bluuebunny/crossref_metadata_2025 huggingface dataset:
Cetuximab plus gemcitabine/oxaliplatin (GEMOX) for patients with unresectable/recurrent intrahepatic cholangiocarcinoma refractory to GEMOX
Authors: Paule B. , Bralet M. , Herelle M. , Rage E. , Ducreux M. , Guettier C. , Adam R.
Published: March 2020

14084

Background: Gemcitabine-oxaliplatin (GEMOX) is active and well tolerated in advanced biliary tract adenocarcinomas. We report a single institution retrospective study on using cetuximab plus GEMOX in patients with intrahepatic cholangiocarcinoma that expresses Epidermal Growth Factor Receptor (EGFR) and who have progressed on first line chemotherapy (GEMOX). Methods: 9 patients (5 females, 4 males, mean age: 54 years, range: 27–74, performance status: 0–1) with a recurrent or unresectable intrahepatic cholangiocarcinoma (peripheral n=6, hilar n=3, histologically proven) resistant to GEMOX received cetuximab 400 mg/m2 on day 1 then 250mg/m2 weekly, in combination with gemcitabine 1,000 mg/m2 as a 10 mg/m2/min infusion on day 1 and oxaliplatin 85mg/m2 as a 4-h infusion on day 2, every 3 weeks. EGFR expression was determined by immunohistochemistry (n=9) and EGFR gene copy number on tumour cells was detected by fluorescent in situ hybridization (FISH) (n=8). Tumor response was measured using standard RECIST criteria. Results: EGFR was detected by immunohistochemistry (9/9) in more than 10% tumour cells without gene amplification (8/8). A total of 57 cycles were given (range: 3–11 per patient). Median duration follow-up was 7 months (range: 6–12). At 3 months, 3/9 had partial response, 3/9 stable disease and 3/9 a progression disease. At 6 months, CT scan showed 1 complete response, 1 partial response, 1 stable disease and 6 progression diseases. The median time to tumour progression was 6 months, with a median duration of response of 3 months (range: 2–8). Five patients died. Of the 4 patients who are still alive, the mean duration follow-up is 11 months (range: 10–14). There was no treatment related death, no anemia, no neurotoxicity. One grade 3 neutropenia was noted and acne-like rash was observed in 7/9 patients. The median survival from time of initiation of treatment was 10 months. Conclusions: Even if there is no amplification of EGFR gene, Cetuximab plus GEMOX is well tolerated and provides good palliative effects in advanced cholangiocarcinoma. A prospective phase II trial with GEMOX with and without cetuximab is being planned to assess the real impact of cetuximab in unresectable cholangiocarcinoma expressing EGFR.

No significant financial relationships to disclose.
A phase II of high dose capecitabine plus irinotecan for patients with advanced or metastatic gastric cancer: preliminary results
Authors: Oh S. , Seo H. , Sung H. , Choi I. , Kim S. , Kim S. , Seo J. , Kim B. , Shin S. , Kim Y. , Kim J.
Published: March 2020

14086

Background: Capecitabine is the prodrug of 5-FU to generate maximal tumor activity in tumor site and/or improve the tolerability, has demonstrated the synergistic activity with irinotecan in some solid cancers . Previous study showed the dose intensification of capecitabine increased the response rate with comparable toxicities in metastatic colorectal cancer. We conducted this study to ascertain the efficacy and toxicity of irinotecan and high dose capecitabine combination chemotherapy for chemotherapy-naïve advanced or metastatic gastric cancer. Methods: Patients who were advanced or metastatic gastric cancer and have not received any chemotherapeutic drug except adjuvant chemotherapy, received irinotecan 130mg/m2 intravenously (i.v) for 90 min on day 1 and day 15 and capecitabine 3500 mg/day, divided two, was administered for 7 consecutive days from day1 and day 15, and this was followed by a 7-day drug-free interval. Results: 35 eligible patients were enrolled in this study from Nov/2003 to Nov/2006. 14 women and 21 men: median age 51 ys, range 27–81. A total 106 courses were administered, and median number of courses per patient was three (range, 1–8). Intent-to-treatment analysis showed the one complete response (2.9%), 13 partial responses (37.1%), 9 stable disease (25.7%), 8 progressive disease (22.9%) and 4 non-evaluable patients (11.4%). The overall response rate was 40% (95% CI: 23.5–56.5). Grade 3–4 toxicities were: neutropenia 8 (22.8%), nausea/vomiting 2 (5.7%), stomatitis 1 (2.9%), ischemic colitis 1 (2.9%), anemia 3 (8.6%), diarrhea 2 (5.7%), alopecia 3 (8.6%). Treatment related death was shown at one patient due to pneumonia. Dose intensity of irinotecan and capecitabine was 94% and 93%, respectively. Median time to progression was 4 months (range, 0.5 - 11 months), median survival duration was 8.5 months (range, 0.5 - 45 months), and median response duration was 2.5 months (range, 0.5 - 9 months). Conclusions: We suggest that irinotecan and high dose capecitabine combination chemotherapy is the tolerable regimen to advanced or metastastic gastric cancer with promising activity.

