patients and 8 in 17 patients and 9 in 20 patients, respectively. Metastatic site was bone in 45 (EOD grade 1:10, 2:18, 3: 15, 4:2), lymph node in 8. Six cases became refractory to docetaxel were treated with CUDD plus CPM (50 mg/day). Results: Among the 45 patients assessable for bone metastasis, 12 (27 %) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 9 were EOD grade 1–3. Eighteen (40 %) were stable and 15 (33%) progressed on bone scan. Among 8 patients of lymph node metastasis, 3 (38%) showed partial response, 2 (25%) no change and 3 (38%) progression. Twenty-five (53 %) out of 47 patients showed a PSA decline of 50% or greater. Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. Their median response duration and median survival time were 8 months (range; 2 to 44 months) and 20 months (range, 4 to 48 months), respectively. Their median response duration was 3 months. Three of 6 refractory to docetaxel were responded to CUDD plus CPM. Their median response duration was 10 months. Conclusions: CUDD is effective in almost half of hormone refractory prostate cancer patients and has advantage of minimal side effect. Three of 6 docetaxel refractory cases also responded to CUDD plus CPM.

No significant financial relationships to disclose.
Expression of hepatoma-derived growth factor in early-stage cervical adenocarcinoma
Authors: Tsai C. , Tai M. , Hu T. , Huang S. , Lin J. , Chang H. , ChangChien C. , Lai C.
Published: March 2020

16002

Background: Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor and plays an important role in the progression of different types of cancer. The current study was designed to elucidate the role of HDGF expression during the development of. early-stage cervical adenocarcinoma. Methods: A total of 63 patients with early-stage cervical adenocarcinoma were enrolled in this retrospective study. The HDGF expression in cervical adenocarcinoma was determined by immunohistochemistry. The HDGF immunostaining in the nuclei and cytoplasm of clinical samples was scored and expressed as labeling index to correlate with the clinical parameters of patients with early-stage cervical adenocarcinoma using SPSS software. Results: HDGF immunostaining was detected in both cytoplasm and nucleus of cervical adenocarcinoma. Compared with adjacent non-tumor tissue samples, HDGF expression was significantly increased in either nuclear or cytoplasmic compartment in cervical adenocarcinoma samples (P < 0.001). Moreover, elevated nuclear HDGF levels were correlated with lymph-vascular space invasion (P < 0.05), lymph node metastasis (P < 0.001), recurrence (P < 0.001), advaced grade(P < 0.001). Conclusions: HDGF overexpression is involved in the carcinogenesis of cervical adenocarcinoma.

[Table: see text]

No significant financial relationships to disclose.
The activity of the synthetic progestin medroxyprogesterone acetate on the invasive phenotype of ovarian cancer cells
Authors: Gogoi R. , Kudla M. , Gill O. , Horwitz K. , Fishman D.
Published: March 2020

16003

Background: Androgens play an integral role in the physiologic and pathologic processes of the ovary. Yet it has been difficult to study the role of the androgen recptors (AR) separately from the other steroid receptors such as the progesterone receptor (PR) in ovarian cancer. This has been made more complicated because most synthetic progestins such as Medroxyprogesterone acetate (MPA) bind both PR and AR. The objectives of our study were: 1. To create an ovarian cancer cell line constitutively expressing only AR. 2. To compare the role of AR activated by the synthetic progestin MPA vs. the pure androgen dihydrotestosterone (DHT) on the invasiveness of human breast and ovarian cancer cells. 3. To investigate the role of matrix metalloproteases (MMP's) associated with invasion. Methods: ER- and PR- human breast (T47D-Y) and ovarian (OvCa 429) cancer cells were engineered to stably express AR. Immunocytochemistry and western blot analyses confirmed that these breast and ovarian cancer cell lines (called Y-AR and OvCa-AR respectively) are PR-, but AR+. Boyden chamber invasion assays were performed using Y-AR and OvCa-AR cells treated with either vehicle, MPA or DHT. The MMP's associated with invasion were further investigated using zymographic assays. Results: AR activation by either MPA or DHT increased the invasive potential of both breast (p<0.05) and ovarian cancer cells with MPA being significantly more effective than DHT at stimulating invasion. However, regardless of the ligand, activation of AR increases tumor cell invasion. To elucidate the MMP's associated with this activation in OvCa-AR cells, we used zymographic analysis. Interestingly, we found that MPA activation of AR decreases both the total level and activation of MMP-9 compared to DHT and vehicle control. Conclusions: Using our model system we are able to study the role of AR independent of PR on the biology of breast and ovarian cancer cells. Our studies suggest that the use of pharmacological doses of synthetic progestins may actually increase the invasive potential of ovarian cancer cells through AR. We hypothesize that blockade of downstream AR targets or the use of selective AR modulators (SARMS) may be of therapeutic value in the treatment of ovarian cancer.

