bluuebunny/crossref_metadata_2025 huggingface dataset:
Thalidomide in patients with advanced hepatocellular carcinoma: A clinical/biological study
Authors: Fazio N. , Petralia G. , Mancuso P. , Lorizzo K. , Jemos C. , Boselli S. , Porcu C. , Bertolini F. , Bellomi M. , de Braud F.
Published: March 2020

15076

Background: thalidomide has been reported to have anti-angiogenic properties and therefore has been studied in several hypervascularized cancers. We evaluated the effect of thalidomide on progression-free survival (PFS) and several surrogate markers of angiogenesis in patients (pts) with advanced hepatocellular carcinoma (HCC). Methods: from June 2005 to November 2006, 19 out of the foreseen 24 HCC pts were treated with oral thalidomide 200 mg/day continuously. All of them had cytological/histological diagnosis of HCC, with no indication for curative treatment. Prior treatment was allowed. Six-month PFS was the main clinical endpoint. Perfusion parameters (Blood Flow -BF-, Blood Volume -BV-, Permeability Surface -PS-, and Mean Transit Time -MTT-) were measured with perfusion Computed Tomography (CTp). Circulating endothelial cells (CEC), progenitor cells (CEP), and apoptotic CECs, were measured by flow cytometry. Results: Eleven pts were HCV-positive and 4 HBV-positive. Eighteen had cirrhosis (80% Child-Pugh A). Five pts had extra-hepatic metastases. The maximum CLIP value was 3, in 5 pts. Six-month PFS was 41%. Constipation and somnolence were the most common G2–3 toxicities, occurring in 50% and 18% of pts, respectively. Three pts stopped treatment because of toxicity (one oedema, one neurotoxicity, and one suspect intratumoral bleeding). Baseline BF and BV of HCC were significantly higher (p<.05) for the background liver in 18 evaluable pts. BF and BV remained quite stable at six months in the 7 pts free of progression, whereas they increased at the time of progression in the 9 pts with progression within 6 months. The baseline BV in the 7 pts free of progression at 6 months was significantly lower compared with that of pts progressive within 6 months (p=0.03). Seven out of 9 pts who underwent both perfusional and circulating evaluations are currently evaluable at 2 months (2 too early). BF and BV showed an inverse trend with respect to CECs in the 4 pts with PD. Pharmacokinetics and QoL evaluation is ongoing. Conclusions: thalidomide may prolong PFS in pts with advanced HCC, with manageable toxicity. CTp and CECs detection could be used to assess the antiangiogenic drug activity, but it requires further studies to be confirmed. The BV grade could be studied as a predictive factor

No significant financial relationships to disclose.
Clinical significance of ERas oncogene on cancer
Authors: Yasuda K. , Yashiro M. , Sawada T. , Ohira M. , Hirakawa K.
Published: March 2020

15083

Background: Embryonic stem (ES) cells are pluripotent cells derived from early mammalian embryos. When ES cells are subcutaneously injected into immunodeficient or isogenic mice, a teratoma is formed within a few weeks. This tumor is composed of all three germ layers in a disorganized fashion. Thus there could be some common molecular mechanisms shared by ES cells and somatic cancer cells. The ERas oncogene is a recently identified gene that supports the tumorigenic growth of ES cells by producing a constitutively active Ras protein. There have been no report about expression of ERas oncogene on cancer cells until now. The aim of this study is to investigate expression and clinical significance of ERas oncogene on cancer cell lines and clinical cancer tissues. Methods: A panel of 35 human cancer cell lines, 5 normal cell lines, and 20 patiants with gastric cancer tissues were used in this study. ERas mRNA expression was examined by reverse transcription-polymerase chain reaction. The effect of the DNA methyl transferase inhibitor, 5-aza-2’- deoxycitydine on the ERas expression was analyzed. Methylation of CpG islands of ERas promoter lesion was investigated using bisulfate-directsequence analysis. Results: Expression of ERas mRNA was not found in any normal cells. In contrast, ERas mRNA was found in 15 of 35 cancer cell lines, including 8 of 15 gastric cancers, 4 of 7 colorectal cancers, 2 of 6 pancreas cancers, 1 of 3 breast cancers and none of esophageal cancers. Eras mRNA was found in all gastric cancer tissues, but not normal tissues. 5-aza-2’-deoxycytidine treatment at 2, 5, and 10μM for 24 h resulted in ERas expression in 10 of 20 cancer cell lines with respect to the silencing of ERas, including 7 of 7 gastric cancers, 1 of 3 colorectal cancers and 2 of 3 breast cancers. Methylation of CpG island were found in the cancer cell lines without ERas expression, but not in these with ERas expression. Conclusions: ERas oncogene is associated with the carcinogenesis pathway in human cancer. Eras might be useful marker for cancer diagnosis.