No significant financial relationships to disclose.
Capcitabine and oxaliplatin (XELOX) in the treatment of advanced gastric cancer
Authors: Quek R. , Lim W. T. , Foo K. F. , Koo W. H. , Toh H. C.
Published: March 2020

14089

Background: Effective 1st line chemotherapy that is easily delivered and tolerable is important in patients with advanced gastric cancer (AGC). This study aimed to evaluate the toxicity and efficacy of combination capecitabine and oxaliplatin (XELOX), given 3 weekly, in patients with AGC. Methods: Twenty-seven patients with AGC, were treated with XELOX at the National Cancer Centre Singapore between June 2003 and December 2005. Capecitabine was given 2000 mg/m2/day, days 1–14, and oxaliplatin was given 130 mg/m2 on day 1, every 21 days. Results: The median age was 61 years with 22% of patients ≥ 70 years. One-third of patients had ECOG 2 - 4, and 33% of patients had signet ring cell histology. Median doses of capecitabine and oxaliplatin achieved were 1500 mg/m2/day (1200 - 2400) and 130mg/m2 (80 - 130) respectively. A median of 5 cycles (range 1 - 8) of XELOX was administered. All 27 patients had toxicity assessment. Toxicities were infrequent and mild. There were 3 cases of grade 3/4 toxicities (thrombocytopenia, neutropenia and fatigue). Twenty-two patients had measurable disease for response evaluation. Complete (CR) and partial (PR) response rates were 9 and 50% respectively. Overall response rate was 59%. Chemo-naïve patients had better responses (80% vs 25%). Four of the remaining 5 patients had reduction in non-measurable disease or in tumor marker levels. Of the 9 patients with ECOG > 1, there was radiological CR in 1 patient and 5 PR; 1 had normalization of CEA, another reversal of disseminated intravascular coagulation and the third decreased ascites. The median time to progression and overall survival were 5.9 months and 7.6 months respectively. Conclusions: XELOX regimen is safe, active and well tolerated in AGC even in patients with poor ECOG status. It is easily administered without requiring a central venous catheter. This regimen should be investigated further in a prospective manner.

No significant financial relationships to disclose.
Phase II study of cetuximab in patients with unresectable or metastatic hepatocellular carcinoma
Authors: Zhu A. X. , Blaszkowsky L. , Enzinger P. C. , Bhargava P. , Ryan D. P. , Meyerhardt J. , Horgan K. , Hale K. , Sheehan S. , Stuart K.
Published: March 2020

14096

Background: Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis with no established systemic treatment regimen. Epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and ligand expression is frequently seen in HCC. Recent studies suggest that erlotinib, an EGFR/HER1 tyrosine kinase inhibitor, may have benefit in stabilizing HCC. We performed a phase II study with cetuximab, a chimeric monoclonal antibody that binds selectively to EGFR, in advanced HCC. Methods: Eligibility criteria include unresectable or metastatic measurable HCC, up to two prior systemic regimens, performance status ≤ 2, CLIP score ≤ 3, and adequate organ functions. The initial dose of cetuximab is 400 mg/m2 intravenously (IV) administered over 120 minutes, followed by weekly infusions at 250 mg/m2 IV over 60 minutes. Each cycle is defined as 6 consecutive weekly treatments. EGFR expression was assayed by immunohistochemistry and trough serum concentrations of cetuximab were determined during the first cycle. The primary endpoint of the study was progression free survival (PFS). Results: The planned 30 patients have been enrolled: median age = 58 (33–82), M/F = 23/7, ECOG 0/1/2 = 16/12/2, CLIP 0/1/2/3=2/9/14/5. No responses were seen. Five patients had stable disease. The median number of cycles on study per patient was 1 (range, 1–3). 16 patients developed progressive disease following one cycle of treatment. Only one patient remains on study. The median PFS and OS were 41 days (95% CI, 36 to 79) and 157 days (95% CI, 112 to not available), respectively. The treatment was generally well tolerated. No treatment related deaths occurred. Treatment related grade 1–2 toxicities included rash (83%), fatigue (47%), hypomagnesemia (27%), nausea (20%), anemia (13%), diarrhea (13%), anorexia (13%), and elevation of SGOT/SGPT (10%). Grade 3 SGOT, hypomagnesemia, and fever without neutropenia were seen in one patient (3%) each. Conclusions: Cetuximab has no activity in HCC in this phase II study. It can be safely given with tolerable toxicity profiles in HCC patients. Updated information on toxicity, efficacy, EGFR expression and pharmacokinetics will be presented at the meeting. Supported by Bristol-Myers Squibb.

[Table: see text]
Arsenic trioxide in patients with hepatocellular carcinoma: A phase II trial
Authors: Lin C. , Hsu C. , Hsu C. , Hsu W. , Cheng A. , Yang C.
Published: March 2020

14129

Background: Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. Methods: Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16–0.24 mg/kg/day for 5–6 days per week for 3–4 weeks followed by one-week rest. Tumor response was accessed every 2 months. Primary endpoint was percentage of patients with 6-month disease stabilization. Results: Twenty-nine patients (M/F = 24:5; median age: 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1–6). One patient had partial remission. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1–27). The median overall survival was 4.8 months (95% CI, 1.4–8.2) and one-year survival estimated by Kaplan-Meier methodology was 30%. Conclusions: Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC patients.

No significant financial relationships to disclose.
Bicarbonate-treated gastroendoscopy
Authors: Kim Y.
Published: March 2020