No significant financial relationships to disclose.
Correlation between c-erb-B2 overexpression with disease-free survival and rate of pelvic relapse in patients with advanced cervical cancer treated with chemo-radiotherapy
Authors: Pérez-Regadera J. , Sánchez-Muñoz A. , De-la-Cruz J. , Ballestín C. , Lora D. , García-Martín R. , Alonso-Carrión L. , Mendiola C. , Lanzós E.
Published: March 2020

16004

Aims: To determine the impact of the c-erb-B2 overexpression receptor on pelvic relapse and on disease-free survival (DFS) in patients with advanced cervical cancer receiving concurrent chemo-radiotherapy. Methods: One hundred thirty six patients with advanced cervical cancer (stage: 12 IB2-IIA, 34 IIB, 71 IIIB, 19 IVA); histology: 86 epidermoid and 14 adenocarcinoma) were analyzed to detect c-erbB-2 level using an immunohistochemical method (Herceptest Dako). Cases c-erbB-2 (+3) were considered positive. All patients received pelvic radiotherapy, brachitherapy and concurrent chemotherapy with two schedules: 48 patients with tegafur (800 mg/day via oral) and 88 with tegafur (same doses) plus five cycles of weekly cisplatin 40 mg/m2/week iv. Results: Of the 136 biopsies, 32 (23.5%) were c- erbB-2 positive. The disease free survival to 3 and 5 years of the patients were 61% and 58% for c-erb-B2 negative and 36% and 36% for c-erb- B2 positive (p=0.02), respectively.We divided our patients in four groups: c-erb-B2 positive treated with cisplatin; c-erb-B2 positive without cisplatin, c-erb-b2 negative treated with cisplatin and c-erb-b2 negative without cisplatin. The group of patients with c-erb-B2 overexpression that did not received platinum treatment had a higher rate of pelvis relapse (p<0.0001) and with a decreased DFS (p=0.0014). Conclusions: c-erbB-2 overexpression may imply a poor prognosis for patients with advanced cervix cancer, especially if they did not receive concurrent radiochemotherapy with cisplatin.

No significant financial relationships to disclose.
Expression of chemokine (C-C motif) ligand-2 (CCL2) is predictive of response to chemotherapy and overall survival in primary ovarian cancer
Authors: Fader A. Nickles , Vaziri S. A. , Rojas-Espaillat L. , Faber P. W. , Elson P. , Biscotti C. V. , Michener C. M. , Rose P. G. , Belinson J. L. , Ganapathi R.
Published: March 2020