No significant financial relationships to disclose.
Neoadjuvant and combined chemoradiotherapy followed by surgery in locally advanced esophageal cancer: A single-centre experience
Authors: Diaz R. , Reynes G. , Tormo A. , Segura A. , Santaballa A. , Ponce J. , Giménez A. , De Juan M. , Artes F. , Fleitas T.
Published: March 2020

15086

Background: Concomitant chemoradiotherapy (CT-RT) with CDDP-5FU CT is a standard treatment in locally advanced esophageal cancer (EC). Long-term results are poor. The role of neoadjuvant CT (nCT) and of radical surgery after CT-RT is unclear. Methods: Single-institution, prospective trial in pts with stage II-IVA EC (TNM). PS 0–1. Staging: CT scan, barium x-ray, esophagoscopy and endoscopic ultrasound. Treatment schema: 1 cycle of neoadjuvant CT (CDDP 100 mg/m2 d1 and 5-FU 1,000 mg/m2/24 h d1–5); after 21 days, 50 Gy of RT (1.8 cGy/day, M to F) and 2 cycles of reduced-dose CT (CDDP 15 mg/m2 d1–5 and 5-FU 800 mg/m2/24 h d1–5, q21 days). In pts deemed resectable, surgery was done after 4–6 weeks. In the remainder, a 10 Gy boost was given with 1 cycle of modified CT. Primary endpoint: clinical and pathological response rate (RR) after 1st phase. Secondary endpoints: OS and toxicity rates. Results: 71 pts accrued between 1998 and 2006. Median age 61 yrs (r 44–80). 96% males. 85% squamous cell carcinomas. Middle third: 51%; upper third: 27%; lower third 22%. Gastric involvement: 11%. cT3: 46%, cT4: 28%. cN positive: 48%. Grade 3–4 toxicity with nCT and CT-RT: mucositis (9 and 19.5%), emesis (9 and 9%) and infection (6 and 9%). Full dose CT-RT: 87%. Clinical RR after 1st phase: CR 50%, PR 25%, SD 9%, PD 7%. Confirmation (CT- biopsy): 69%. Surgery: 30%. Reasons for no surgery: comorbidity (11%) and age (10%). Pathologic RR: CR 39%, microscopic rest 39% and macroscopic rest 22%. Downstaging 50%. No pN positive. 3 pts had unresectable disease. 62% received 2nd phase RT boost, 31% with CT. Clinical RR: CR 69%, PR 6%, PD 25%. Median follow-up 50 m (r 6–129 m). Median OS 10.5 m (r 7.4–12.8 m). 4-year OS of 18%. 47% deaths due to progression, 5% treatment-related deaths and 10% in the postoperative period. Only a clinical CR after 1st phase was found to improve OS (13.5 vs 7 m, p 0.0141). Conclusions: This regimen is well tolerated and offers a high response rate. Clinical response evaluation overestimates the pathologic response rate. In our series, the possible survival benefit of surgery is offset by the postoperative death rate.