14138

Background: Endoscopy is the most powerful examination to detect cancer. We showed efficacy and feasibility of the bicarbonate(bC)-treated gastroendoscopy (bCGE) to the patients (Y. Kim, et al. ICACT2004, Paris, France, and Y. Kim. 2006 GI Cancers Symposium, San Francisco, CA, USA). We tried an alternative preparation, divided alkalization, to modify the bCGE to less threaten patients in the examination. Methods: Enrollment-criteria was described; age 20 to 85, Performance Status 0 to 2, and no history of lidocaine (L) allergy, no wound in the oral cavity, and no severe organ dysfunction. The alkalizing-agent was 7-% sodium-bC solution (S-bC). The divided bC-treatment was shown: gurgling and swallowing a half, 10-mL, of 20-mL S-bC divided by L application into two parts, the 1st and the 2nd alkalization. pH Levels in the left pharyngeal-arch were measured. The patients were applied a deffervescent agent orally, L sprays in the pharyngeal-arch and L gel onto the pharyngeal-wall for 5-minute, and gastrointestinal-paralyzing agents intramuscularly. The reflexes (coughing and nausea), and pulse rates (PR) of the patients were monitored in the bCGE. Results: This study analyzed 9-patient in intent-to-treat method. All patients, 100%, accomplished the bCGE with the divided alkalization. Course of pH Levels, incidence of the reflexes and increasing ratio of PR were given in the table below. The divided alkalization enhanced the L effects in the pH Levels after the 2nd alkalization depending manner. Conclusions: We found the bCGE with the divided alkalization might be effective and feasible. The pH Levels after the 2nd alkalization could be the predictive factors for the successful bCGE with the divided alkalization. [Table: see text]

No significant financial relationships to disclose.
Poorly differentiated neuroendocrine carcinoma-small cell of the gastrointestinal tract. Institutional experience
Authors: O′connor J. M. , Sade J. P. , Pairola A. , Domenichini E. , Cabanne A. , Marmisole F. , Mendez G. , Bestani C. , Chacón M. , Roca E.
Published: March 2020

14142

Background: PDNEC-Small cell (OMS Clasification, grade III)of the GI tract are rare diseases. Small cel represent 0,1% to 1% of all GI malignancies, and are included in the group of PDNEC but: Do these group behave biologically and respond to treatment in the same way? Trying to elucidate this matter, we performed a retrospective analysis of our group of pts. with PDNEC. Methods: A database search was done. from 1997 to 2005 we found 31 pts. with PDNEC/Small cell from the GI Tract treated in our Centers. A review of the clinical records was performed with special interest in response rate and overall survival. interest. Results: 14 pts. were informed by the pathologist at diagnosis PDNEC and 17 pts. as small cell. Median age: 50 years (r 19–84). The most common primary site was Esophagus-Stomach (29%), followed by pancreas 9 pts. (29%. 9 pts.(29%) presented with metastatic disease with unknown orimary Sistemic symptoms were common. A majority of our pts. (61%) presented with overt metastases. The liver was involved in 14 pts. (61%) follow by lymph nodes in 5 (16%). The most common chemotherapy used was a combination Platinum based. Overall response rate was 43%. TTP for all pts were 7 months (95% IC 0.34–0.69). Overall survival was 12 months (95% IC 0,31–0,70). We observed differences in term of overall survival and TTP in favor of PDNEC (15 months vs 10 months and 8 vs 4 months respectively) pNS. Conclusions: PDNEC-Small cell had bad prognosis. In our Serie we found differences between both groups, although not statiscally significant (due to a low number of patients). Definitive data of treatment for the management of this group of pts. still lacks.

No significant financial relationships to disclose.
Response to the combination of thalidomide and capecitabine as second-line therapy in pancreatic carcinoma after treatment and failure with gemcitabine
Authors: Beganovic S. , Loesh D.
Published: March 2020

14150

Background: A literature search shows only one published case report utilizing the combination of thalidomide and capecitabine as second-line therapy in adenocarcinoma of the pancreas. We report two patients with pancreatic carcinoma treated as second-line therapy with this combination. Methods: CASE #1: Fifty five-year-old female with metastatic pancreatic carcinoma demonstrated clear evidence of progression after 8 months of treatment with gemcitabine At this time, she was started on thalidomide 50 mg at bedtime every other night with capecitabine 1500 mg p.o. b.i.d. for two weeks with one week off. After eight weeks of this regimen, the patient had clinical response with a decrease in abdominal pain, improvement in performance status, and a decrease in her CA 19–9 from 1154 units/mL to 101 units/mL. With this treatment the patient was fully ambulatory and without symptoms for 7 months. CASE #2: The patient is 55-year-old male treated with adjuvant radiation therapy and chemotherapy after surgical resection of his adenocarcinoma of the pancreas. Eight months later, he developed hepatic metastasis and was treated with gemcitabine with progression of disease on that agent. Palliative treatment with capecitabine 1500 mg p.o. b.i.d. for two weeks and one week off was instituted with thalidomide 50 mg at bedtime every other day. After four months of this regimen, the patient had a clinical response with no abdominal pain and decrease in his CA 19–9 from 4647 units/mL to 55 units/mL. Ten months after initiation this regimen patient is asymptomatic, working full time and continues to take thalidomide and capecitabine. Conclusions: Response to second line therapy in adenocarcionoma of pancreas is rare. We are reporting two cases of second-line therapy of adenocarcinoma of the pancreas treated with the combination of thalidomide and capecitabine. Decline in CA 19–9, duration of response, and improvement in functional patient status were unexpected findings. Use of combination of capecitabine and thalidomide in the treatment of the pancreatic adenocarcinoma should be evaluated further in clinical trials.