16013

Background: CCL2, a determinant of macrophage infiltration in tumors, is expressed in normal human ovarian surface epithelium but silenced or down-regulated in ovarian adenocarcinomas (Br J Cancer 92:2024, 2005). We determined the association between quantitative expression of CCL2 with platinum-taxane based chemotherapy response and clinical outcome in patients with primary ovarian cancer. Methods: Tumor samples from chemotherapy-naïve patients with advanced serous ovarian adenocarcinoma were obtained at the time of primary cytoreductive surgery. Gene expression profiles using RNA extracted from tissue enriched for >90% tumor from 2 chemotherapy sensitive (CS) and 8 chemotherapy resistant (CR) patients were performed using the Illumina Sentrix Human-6 Expression Bead-Chip microarray. Gene expression was quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in a larger patient cohort. Statistics were generated using Wilcoxon rank sum tests and Kaplan-Meier survival curves. Results: Clustering analysis of gene expression profiles identified several genes, including CCL2, that were differentially expressed between the CS and CR tumor specimens. Levels of CCL2 were significantly (p<.001) under-expressed in all 8 CR patient tumors as compared to the 2 CS tumors. Quantification of CCL2 gene expression in 9 CS and 16 CR tumors by RT-PCR demonstrated that CCL2 was significantly down-regulated in the CR tumors when compared to the CS tumors (p<.001). Using normalized PCR cycle threshold scores, 22 of the 25 tumors were correctly classified, i.e., 8/9 CS had low CCL2 expression (sensitivity = 89%) and 14/16 CR had high expression (specificity = 88%). For patients with low CCL2 expression, progression free survival was 12 months versus 18.6 months for those with high CCL2 expression (p=.05). Median overall survival (OS) was 20.8 months for patients with low CCL2 expression, while OS was not yet reached for those with high CCL2 levels (p=.01). Conclusions: Results demonstrate that expression of CCL2 correlates with response to chemotherapy and survival in patients with primary ovarian cancer. Expression of CCL2 may be a useful independent biomarker of response to treatment and clinical outcome.

No significant financial relationships to disclose.
Weekly association of gemcitabine and topotecan in early recurrent ovarian cancer patients: A French multicenter phase II study
Authors: Joly F. , Petit T. , Pautier P. , Guardiola E. , Mayer F. , Chevalier-Place A. , Delva R. , Sevin E. , Henry-Amar M. , Bourgeois H.
Published: March 2020

16016

Background: A weekly association of gemcitabine and topotecan was tested with the aim of evaluating its efficacy and tolerance in patients recurring after first line platinum and taxane-based chemotherapy. Methods: From December 2004 to April 2006, 77 patients whose disease has progressed within 12 months (time-free interval, TFI) after first line chemotherapy were enrolled in a multicenter phase II study. Primary endpoint was overall response rate (ORR). Gemcitabine (1000 mg/m2) and topotecan (2.5 mg/m2) were given day 1, 8 and 15 (q 28 d) for 6 to 9 cycles. Tumor response was assessed according to RECIST or Rustin criteria. Clinical response was assessed using symptoms improvement in responders and patients with stable disease. Follow-up was updated December 2006. Results: Initial characteristics were: median age 63 years (38 to 80), WHO PS 0–1 93%, serous histology 85%, TFI < 6 months 45%, measurable disease 71%. Four cycles (1 to 8) were administered in average. The only major toxicity was neutropenia (Grade 3 and 4 in 17% and 6% of patients) with one febrile neutropenia; one toxic death (pneumopathy) was observed. 34% of cycles were incomplete (d8 and/or d15 not administered) because of grade 1–2 thrombopenia or grade 1–4 neutropenia. Lenograstim and erythropoietin were administered in 14% and 34% of patients, respectively. Sixty-six (86%) patients were evaluable for response (2 cycles administered). The ORR was 14% (CR=3%, PR=11%); there were 53% of stable disease. ORR was 7% and 20% in patients with TFI < 6 months and = 6 months, respectively. Symptoms were improved in 18 (64%) of 28 patients and pain in 11 (39%) of 28 patients. Median event-free survival time was 3.7 months. Median overall survival time was 12.3 months (7.5 and 15.6 months in patients with TFI < 6 months and = 6 months, respectively; p=0.0244). Conclusions: In resistant/refractory ovarian cancer, weekly gemcitabine and topotecan is associated with low objective response rate but with a high proportion of stable disease and symptoms control leading to acceptable quality of life.

No significant financial relationships to disclose.
Pelvic node control in patients with locally advanced uterine cervical cancer treated with concurrent chemoradiotherapy
Authors: Toita T. , Nagai Y. , Tamaki W. , Ogawa K. , Gibo S. , Kakinohana Y. , Kamiyama K. , Inamine M. , Aoki Y. , Murayama S.
Published: March 2020