No significant financial relationships to disclose.
Comparison of gross tumor volume delineated by anatomic imaging and FDG PET/CT for esophageal carcinoma and validation with pathological specimen
Authors: Yu J. M. , Zhong X. J. , Zhang B. J. , Mu D. B. , Han A. Q. , Sun X. D. , Yuan S. H. , Song P. P. , Li H. , Fu Z.
Published: March 2020

15090

Background: Although results of clinical studies have demonstrated FDG PET/CT improved target volume delineation in various tumors, only few studies compared delineation based on PET/CT with pathologic examination. Aim of our study was to compare anatomic imaging modalities including computed tomography (CT), esophagram, endoscopy with FDG PET/CT for delineation of gross tumor volume (GTV) in esophageal carcinoma and to validate the results with the pathologic examination. Methods: Thirty patients with stages II-III squamous cell carcinoma underwent transthoracic esophagectomy were enrolled. PET/CT, esophagram and endoscopy were performed with patients before operations. The length of the lesion on the PET/CT scan and on the CT portion of the PET/CT and the PET scan alone was determined independently by 3 separate investigative groups. PET/CT scan was evaluated by visual inspection for abnormality. A standard uptake value (SUV) of 2.5 was used in the PET scan to delineate the tumor extent. The lengths of GTVs determined with the five modalities (PET/CT, PET, CT, esophagram and endoscopy) were compared quantitatively and validated with the pathologic specimen. The sizes of the tumors were measured by pathologic examination which was considered as the gold standard. Results: Of the 30 patients, 9 had T2 tumors, 20 had T3 tumors and 1 had T4 tumor with an involvement of pleura. Three tumors were located at the upper esophagus, 14 at the middle esophagus, 13 at the lower esophagus. The mean length of the carcinoma was 5.85cm(SD 2.50cm) measured by pathologic examination, 5.79cm (SD 2.04cm) as determined by PET scan, 5.14cm (SD 1.65cm) by PET/CT scan, 5.42 cm(SD 2.42cm)by CT scan, 5.50cm(SD 2.79cm) by endoscopy, and 6.07cm(SD 2.75cm) by esophagram respectively. Although the lengths of the tumors as measured by the five imaging modalities were no significant difference, the result of PET was the most accurate. Conclusions: Compared with tumor lengths measured by pathologic examination, PET with a SUV 2.5 was found to be the most accurate modality and can help the radiation oncologist delineate the GTV of esophageal carcinoma precisely.

No significant financial relationships to disclose.
Adjuvant treatment in resected pancreatic adenocarcinoma: A retrospective analysis of survival and prognostic factors in 141 patients
Authors: Bujold A. , Létourneau R. , Lapointe R. , Dagenais M. , Roy A. , Lambert C. , Donath D. , Fortin B. , Tardif M. , Jolicoeur M.
Published: March 2020

15104

Background: Resectable pancreatic adenocarcinoma (PA) remains highly lethal. It is debatable whether adjuvant therapy can improve prognosis. Furthermore, what treatment should be delivered and for whom it is indicated is still of controversy. Methods: Between 1992–2004, retrospective data from the 141 patients who had a PA resected with curative intent in our centres were reviewed. Adjuvant treatment was as follows: 41 had chemoradiation (CRT), 1 neoadjuvant CRT, 10 chemotherapy alone (CT), 1 radiotherapy alone, and for 7 adjuvant treatment is unknown. The other 81 patients were observed. Overall survival (OS), relapse-free survival (RFS), locoregional and distant failure-free survival (LRFFS and DFFS) were analysed according to published prognostic factors. Kaplan-Meier curves with log-rank tests and Chi-2 coefficients were computed for the analysis. Results: Median age at diagnosis was 61 years. Overall, 63% of the patients were node positive, 67% had lymphovascular invasion (LVI), 71% had elevated CA-19.9 values and 50% operative blood loss >550cc. Table 1 displays these prognostics factors by treatment groups. For the entire cohort, median OS was 16.9 months; 1-year and 3-year OS were 76% and 43% respectively. No influence of treatment arm was found on OS (p=0.71). Negative nodes, normal CA-19.9 values, absence of LVI and blood loss <=550cc had all a positive influence on OS (all p<0.05). RFS and DFFS were not affected by adjuvant treatment (p=0.61 and 0.68, resp.), but a lower LRFFS was associated with it (p=0.006). Conclusions: In this retrospective analysis, despite the imbalance of prognostic factors among treatment groups, toward more ill patients in CT and CRT arms, there is no difference in OS, DFS and DFFS between arms. Therefore, adjuvant treatment seems to counterbalance the effect of poor prognostic factors. A randomized prospective trial would be needed to further address the issue.