No significant financial relationships to disclose.
Effect of anti-inflammatory therapy in patients with metastatic renal cell carcinoma on clinical response
Authors: Reichle A. , Grassinger J. , Bross K. , Wilke J. , Suedhoff T. , Berand A. , Wieland W. , Andreesen R.
Published: March 2020

14500

Background: Interaction among signalling networks from tumor and neighbouring stroma cells in complex disease traits is poorly understood. Methods: Two consecutive multi-centre phase II trials were designed (case calculation according response rate, T. Chen two stage design) to prove the hypothesis, whether the activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone, and interferon alpha, IFNa) could result in synergistic clinical effects. Therapy in both trials consisted of low-dose capecitabine 1 g/m2 twice daily po for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily, day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily, day 1+. In study II low-dose IFNa 4.5 MU sc three times a week, week 1+, was added until disease progression. Results: Eighteen, and 33 patients (pts, 31 eligible for analysis), respectively, with clear cell carcinoma, progressive disease, and ECOG 0–2 were enrolled between 2/02 to 2/03 and 4/03 to 4/05, respectively. Mean Bradley score in both trials was not significantly different, 4.1(I)/4.9(II), however, the rate of previous systemic treatments 33%/19%. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response (after 4 weeks on treatment) in all 29 pts with elevated CRP levels (93%) (study I: no significant CRP response): CRP values decreased from mean 41.3 mg/l, range 8.1 to 221, to 5.1 mg/l, range 2.1 to 15.6, p = 0.005. Stable disease > 2 months (mos) occurred in 50%/48%. Median progression-free survival could be more than doubled from a median of 4.7 mos (95% CI, 1.0 to 10.4) to 11.5 mos (6.8 to 16.2) in study II, p = 0.0000. Median overall survival of population II has not been reached, yet. Toxicities > WHO grade II were reported (study I/II): Hand-foot syndrome (3/3), diarrhoea (2/2), depression (0/1), pneumonia (0/1). Conclusions: (1) Clinical results of anti-inflammatory/angiostatic therapy compare with available immuno-therapies. (2) Improved outcome with additive IFNa argues for a synergistic drug interaction. (3) Control of tumor-associated inflammation is an important therapeutic principle in metastatic clear cell carcinoma.

No significant financial relationships to disclose.
Combination therapy with docetaxel (D) and celecoxib (C) in patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: Kasimis B. , Chang V. , Cogswell J. , Sambamoorthi N. , Gonzalez M. , Srinivas S. , Zhong F. , Morales E. , Duque L. , Blumenfrucht M.
Published: March 2020

14519

Background: Cox-2 expression is an independent predictor of survival and is over expressed in 89.3% of pts with HRPC. Cox-2 expression has angiogenic and cytoprotective effects. Its suppression could lead to angiogenesis inhibition and increase chemotherapy sensitivity. D in low doses and C are angiogenesis inhibitors. The main objectives were to study the effects on PSA, time to progression (TTP), toxicity and survival. Methods: In a two stage, phase II trial designed for 66 pts, 30 pts with HRPC and evidence of biochemical and radiographic progression were treated with D 30 mg/m2 IV/wk for 3 wks and C 400 mg po bid for 4 wks of each cycle. Response evaluation after every two cycles was made. RECIST criteria and PSA reduction by >50% for biochemical response were used. Independent safety monitoring for renal (R) and cardiovascular (CV) toxicity were made. Results: Thirty (30) evaluable pts received minimum of 2 cycles, median (M) 4.5 (range 2–8). The M age was 74 yr (55–94), ECOG PS 1 (0–2), Hb 11.8 g/dl (8.6–14.6), and PSA 92.5 ng/dl (15.3–4192). Metastases were present in 24 pts (80%) by bone scan and 25 pts (83.3%) by CT scan. Twelve (12) pts (40%) had PSA response of >50% and 4 pts (13.3%) had PSA normalization. By CAT scan, 3 pts (10%) had CR, 5 pts (16.7%) had PR, and 12 pts (40%) had SD. By bone scan 1 pt (4.8%) had a major response. The M TTP by PSA was 3.65 mos (0.87–12.0). With 27% pts still alive, the M survival was 10.9 mos (3.0– 30.7+), with 95% CI for the mean (9.3–15.2). One pt (3.3%) withdrew due to abdominal discomfort, 2 pts (6.6%) had grade III diarrhea and 1 pt (3.3%) had grade III nail toxicity. Conclusions: 66.7% pts had soft tissue response (CR+PR+SD), and 13.3% pts had PSA normalization. Safety analysis for R and CV toxicity demonstrated excellent safety of this regimen. Considering the unfavorable prognostic indicators of this population the MST of 10.9 mos indicates the activity of this combination.

[Table: see text]
USP2a is an oncogenic isopeptidase and a potential target in prostate cancer
Authors: Priolo C. , Tang D. , Brahmandam M. , Benassi B. , Sicinska E. , Ogino S. , Farsetti A. , Porrello A. , Febbo P. G. , Zimmermann J. , Loda M. F.
Published: March 2020

14522

Background: De-ubiquitinating enzymes (isopeptidases) remove ubiquitin side chains prior to degradation by the proteosome thus stabilizing their protein targets. We have identified a novel androgen regulated isopeptidase, USP2a, and demonstrated that it binds and prolongs the half-life of fatty acid synthase (FAS), a key enzyme in lipid metabolism of tumor cells. Methods: We determined whether USP2a has oncogenic properties in vitro and in vivo. Wild-type and catalytically inactive USP2a were introduced in immortalized normal prostate epithelial cells (AR-iPrECs). Clonogenicity assays and apoptosis induction by chemotherapeutic agents were performed on these cells. Anti-USP2a siRNA were transfected in normal and transformed (LNCaP, DU145 and PC-3) prostate cell lines. Oncogenicity in vivo was shown by s.c. injection of NIH3T3-USP2a cells in nude mice. Furthermore, USP2a mRNA expression and gene microarrays were tested in 52 human prostate adenocarcinomas. Results: Wild-type USP2a overexpression in AR-iPrEC cells resulted in a significant increase in number and size of colonies compared to those obtained in parental cells. Growth in soft agar was significantly enhanced as well. Silencing of USP2a in LNCAP and DU145 cells resulted in a strong apoptotic effect, evaluated by FACS analysis and cleaved-PARP expression. The role of this isopeptidase in apoptosis regulation was confirmed on AR-iPrEC-USP2a cells, that showed resistance to apoptosis induced by cisplatin and taxol. Importantly, USP2a overexpression was able to transform NIH3T3 cells, generating greater than or equal to 0.5 cm subcutaneous tumors in 12/12 nude mice within 3 weeks, while none of the negative controls grew. USP2a mRNA was overexpressed in 39% of human prostate cancers, showing 1.6–104 (median 5.48) fold induction relative to normal tissues by qRT-PCR. Gene expression profiling of the same tumors revealed specific signatures in USP2a-overexpressing tumors. Conclusions: Our results demonstrate that USP2a behaves as an oncogene in vitro and in vivo and is overexpressed in organ-confined prostate cancer. These data strongly suggest that this isopeptidase is a potential drug target in prostate cancer.