16018

Background: To evaluate pelvic node control in cervical cancer patients treated with concurrent chemoradiotherapy (CCRT) without surgical resection. Methods: Ninety-six patients (stage IB2, 3; IIA, 2; IIB, 49; IIIA, 1; IIIB, 40; IVA, 1) with uterine cervical squamous cell carcinoma treated with CCRT were analyzed. Cervical tumor diameter and pelvic node status were assessed by MRI. The median maximum tumor diameter was 58 mm (range, 36–86 mm). Thirty-four patients had positive pelvic nodes (= 10 mm in shortest diameter). The largest diameter of the positive nodes ranged from 10–50 mm (median, 18 mm). All patients received CDDP (20 mg/m2 for 5 days every 21 days), pelvic external beam RT (PERT), and high-dose-rate intracavitary brachytherapy (HDR-ICBT). The planned RT schedule consisted of PERT with 40 Gy/20 fractions (frs) followed by HDR-ICBT with 18–24 Gy/3–4 frs and PERT with 10 Gy/5 frs using a midline block. Thirty of thirty-four node-positive patients received boost RT (6–10 Gy/3–5 frs) to involved nodes. The dose from HDR-ICBT to the pelvic nodes was estimated at a point 6 cm lateral to the midline at the level of the vaginal fornix. Doses of ERT and HDR-ICBT were simply summed and used for pelvic node dose-response analysis. The median total dose was 60 Gy (range, 52–64 Gy) for positive nodes and 54 Gy (range, 51–55 Gy) for negative nodes. Median follow-up of the surviving 79 patients was 41 months (range, 8–98 months). Results: Four-year overall survival (OAS), pelvic control (PC), and distant metastasis-free (DMF) rates for all 96 patients were 79%, 90%, and 79%, respectively. Four-year OAS, PC, and DMF rates for node-positive/node-negative patients were 60%/89% (P=0.002), 82%/95% (P=0.08), and 66%/86% (P=0.008), respectively. Pelvic nodal recurrence was observed in 4 patients. One patient developed isolated pelvic node recurrence while the other 3 had concurrent recurrences at other sites, including 1 with a cervical tumor and 2 with cervical tumor and distant metastases. Nodal recurrence rates by largest diameter were 1/62 for node-negative patients, 1/14 for nodes 10–14 mm, 0/13 for nodes 15–29 mm, and 2/7 for nodes = 30 mm. Conclusions: Pelvic nodal metastases < 30 mm were well controlled by CCRT without surgical resections using RT dose delivered.

No significant financial relationships to disclose.
Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Symptom Index (FOSI) in a phase II clinical trial of pertuzumab in patients with advanced ovarian cancer
Authors: Beaumont J. , Yount S. , Lalla D. , Lubeck D. , Derynck M. , Karlan B. , Cella D.
Published: March 2020

16021

Background: The FOSI is a very brief(8-item) index derived from the FACT-O to measure symptom response to treatment for ovarian cancer(OC). We evaluated its performance in a single arm Phase II clinical trial. Methods: The FOSI was administered to patients with advanced OC participating in a single arm Ph II clinical trial of pertuzumab(Gordon et al, JCO (2006) v24:4324;2006)). Pertuzumab, a humanized HER2 antibody is the first in a new class of investigational agents known as HER dimerization inhibitors(HDIs). Patients completed the FOSI at D1 of each 3 week cycle, up to 17 cycles. Validation analyses focused on data from the first 4 cycles and included Cronbach's alpha coefficients plus cross-sectional and longitudinal comparisons of groups defined by ECOG performance status (PS). Results: 62 patients completed the FOSI at baseline (B), 54 at cycle 2, 44 at cycle 3 and 27 at cycle 4. The FOSI showed acceptable internal consistency reliability with alphas of 0.73 to 0.80. The FOSI differentiated patients with PS 0 from those with PS =1 at each cycle (Table). There was a difference in FOSI scores in patients with worsened PS from those whose PS improved or was unchanged at cycle 2 only (p<0.001). The ES (mean change/ SD of change scores) for the group with worsened PS was -0.77. The minimally important difference was estimated to be 2–3 points. Conclusions: The FOSI is a valid symptom measure in this population of OC patients, demonstrating acceptable reliability, validity and responsiveness to clinical change. [Table: see text]

No significant financial relationships to disclose.
A pilot study of sentinel lymph nodes identification in patients with endometrial cancer
Authors: Li B. , Wu L. , Li X. , Zhang W. , Li S. , Gao J.
Published: March 2020