[Table: see text]

No significant financial relationships to disclose.
The nuclear expressions of ERK1/2 and p38 can be useful markers for tumor invasiveness and lymph node metastasis in stomach cancer
Authors: Chang H. , Choi K. , Lee S. , Yoon K.
Published: March 2020

15109

Background: Extracellular-regulated kinases (ERKs) were shown to have a function in cellular proliferation or differentiation and p38 were known as to be involved in apoptotic processes in tumor development. Tissue inhibitors of metalloproteinase(TIMP) have been known to be a important role in tumor cell invasion, which was postulated to be regulated by ERKs and p38. The clinical implication of ERKs and p38 on stomach cancer was investigated Methods: By immunohistochemistry with an antibody specific for dually phosphorylated ERK 1 /2 and 2 , TIMP-1 and -2, and p38 on formaline-fixed paraffin-embedded tissue, we have examined 57 primary stomach cancer consisting of 36 cases of intestinal type and 21 cases of diffuse type carcinomas. One-way ANOV(non-parametric) was used to compare differences among more three groups and paired T-test were used between groups.P<0.05 was considered as statistic significant. Results: The expression rate of ERK1/2 in the nuclei of the tumor cells was 21.5%, The expressions of ERK 2, TIMP-1 TIMP-2, were 56.4%, 50.9%, 61.4%. The expression rate of p38 in the tumor cells was 37.7%.. The p38 expression had significant correlation with invasion depth of tumor(p=0.016), lymph node metastasis(p=0.030), and TIMP-2 expression(p=0.038). ERK1/2 had significant association with tumor invasion(p=0.003), lymph node metastasis(p-0.013), tumor cell grades(p=0.030), and TIMP-1(p=0.029). ERK-2, TIMP-1 and 2 had no significant relationship to tumor invasion and metastasis Conclusions: These results suggest that the nuclear expressions of ERK1/2 and p38 can be the useful markers predicting the progression of stomach cancer towards invasiveness and metastasis

No significant financial relationships to disclose.
Erythropoetin (epoetin beta) once weekly in anemic patients with advanced cancer of the stomach or gastroesophageal junction: Interim results of a randomized German AIO phase II trail
Authors: Moehler M. H. , Geissler M. , Raedle J. , Ebert M. , Scherubl H. , Flieger D. , Seufferlein T. , Galle P. , Kanzler S. ,   Upper-GI Group of German AIO
Published: March 2020