[Table: see text]
Treatment outcomes of patients (pts) with primary mediastinal germ cell tumors (PMGCT): The M. D. Anderson Cancer Center (MDACC) experience
Authors: Rodney A. J. , Siefker-Radtke A. , Tannir N. M. , Swisher S. , Walsh G. , Millikan R. E. , Pagliaro L. C.
Published: March 2020

14538

Background: PMGCT are uncommon germ cell malignancies. Mediastinal nonseminomatous germ cell tumors (NSGCT) have a poor prognosis, whereas pure seminoma (Sem) has a good or intermediate prognosis irrespective of mediastinal presentation. Methods: We retrospectively identified 19 male pts with PMGCT seen at MDACC between October 1998 and September 2004 from a clinical database. Pts with resectable NSGCT were offered surgery upon plateau of their chemotherapy response. Prior to referral, 1 pt had primary surgical resection without preoperative (preop) chemotherapy. Results: There were 14 pts with NSGCT and 5 with good prognosis Sem. The median age was 29.5 (20–60). Seven pts with NSGCT had mixed or undifferentiated histology, and the remainder had pure yolk sac (5 pts) or choriocarcinoma (2 pts). The estimated median survival (Kaplan-Meier) for all patients (Sem + NSGCT) was 21 months. All pts with Sem were alive and disease-free at last follow-up (median 12 months, range 7–34). All pts with Sem received 4 courses of etoposide and cisplatin (EP); one also received bleomycin (BEP); one received radiotherapy consolidation; none received surgery. Of the pts with NSGCT, 9 (64%) have died, including 1 who refused surgery. Five pts with NSGCT were alive at last follow-up and 3 (21%) were disease-free (15+, 27+ and 35+ months). Four pts with NSGCT (29%) reached beyond 2 years survival (27+, 28, 35+, and 63+ months) including 3 with lung metastases and one with elevated preop alpha-fetoprotein (28,022 ng/ml). Each of these pts received 6–10 courses of multiple-regimen preop chemotherapy, and 2 received initially 4 courses of BEP without marker normalization. Conclusions: Mediastinal Sem treated with 4 courses EP had an excellent outcome without surgery. Pts with mediastinal NSGCT had a 64% mortality rate despite aggressive treatment. Several pts with mediastinal NSGCT did achieve long-term survival following aggressive chemotherapy and surgery, even with lung metastases and failure to normalize markers. A phase III trial of BEP versus dose-dense chemotherapy for poor-prognosis NSGCT is now in progress at MDACC.

No significant financial relationships to disclose.
Pilot study of VHL mutation analysis to predict response to interleukin-2 in patients with metastatic renal cell carcinoma
Authors: Pantuck A. J. , Fergelot P. , Patard J. , Lam J. , Belldegrun A. S. , Figlin R. A.
Published: March 2020

14539

Background: More than 300 different mutations have been described in von Hippel-Lindau (VHL) families and nearly 100 in sporadic RCC. In familial cases, there is an excess of mutations in exon 3 and exon 1, whereas mutations are evenly distributed in sporadic cases. Recent evidence suggests the importance of genotype/phenotype correlations with different VHL gene mutations contributing to a tumor’s unique biological behavior. We performed a pilot study to compare the incidence and type of VHL mutation in IL-2 complete responders (CR) and non-responders (NR). Methods: Genomic DNA was extracted from 20 frozen clear cell tumour samples (10 CR and 10 NR) using Qiamp DNA mini kits (Qiagen). Four amplimers covering the entire coding sequence and three exon/intron junctions of the VHL gene were synthesized by PCR. PCR products were subsequently purified and were sequenced using Big Dye Primer Cycle Sequencing kit (Perkin-Elmer Applied Biosystems) and an automated DNA sequencer (Perkin-Elmer Applied Biosystems). Point mutation detection was performed on DNA sequencing gels from colored peak chromatograms. Mutation bearing sequences were confirmed by a second round of PCR and sequencing. Results: In the CR patients, only 2 out of 10 samples (20%) had evidence of a VHL mutation. These VHL mutations included a false sense mutations in exon 2, comprised of a C to T transition at position 646 in the cDNA, creating a stop codon, and a frameshift mutation in exon 1 introducing in one allele an abnormal stop codon at the beginning of exon 3 potentially leading to a shorter protein product. In the 10 non-responder samples, there was also a 2 out of 10 (20%) incidence of VHL mutations. These mutations included a complex 12 nucleotide deletion in the third exon in the a domain of the protein, and a G deletion in the first exon introducing a premature stop codon. Conclusions: In this small pilot study of metastatic RCC patients, there were relatively few VHL gene mutations, and VHL mutations did not appear to correlate with response to IL-2 therapy. This study, however, does not assess inactivation of VHL genes due to hypermethylation. An expanded genetic profile to evaluate IL-2 responders versus non-responders using 500k SNP Chips is underway.