16022

Background: The sentinel lymph node (SLN) biopsy has showed the feasibility to limit the extent of lymphadenectomy in vulvar and cervical cancer, but few studies have examined this procedure in endometrial cancer. The aim of this study is to examine the feasibility of SLN identification for the patients with endometrial cancer. Methods: Twenty patients with endometrial cancer undergoing hysterectomy and lymphadenectomy were included in the study. At laparotomy, methylene blue dye was injected into the subserosal myometrium of corpus uteri at multiple sites. Dye uptake into lymphatic channels was observed and blue nodes were identified as SLNs. The SLNs were biopsied before lymphadenectomy performed. The samples of SLNs and non-SLNs were recorded separately and correlated with the final pathological results. Results: Dye uptake into lymphatic channels was seen in all 20 cases. Among them, SLN was identified in 15 (75%) cases. A total of 71 SLNs with a mean number of 4.7 (range, 1–10) were identified from all pelvic sites. The most frequent locations of SLNs included obturator in 29 (41%), interiliac in 16 (26%). No dye-containing paraaortic node was found. Two patients (10%) had nodal metastases, and they all had at least one SLN found to be positive, the false-negative-rate was 0. No adverse reactions or injures were attributed to the study. Conclusions: This study shows the feasibility and safety of SLN identification with blue dye in patients with endometrial cancer undergoing staging surgery. The SLNs accuratly predicted the nodal metastases in the study.This approach might provide an alternative to limit the extent of nodal sampling.

No significant financial relationships to disclose.
Surgical management and prognostic indicators of uterine leiomyosarcoma
Authors: Gagua I. R. , Kuznetsov V. V. , Lazareva N. I. , Nechushkina V. M. , Zavolskaya Z. A.
Published: March 2020

16024

Background: Uterine leiomyosarcoma (LMS) is a rare malignant tumor. Preoperative diagnosis is established only in 13.5% patients at our center. Currently, the main method of treatment of LMS is surgery. The efficacy of chemotherapy and radiotherapy are questionable. So, the aim of our study is to establish the optimal treatment modalities and prognostic indicators for this tumor. Methods: A retrospective chart review was done to 163 patients with LMS treated at the NNBRCRC from 1970 to 2002. Multivariate statistical analysis was performed to determine the most important prognostic indicators for LMS. Surgical treatment, as independent method, was performed to 108 patients (66.3 %). Combined treatment, including surgery and postoperative chemotherapy was performed to 30 patients (18.4 %), surgery + radiotherapy - 12 (7.4 %) patients. Complex treatment (surgery + chemotherapy + radiotherapy) was performed to 11 (6.7 %) patients. Results: Histologically, LMS is the most common (41,4%) among all sarcomas of female genital tract. Immunohistochemistry and electronmicroscopy play a major role in establishing the diagnosis. 5 year overall and disease - free survival of patients with LMS is 48.5± 4.2% and 44.3 ± 4.3 %, respectively. We observed association between ovarian preservation and improved survival: overall 5 year survival in patients with ovarian preservation and those who underwent oophorectomy is 87.3 ± 8.4 % and 49.0 ± 5.3 %, respectively (p<0,05). On the basis of multivariate analysis we determined the following prognostic indicators, affecting the outcome of patients with LMS: disease stage, mitotic index, tumor cell necrosis, depth of tumor invasion in myometrium, tumor size, age, menstrual status of the patients and optimal surgery. Conclusions: According to our data, the optimal surgery for LMS is total abdominal hysterectomy in the reproductive age and total abdominal hysterectomy with bilateral salpingo-oophorectomy in the postmenopausal period. The most favorable prognostic indicators are: patient age younger than 30, I stage of disease, tumor size less than 10 cm, less than 10 mitotic figures per 10 high - power fields, submucosal or subserosal location of well-differentiated tumor.