15133

Background: Tumor-related or chemotherapy-induced anemia is common in gastrointestinal cancer patients and results in reduced quality of life and worse prognosis. Thus, the effectiveness of erythropoetin (epoetin beta) treatment (EB) to achieve and maintain a target haemoglobin (Hb) level of ≥ 11 g/dl was assessed within a randomised German AIO phase II study to assess efficacy of irinotecan/capecitabine versus cisplatin/capecitabine in advanced gastric or lower esophageal cancer. Methods: Patients (pts) with untreated locally advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction (KPS ≥ 60%, > one measurable lesion, adequate organ functions) were randomized to receive 3-weekly cycles of either irinotecan 250 mg/m2 d1 (arm A) or cisplatin 80 mg/m2 d1 (arm B). Capecitabine was administered at 2000 mg/m2 for 14 days in both arms. In both arms, EB (30,000 I.E. once weekly) was given at Hb of < 11 g/dl and continued until Hb ≥ 12 g/dl. If after 4 treatment weeks, Hb increase was < 0.5 g/dl, EB was increased to 30,000 I.E. twice weekly. FACT-An questionnaires were completed at each cycle. Results: At time of abstract submission, 81 pts were randomized to A (37 pts) or B (44 pts). 23 pts received at least 3 EB injections (A: 10 pts, B: 13 pts). Median Hb prior to EB was 10.5 g/dl (A: 10.4 g/dl, B: 10.5 g/dl) and median Hb at end of EB was 11.6 g/dl (A: 11.5 g/dl, B: 11.75 g/dl). During EB, 80 % of A and 77 % of B achieved target Hb of ≥ 11 g/dl with a median rise in Hb of 2.0 g/dl (A: 1.4 g/dl, B: 2 g/dl). 5 pts in A and 7 pts in B responded with a ≥ 1 g/dl rise in Hb during first 4 weeks. FACT-An questionnaires showed no change from baseline to end of EB. Among evaluable pts with EB (20 pts) versus without EB (34 pts), response (CR + PR) and tumor control rates (CR + PR + SD) were 60% vs 35% and 85% vs 70%, respectively. Conclusions: EB is effective in raising Hb levels in advanced or metastatic gastric cancer. Patients receiving EB tend to show a better response to chemotherapy.

No significant financial relationships to disclose.
Two-fraction carbon ion radiotherapy for hepatocellular carcinoma
Authors: Kato H. , Yasuda S. , Yamada S. , Hara R. , Kano M. , Kamada T. , Mizoe J. , Tsujii H.
Published: March 2020

15134

Background: In Japan, most patients with Hepatocellular Carcinoma (HCC) have liver cirrhosis, an advanced hepatic disorder, and they often require repeated therapies owing to the multicentric nature of carcinogenesis in the cirrhotic liver. Therefore, both radical effect and minimal invasiveness are essential for the treatment of HCC. However, there were no therapies satisfying both of these essential requirements for every-sized HCC. The purpose of this trial was to evaluate the safety and efficacy of two-fraction carbon ion radiotherapy (CIRT) for HCC. Methods: Eligibility criteria for this study were as follows: biopsy-proven HCC; recurrent or residual tumor after other ineffective treatments or no indication for any other treatment; no prior radiotherapy for target tumors; hepatic disorder of Child-Pugh grade A or B; Karnofsky performance status of 60–100; no other active cancer; and digestive tract not in contact with clinical target volume. CIRT was administered within dose escalation study of 32.0 to 38.8 cobalt gray equivalent (GyE) in 2 fractions for 2 days. Results: Between April 2004 and August 2006, 40 patients were totally enrolled. All patients had chronic liver diseases of Child-Pugh grade A in 37, B in 3. The median tumor size was 4.7 cm in diameter (2.0 to 6.7 cm). During a median follow-up of 32 months (range, 5–45 months), no hepatic failure resulting from the therapy and no treatment-related death occurred. Incidence of grade 3 early hepatic toxicity according to NCI-CTC ver.2 in the essential valuables concerning hepatic function was 0% in serum-GPT, ALB, prothrombin activity (PT%) and ALP, and 3% in T.BIL. No grade 4 toxicity has occurred. In 94% and 86% out of the patients, Child-Pugh score did not increase by more than 1 point in the early and late phases, respectively. In the lower-dose group (32.0, 33.6, 35.2 GyE: n=18), 2-year local control rate and overall survival rate were 71% and 83%, respectively. In the higher-dose group (37.0, 38.8 GyE: n=22), they were 100% and 90%, respectively. Conclusions: Although 2-fraction carbon ion radiotherapy seems to be safe and effective, and to have a promising potential as a new, radical, and minimally invasive therapeutic option for Hepatocellular Carcinoma, further careful follow-up is needed to confirm it’s clinical efficacy.