No significant financial relationships to disclose.
The role of androgen ablation with low dose rate brachytherapy in the treatment of prostate cancer
Authors: Jani A. B. , Shoushtari A. , Feinstein J.
Published: March 2020

14546

Background: We report a single-institution analysis of the role of androgen ablation (AA) with low-dose rate brachytherapy. Methods: A cohort of 189 consecutive patients (AA: n = 68, no-AA: n = 121) receiving brachytherapy (iodine-125: n = 125; palladium-109: n = 64) at our institution who had demographic (age), disease (T-stage [T1–70%, T2–28%, T3–2%], Gleason Score [median score 6], PSA [median-7.7 ng/mL]), and treatment (isotope, dosimetric endpoints, use of supplemental external beam radiotherapy [EBRT, administered as 45 Gy/1.8 Gy to the pelvis using 4-field technique with isocentric prescription]) information available, and a minimum of 2 years of follow-up available, constitute the analysis study group (median follow-up - 4.0 years). This cohort was divided into 2 major groups based on the use of AA (leuprolide 22.5 mg IM injection(s) 3–6 months [mean 4.0 months] prior to brachytherapy). Using 2 successive PSA rises > 1 ng/mL as the failure definition, biochemical failure-free survival (BFFS) curves were constructed and compared using the logrank test; additionally, multivariate analysis of all major patient and treatment factors was performed using the Cox proportional hazards model. These analyses were done for the whole cohort as well as for subgroups defined by the use of EBRT and for subgroups of patients with low-, intermediate-, and high-risk prognostic factors (defined as the basis of 0, 1, or ≥ 2 prognostic factors [PSA > 10 ng/mL, Gleason score > 6, T-stage > T2a], repectively). Results: The 4-year BFFS in the AA vs no-AA groups was 76 vs 70% (p = 0.230) for the whole cohort, 75 vs 62% (p = 0.182) for EBRT patients, and 75 vs 82% (p = 0.764) for no-EBRT patients. For the whole cohort, the use of EBRT was the only factor reaching significance on multivariate analysis (p = 0.040). When analyzing the EBRT and no-EBRT subgroups separately, no factor, including AA, reached significance on multivariate analysis. 4Y-BFFS of the AA vs no-AA subgroups were 82 vs 76% (p = 0.236) for the low-risk, 76 vs 70% (p = 0.437) for the intermediate-risk, and 75 vs 70% (p = 0.185) for the high-risk subgroup. Conclusions: In our study, short-course AA conferred no significant biochemical control advantage when added to low-dose rate brachytherapy overall or for any subgroup based on prognostic risk.

No significant financial relationships to disclose.
Testicular ultrasound (TU) screening in men from familial testicular cancer (FTC) kindreds
Authors: Korde L. A. , Premkumar A. , Kramer J. L. , Linehan W. , Pfeiffer S. , Bratslavsky G. , Greene M. H.
Published: March 2020

14547

Background: A family history of testicular cancer (TC) is associated with a 2- to 10-fold increase in TC risk. Specific abnormalities of the urogenital tract (e.g., cryptorchidism, inguinal hernia) also increase risk. The association between testicular microlithiasis (TM) and testicular intraepithelial neoplasia (TIN) has suggested that the former may be a TC risk factor. The finding of inhomogenous echotexture on ultrasound has also been associated with an increased risk of TIN. In this study, we evaluate ultrasongraphic abnormalities in men with a history of TC and their kindreds. Methods: We analyzed testicular ultrasounds (TU) from 45 FTC cases and 35 unaffected male relatives, drawn from 31 multiple-case FTC families. TU were performed between January 2003 and November 2005 as part of an NCI multidisciplinary etiologic study of FTC. All studies were reviewed by a single radiologist. Results: We found no incident TC. Five focal lesions were seen. Three were thought to be cysts and 2 required further follow-up. The frequency of varicocele and epididymal cyst was similar in both groups. Hydrocele was seen in 7 (16%) cases and 3 (9%) unaffecteds (OR = 2.0; 95% CI = 0.5–8.3). Inhomogenous testicular parenchyma was noted in 12 (27%) cases and 3 (9%) unaffected family members (OR = 3.9; 95% CI = 1.0–15.0). TM was seen in 20 subjects [15 (34%) cases and 5 (14%) unaffecteds, OR = 3.1; 95% CI = 1.0–9.6]. An additional 10 subjects (7 cases, 3 unaffecteds) had calcifications that did not meet diagnostic criteria for TM. The finding of TM was confined to 13 of the 31 families. In 6 of these 13 families, 2 or more subjects had TM. Conclusion: A number of genitourinary conditions were more common in FTC cases than in unaffected blood relatives, providing support for the testicular dysgenesis hypothesis related to TC etiology. TM was found in a high proportion of cases and in a smaller proportion of unaffecteds. In this small series, TM appeared to cluster in families. If validated, these findings could have important implications for both screening and follow-up of FTC families.

No significant financial relationships to disclose.
Predicting the pathology of post-BCG lesions
Authors: Blitstein J. , Macchia R.
Published: March 2020

14573

Background: This study evaluated the accuracy of office cystoscopy and urinary cytology in predicting the histopathology of post-BCG bladder lesions. Methods: A retrospective chart review was performed of all patients who had received intravesical BCG at two Veteran Affairs Hospitals from July 1995 to July 2005. The initial pathology, the post-treatment cystoscopy findings, urinary cytology and post-BCG biopsy were correlated. Results: A total of 136 biopsies from 64 patients who had received 79 courses of BCG were reviewed. The mean time to the first repeat bladder biopsy and to the first recurrence was 8.8 months and 11.7 months, respectively. During the study, 83% of patients developed recurrence. Malignancy was confirmed in 61% of all biopsies. For all lesions, cytology alone had a sensitivity of 53.7%, specificity of 90.5%, PPV 85%, NPV 47%. The biopsy was positive in 84% of patients with visible papillary lesions and a negative cytology. Improved accuracy was seen in papillary lesions with a positive cytology; 94% positive biopsy. The bladder biopsy was positive in 91% of patients with erythema and a positive cytology in comparison to 9.5% of patients with erythema and a negative cytology. Conclusions: There is controversy regarding the necessity of obtaining transurethral biopsies of erythematous lesions in patients who have undergone intravesical BCG therapy. Combining the cystoscopic findings and the urine cytology increases the ability to delineate BCG effect from recurrence. This study suggests that patients with post-BCG erythematous patches and a negative cytology can avoid an unnecessary transurethral bladder biopsy. This study also demonstrates that most BCG failures occur after the traditionally believed 3-month evaluation.