No significant financial relationships to disclose.
Effects of PKC beta inhibitor enzastaurin on chemoresistant ovarian cancer cell lines
Authors: Meinhold-Heerlein I. , Bräutigam K. , Bauerschlag D. , Maass N. , Mundhenke C. , von Kaisenberg C. , Schollmeyer T. , Jonat W. , Arnold N. , Bauknecht T.
Published: March 2020

16030

Background: Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta II (PKCβII), leads to apoptosis and suppression of angiogenesis and represents a promising drug for clinical development. The effects of Enzastaurin were investigated utilizing the ovarian cancer cell line HEY and several chemoresistant subclones. Methods: The cell line HEY was used to develop subclones with selective resistance against cisplatin, etoposide, docetaxel, paclitaxel, gemcitabine, and pemetrexed. PKCβII expression was determined by immunoblotting and RT-PCR analyses. The platin-sensitive ovarian cell line IGROV1 with high expression of PKCβII served as control. All cell lines were exposed to 5 μM Enzastaurin for up to three hours. Immunoblotting analyses determined the expression of Enzastaurin targets PKCβII and glycogen synthase kinase 3β (GSK3β). Proliferation and apoptosis induction after Enzastaurin treatment was evaluated using MTT assay and DAPI staining. Results: All resistant cells showed a significantly higher expression of phosphorylated GSK3β than the parental cells. The highest expression level was detected in cisplatin- and paclitaxel-resistant cells. A decrease of phosphorylation occurred after exposure to Enzastaurin for 30 minutes, most obvious in parental, cisplatin- and gemcitabine-resistant cells. Proliferation and apoptosis assays demonstrated the paclitaxel and docetaxel resistant cells as the most sensitive cells. In contrast, cisplatin-resistant cells exhibited the highest resistance. Enzastaurin resistance also correlated with elevated PKCβII expression. Conclusion: The results indicate that ovarian cell lines with high expression of phosphorylated GSK3β display also a strong dephosphorylation. Though in these cell lines the inhibitory effect of Enzastaurin is most prominent, cell proliferation is hardly affected, nor apoptosis is accelerated. There is cross-resistance between platinum and Enzastaurin in some cell lines; however Enzastaurin demonstrated promising activity against taxane resistant cell lines.

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Use of systemic therapy in women with recurrent ovarian cancer—Development of a national clinical practice guideline
Authors: Elit L. , Zitzelberger L. , Fung Kee Fung M. , Brouwers M. , Graham I. D. , Browman G.
Published: March 2020

16033

Background: To develop a national guideline on the use of systemic therapy for women with recurrent ovarian cancer. Methods: In March 2005, the Society of Gynecologic Oncologists of Canada (GOC) held a workshop with clinicians and methodologists to begin the process of defining specific recommendations for the management of recurrent ovarian cancer in the Canadian context. An adaptation process developed by the Canadian Strategy for Cancer Control (CSCC) Clinical practice Guidelines Action Group (CPG-AG) was used. Guideline adaptation modifies existing guidelines to fit a local organizational and cultural context. A draft guideline was developed and sent to practitioners from across Canada for feedback. Relevant comments were incorporated. Results: A literature review identified seven guidelines which were assessed for quality by six reviewers using the AGREE instrument. Data on guideline quality, currency and content (recommendations) was used by the pan-Canadian panel in an informal consensus process which resulted in the initial draft of a guideline. A sub-panel reviewed the draft and made further edits to ensure the guideline's appropriateness for a national context. Practitioner feedback was requested from 165 health care providers who treat ovarian cancer from across Canada. Overall response rate was 37%. Respondents included gynecologic oncologists (62.5%), medical oncologists (25%), radiation oncologists (3%), internal medicine (3%), gynecologists (1%) and psychosocial oncology (1%). Overall response to the guideline was positive. All comments were reviewed by the sub-panel and the guideline was edited appropriately. Conclusions: This was the first undertaking of the creation of an interdisciplinary guideline in gynecologic oncology with input from health care providers from across Canada. Feedback from the panel and external practitioners indicated that this was a worthwhile process. Our goal was to vet this work in the Canadian context so as to inform provincial decision-makers concerning access to expensive systemic therapy. The guideline has been endorsed by the national organization and will be available to practitioners and decision makers on the organization's website.