No significant financial relationships to disclose.
Looking for new targets for prostate cancer therapy: Nuclear factor kappa B and CXCR4 co-expression in prostate specimens from RTOG-8610
Authors: Bernstein E. D. , Bae K. , Baldridge L. A. , Zhang S. , Cheng L. , Wolkov H. , Pilepich M. , Dicker A. P. , Sweeney C. J.
Published: March 2020

14578

Background: The transcription factor Nuclear Factor-kappa B (NFκB) promotes the production of angiogenic, anti-apoptotic and prometastatic factors that are involved in carcinogenesis. The chemokine receptor CXCR4, which is under the control of NFκB, has been implicated in regulating metastasis of breast, pancreatic, and prostate cancer. This retrospective cohort study evaluated the frequency and co-expression of NFκB and CXCR4 in human prostate cancer specimens. Methods: Paraffin embedded samples from a subset of patients in the RTOG 8610 trial underwent immunohistochemical staining for NFκB and CXCR4. This study compared radiotherapy plus hormonal therapy to radiation therapy alone. The amount of NFκB and CXCR4 was scored by a blinded pathologist for the percentage of cells stained (0 to 100%) and staining intensity (0 to 3+). Results: NFκB and CXCR4 status was determined for 55 and 63 patients, respectively. Both NFκB and CXCR4 status were available for 51 of these patients. Of these, 51% were 2/3+ for NFκB and 61% were 2/3+ for CXCR4. There was a trend towards correlation between CXCR4 and NFκB staining as 18 of the 36 patients who were 2/3+ positive for NFκB were 2/3+ for CXCR4. 10 of the 11 pts with 3+ NFκB had 2/3+ CXCR4. This was consistent with the understanding that CXCR4 is regulated by NFκB, but did not reach statistical significance (p = 0.1298). Neither NFκB or CXCR4 were statistically significantly prognostic factors in this small subset of patients. Conclusion: NFκB and CXCR4 are expressed in a significant number of patients with organ confined prostate cancer. Neither predicted outcomes in this analysis, which may be due to the small sample size. This data supports the notion that NFκB regulates CXCR4 expression in prostate cancer and that one or both may be potential new targets for therapeutic intervention. Studies in larger prospective studies to determine the utility of NFκB and CXCR4 as predictive biomarkers and/or therapeutic targets is warranted. [Table: see text]

No significant financial relationships to disclose.
A phase II study utilizing oxaliplatin and docetaxel in androgen independent prostate cancer in men treated with up to two prior chemotherapy regimens
Authors: Feinstein T. M. , Friedland D. M. , McIntire K. E. , Jacobs S. A. , Ferri W. A. , Earle M. F. , Hyoung K. D. , Brown L. M. , Chatta G. S.
Published: March 2020

14580

Background: Second line treatment of androgen independent prostate cancer (AIPC) is unsatisfactory. Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase-I study utilizing oxaliplatin at the University of Pittsburgh (UP), two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of docetaxel and oxaliplatin may be synergistic in AIPC. Methods: This single arm phase II trial commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. Using Simon stage II design, a total of 37 patients (pts) with AIPC will be accrued. To date, 20 men have been enrolled: median age 67 yrs (56–84); 9 patients being chemo-naïve and 11 having received prior chemotherapy. Treatment consisted of docetaxel (60 mg/m2) and oxaliplatin (110 mg/m2), infused every 21 days. Follow-up assessments (every two cycles) include serum PSA and imaging studies. Results: 14 of 20 men have completed at least two cycles and are evaluable. In the chemo-naïve subset (n = 8), the average pre-treatment PSA was 312.8 ± 275.8 ng/ml, with 3 of 8 pts experiencing > 50% reduction in PSA and 2 of 8 pts with > 25% reduction. In pts with prior chemotherapy (n = 6), the average pre-treatment PSA was 1194.4 ± 1777.8 ng/ml, with 3 of 6 pts experiencing > 50% reduction in PSA and 1 of 6 pts with > 25% reduction. 4 of 8 men with measurable soft tissue disease had a partial response. There were < 7% grade 3/4 adverse events (AEs). Treatment-related AEs include: neutropenia (41%), thrombocytopenia (11.8%) and anemia (5.9%). Non-hematologic toxicity included neuropathy (53%) diarrhea (47%), nausea (41%) fatigue (76%) and anorexia (29.4%). Conclusions: The combination of oxaliplatin and doxetaxel is well tolerated in patients with AIPC, and has significant activity even in patients with prior exposure to chemotherapy. The study continues to accrue pts, and the results will be updated at presentation.