No significant financial relationships to disclose.
Pilot study of FLT-PET/CT uptake in ovarian cancer patients with biologic correlates
Authors: Deloia J. , Richard S. D. , Edwards R. P. , Elishaev E. , Mason S. , Shinde D. , Mountz J. J. , Bencherif B.
Published: March 2020

16045

Background: New imaging modalities for ovarian cancer disease burden are needed. Positron emission tomography (PET) with [F-18] fluorodeoxyglucose (FDG) has shown promise for early prediction of outcome and response to therapy when compared to CT alone. Recent studies have suggested that 3’-fluoro-3’ [F-18] deoxythymidine (FLT) has a higher specificity than FDG. The objective of this study was to correlate FLT tracer uptake with different in vitro quantitation of cellular proliferation. Methods: Patients with suspected or know ovarian cancer and an elevated Ca 125 were recruited for this trial. These patients were injected with 5 mCi of [F-18]FLT intravenously as a slow bolus. After an uptake period of 60 minutes, patients were scanned for approximately 36 minutes by CT and then PET, and images were co- registered. Standardized uptake values (SUV) of both hot and cold areas were obtained and these lesions were biopsied at the time of surgery. Tissue was divided and used for Ki-67 proliferation index staining to determine mitotic index, RNA isolation for rt-PCR for thymidine kinase-1 (TK1) levels, and grown ex vivo for cell proliferation analysis. Univariate analysis was preformed using the student's t-test. Results: PET positive lesions were found to have a significantly increased mitotic index when compared to control lesions (0.134 vs. 0.004, p<0.001). There were no significant differences in relative TK1 levels or ex vivo cell proliferation ability between PET positive and control lesions in the initial four patients. Conclusions: Increased mitotic index by Ki-67 staining correlates with increased FLT activity by PET scan, but not TK1 levels or DNA content. We will continue to explore this modality as compared to FDG-PET in patients with ovarian cancer.

No significant financial relationships to disclose.
A retrospective review of adenosquamous carcinoma of the uterine cervix
Authors: Kawakami Y. , Takehara K. , Kumagai M. , Hanaoka M. , Akimoto Y. , Mizunoe T. , Saji F.
Published: March 2020

16049

Background: Adenosquamous carcinoma (ASC) of the uterine cervix is a rare mixture of malignant squamous and glandular epithelial elements. Clinical analyses of this disease were hardly performed independently from those of adenocarcinoma (AC) of the uterine cervix since both of the patients with these diseases show poorer outcome, compared with those with squamous cell carcinoma, which is present in the majority of cervical cancer. In this study, we investigated clinical features including diagnosis and treatment of this disease. Methods: During 1980–2006, total of 270 patients, who were diagnosed as carcinoma of the uterine cervix, were included in our analysis. A retrospective review of patients with ASC were preformed in their age, stage, lymph node metastasis, tumor markers (SCC, CEA, CA125 and CA19–9), treatment, relapse rate and its location, and survival. Results: There were total of 17 and 34 patients, who were histologically confirmed as having ASC (6.3%) and AC (12.6%) of the uterine cervix, respectively. All the ASC patients underwent surgery. The average age of the patients was 45.0 (26–78). The distribution of illness stages among the patients were IA, 4; IB, 8; IIA, 2; IIB, 2; IIIB, 1. Lymph node metastasis was seen in two patients (11.8%). There were no significant difference in these indexes between ASC and AC. Elevation of serum CA125 was observed in two ASC patients but no AC patients. The recurrence rates were 17.6% and 14.7% in ASC and AC, respectively. Five-year survival were 77.8% in ASC and 78.0% in AC, whereas 92.2% in SCC. Conclusions: These analyses indicate that clinical behavior and its outcome of ASC is similar to those of AC. The treatment based on these clinical features may be a useful to improve the prognosis of this disease.

No significant financial relationships to disclose.
Anti-tumor activity of ADH-1 in vitro and in vivo in combination with paclitaxel in ovarian cancer cell lines
Authors: Gupta M. , Barnes D. , Losos J. , Spehar G. , Bednarcik M. , Peters W. P.
Published: March 2020