[Table: see text]
Rapamycin for androgen-independent prostrate cancer (AIPC)
Authors: Sharef S. , Jac J. , Khan M. , Amato R. J.
Published: March 2020

14584

Background: Genetic alterations targeting the PTEN tumor-suppressive gene are among the most frequently noted mutations in human cancers. Prostate cancer has been reported as a PTEN-null cancer. Absence of functional PTEN in cancer cells leads to activation of downstream components of the P13K pathway, including the Akt and mTOR kinases. Drug targeting of these kinases might have significant therapeutic activity in PTEN-null cancers. Rapamycin has been reported to inhibit metastatic prostate tumor growth and angiogenesis in in vivo mouse models. This clinical trial is designed to assess the anti-tumor activity, toxicity and the clinical relationship between tissue and plasma levels of vascular endothelial growth factor and tissue microarray for PTEN tumor-suppressive gene. Methods: Eligibility included: a minimum of 2 consecutive rises in prostate-specific antigen (PSA), with or without radiographic evidence of disease, castrate levels of serum testosterone (≤ 50 ug/l), anti-androgen withdrawal, no more than 2 prior therapeutic regimens, Zubrod performance status of ≤ 2 and adequate organ/marrow function. The initial dose of Rapamycin is 0.15 mg/kg followed by 0.04 mg/kg daily without interruption. Rapamycin levels are obtained every 28 days with a dose adjustment of 0.04 to 0.06 mg/kg in order to maintain a level between 6–10 ng/ml. Results: To date, 12 patients (pts) have been enrolled. 2 pts have demonstrated a definitive change in their PSA velocity, 1 pt > 40% regression in their absolute PSA. 2 pts with measurable disease have demonstrated regression of < 20%. Toxicity consisted of grade 1/2: fatigue, mucositis, elevated transaminases, diarrhea and rash. 1 pt continues to receive Rapamycin. Median duration of Rapamycin is 32.5 weeks (4–40+). Conclusion: Rapamycin has been well tolerated with signs of anti-tumor activity observed. Information regarding PSA response and time to progression in association with Rapamycin level will be presented.

[Table: see text]
Quality of life in intermediate or high risk prostate cancer patients treated by 3-D external beam radiotherapy and brachytherapy with or without androgen deprivation
Authors: Guix B. , Lacorte T. M. , Guedea F.
Published: March 2020

14587

Background: To elucidate long-term changes in health-related quality-of-life (HRQOL) outcomes by prospectively re-evaluating a cohort of intermediate- or high-risk prostate cancer patients treated by a combination of 3-D External Beam Radiotherapy (EBRT) and Brachytherapy (BT) with or without androgen deprivation (AD). Methods: A cross-sectional survey was administered to 200 consecutive patients with intermediate (Gleason 7 or PSA 10–20 or T2A-B) or high (Gleason >7 and/or PSA >20 and/or >T2B) - Risk Prostate cancer who were treated by EBRT to the prostate followed by BT to the prostate given either by permanent 125-I seeds (LDR) or high dose rate (HDR) implants before treatment and at 6 months interval during 4 years follow-up. The EORTC CLQ-C30 with the PR-25 module was employed. HRQOL was compared among therapy groups. Comparisons between therapy groups was performed using regression models to control covariates. HRQOL of treatment parameters were evaluated. Distribution of responses for bowel-, urinary- and sexual-related functions were analyzed. Results: 200 patients completed the questionnaires. Significant changes in HRQOL were found depending of the time after treatment. After a temporal decline in HRQOL, an improvement owas found during the first 18 months after end of treatment. Significant improvement in the urinary irritative-obstructive performance (p < 0.006) was found after 6 months post-treatment. Bowel domains worsened after therapies (p < 0,05) but improved after 18 months follow-up (p < 0.02). Overall sexual HRQOL deteriorated depending greatly on treatment (p < 0.008). Patients who were given AD presented a significant lower Sexual Function values, that were difficult to recover after AD cessation (p < 0.007). No differences in HRQOL were found between LDR or HDR BT implants. Satisfaction with either treatment was high. Conclusions: After a decline in HRQOL after treatment, it recovered fully during follow-up. In patients treated by AD, sexual function was the most adversely affected quality-of-life domain. Sexual impairment induced by AD was difficult to recover. These results may be of assistance to men and to clinicians when making treatment decisions, mainly relating AD.

No significant financial relationships to disclose.
Retrospective study of patients with advanced upper urinary tract transitional cell carcinoma (UUT-TCC)
Authors: Dufresne A. , Fléchon A. , Pommier P. , Droz J.
Published: March 2020

14611

Background: UUT-TCC is a rare disease with poor prognosis. The aim of the study was to review retrospectively the outcome of 66 patients treated in a single cancer center. Methods: Clinical records of patients treated between 1993 and 2005 were reviewed to identify treatment modalities and outcome. Results: There were 47 (71%) males, median age was 60 years (range: 40–85) and UUT-TCC was associated with superficial bladder cancer in 14 (21%) patients. Forty-one patients had pT2–4 pN0–2 M0 disease after radical nephro-ureterectomy. Adjuvant treatment was: none for 25 patients, chemotherapy for 6 patients, radiotherapy for 1 patient, chemotherapy then radiotherapy for 9 patients. Twenty-seven patients relapsed after a median time interval of 12 months (range: 2–88). Fifty-two patients had metastatic disease (25 at initial diagnosis and 27 after relapse). Respectively 19 and 33 patients had one or multiple metastatic sites. Sites of metastases were: local in 12 patients, retroperitoneal lymph nodes in 30, liver in 23, lung in 19 and bone in 15. Thirty-six patients received platinum-based chemotherapy, 10 received palliative radiotherapy, 5 received best supportive care, and 1 had surgery. Response rate to chemotherapy was 40% with median response duration of 5.5 months (range: 0.2–18.5). Overall survival was 14.6 months. Conclusion: UUT-TCC has a worse prognosis than bladder TCC. However response to chemotherapy and overall survival seem worse than in metastatic bladder cancer.

No significant financial relationships to disclose.