16050

Background: ADH-1 is a novel N-cadherin (Ncad) antagonist. Ncad is a protein present on certain tumor cells and established tumor blood vessels. Its expression on tumor cells increases as they become more aggressive, invasive and metastatic, making it an important target for anti-cancer therapy. ADH-1 was well tolerated in phase I studies and demonstrated evidence of anti-tumor activity in 7 patients whose tumors expressed Ncad. Patient enrollment in two phase II single agent trials concluded at the end of 2006. We report on the anti-tumor activity of ADH-1 in combination with paclitaxel in cancer cell lines in vitro and in the A2780 (Ncad positive) ovarian xenograft model in vivo. Methods: In vitro cytotoxicity of SKOV-3 (ovarian) cells exposed to a fixed ratio of ADH-1 and paclitaxel simultaneously was evaluated by the WST-1 cell proliferation assay. In vivo anti-tumor activity of ADH-1, paclitaxel, and the combination was evaluated in the A2780 xenograft model. ADH-1 100 mg/kg was administered bid IP for 21 days and paclitaxel was administered qod IV for 5 days. Results: In vitro cytotoxicity assays evaluated for combination effects using CalcuSyn software indicated a strong synergistic effect of ADH-1 in combination with paclitaxel (CI <1). In vivo paclitaxel treatment produced a median Time to Endpoint (TTE) (tumor volume >2gm or study end at 60 day) of 32.1 days and 73% Tumor Growth Delay (TGD), compared to control (p=0.028). For the paclitaxel group, there was only one Tumor Free Survivor (TFS) and one transient Complete Responder (CR). ADH-1 produced a TTE of 16.1 and a -13% TGD (p>0.05). The combination of ADH-1 and paclitaxel produced a median TTE of 48.6 days, corresponding to 161% TGD (p<0.0016 compared to untreated controls, p<0.003 for vehicle treated, and p<0.005 compared to paclitaxel alone). The combination therapy generated durable CR in 5 animals, 1 transient CR and 2 PR. The combination therapy had similar toxicity to paclitaxel alone. Conclusions: In this ovarian cancer model, the combination of ADH-1 with paclitaxel produced a synergistic anti-tumor effect. Based in part on these encouraging pre-clinical results, a clinical program of ADH-1 in combination with chemotherapeutic agents has been initiated.

No significant financial relationships to disclose.
Serum biomarker discovery for ovarian serous carcinoma using novel proteomic methods
Authors: Borgia J. A. , Frankenberger C. , Kaiser K. , McCormack S. E. , Usha L. , Rotmensch J. , Coon J. S.
Published: March 2020

16058

Background: Ovarian serous carcinoma (OSC) is the most common ovarian cancer sub-type and fourth leading cause of cancer-related deaths for women in the US. Unfortunately, more than two-thirds of women with ovarian cancer present at an advanced stage, when prognosis is poor. Developing methods to detect ovarian cancer at stage I, when it is 90% curable by surgery, or at stage II where survival is 70%, offers the best prospect for changing the clinical course of this dread malignancy. Methods: Serum specimens were collected both before and 3–6 weeks after tumor resection for patients with Stage I/ II high-grade serous carcinoma. None suffered recurrence within 6 months. We collected 98 ‘paired’ (pre- and post operative) serum specimens; including 41 benign paired specimens for comparison. A SELDI-TOF mass spectrometer was used to generate the serum proteomic profiles, optimized for the 2,000–40,000 m/z range. All data analyses were performed in a blinded manner using Bioconductor, an extension of the R-project statistical platform (v2.2.0). Raw spectra were processed as follows: baseline subtraction, spectra normalization, and differential peak detection. Aligned peaks were sorted into groups, based on tumor pathology and pre- vs. post-operative specimen type, and compared using a two tailed homoscedastic t-test. Results: The proteomes of pre- and post-operative serum from 10 patients with OSC were evaluated for significant changes in composition and compared with a set of 8 ‘normal’ specimens (i.e. patients undergoing major surgery for benign disease). We identified 18 serum components common to all OSC pre-op specimens that were extensively reduced or absent (p < 0.05) after tumor resection and 26 components capable of discerning pre-op OSC from pre-op normal specimens (p < 0.05). Most notable of these are components with m/z ratios of 2029.1, 2203.6, 6442.3, and 6851.9, based on level of significance (p < 0.001). Conclusions: These results validate the power of our ‘pre- vs. post- operative’ analysis strategy for the identification of novel serum biomarker candidates. Efforts are currently focused on expanding the scope of our specimen bank and identifying the putative biomarker candidates via mass spectrometry.

No significant financial relationships to disclose.