No significant financial relationships to disclose.
Phase I/II study of PHY906/capecitabine in hepatocellular carcinoma
Authors: Rose M. G. , Yen Y. , So S. , Saif M. W. , Chu E. , Liu S. , Jiang Z. , Foo A. , Tilton R. , Cheng Y.
Published: March 2020

15152

Traditional botanical formulations in combination with conventional antitumor chemotherapeutics may prove a powerful approach in reducing toxicity and improving clinical outcomes. In vivo studies show that PHY906, a traditional Chinese formulation, can reduce chemo-induced gastrointestinal toxicity while enhancing the therapeutic efficacy of a broad-spectrum of common anticancer agents in various cancer models, including capecitabine, CPT-11, thalidomide, adriamycin, and sorafenib in liver cancer; gemcitabine, capecitabine, oxaliplatin, gem/ox in pancreatic cancer; and CPT-11, 5-FU, sorafenib, VP-16, L-OddC, CPT-11/5-FU/LV, and oxaliplatin/5-FU/LV in colorectal cancer. Co- administration of PHY906 with a host of chemotherapeutic agents appears to neither alter the pharmacokinetic profiles of the chemotherapeutic agents nor their respective metabolites. PHY906 is currently being studied in a phase I/II, multicenter, open-label, dose-modification, safety and efficacy study in combination with capecitabine in patients with non-resectable HCC in the U.S. and Taiwan. Phase I patients (n=18) were enrolled at COH, Yale, VA and Stanford beginning November 2003. The primary objective of phase I was the determination of a safe dose regimen by varying the dose levels of PHY906 and/or capecitabine. Three dose levels of PHY906 + capecitabine were evaluated: PHY906 1000 mg BID + Capecitabine 1000 mg/m2 BID; PHY906 600 mg BID + Capecitabine 750 mg/m2 BID; and PHY906 800 mg BID + Capecitabine 750 mg/m2 BID. The final dosing level was chosen for the phase II portion of the study. Preliminary results suggest that the quality of life of patients on PHY906 + capecitabine was improved when compared to historical controls studying capecitabine alone. There is also no evidence of drug-induced toxicity caused by PHY906; nor does PHY906 reduce capecitabine antitumor activity. For patients receiving capecitabine at 750 mg/m2 BID and PHY906 at either 600 mg BID (N=4) or 800 mg BID (N=24), 10.7% (N=3) achieved minor response (MR), 50% (N=14) had stable disease (SD) and 39.3% (N=11) had progressive disease (PD). These findings support the further investigation of PHY906 as an adjuvant therapy of capecitabine in a larger HCC population.

No significant financial relationships to disclose.
Rapamycin inhibits the growth of cholangiocarcinoma cells in vitro
Authors: Sawada T. , Okada T. , Kubota K.
Published: March 2020

15153

Background: In the present study, anti-neoplastic effect of rapamycin against cholangiocarcinoma was studied in vitro. Methods: Expression of mTOR in 4 cholangiocarcinoma cell lines, TFK1, HuCCT1, NOZW, and OZ was evaluated by real-time PCR. Then, the four cholangiocarcinoma cell lines were cultured with rapamycin (0, 25, 50, 100, 200 nM), gemcitabine (0, 0.5, 1, 2 μM), or both, and anti-proliferative effect was evaluated by MTT assay. Results: All the four cholangiocarcinoma cell lines expressed endogenous mTOR- mRNA. Level of expression was the highest in HuCCT1 (65.8), and the lowest in TFK1 (17.6). Then, rapamycin significantly inhibited the growth of all the four cholangiocarcinoma cell lines, in dose-dependent manner. Gemcitabine inhibited the growth of NOZW (48.4%) and HuCCT1 (48.9%), but less efficiently in TFK1 (5.9%) and OZ (27.4%). Furthermore, synergistic anti-proliferative effect of rapamycin and gemcitabine was observed in TFK1 (39.1%), NOZW (38.9%), and OZ (47.1%), not in HuCCT1 (18.9%). Conclusion: Rapamycin effectively inhibited the growth of the cholangiocarcinoma cell lines, and synergistic effect with gemcitabine was observed in three of the four cell lines.

No significant financial relationships to disclose.
A phase I dose escalation study of pharmacobiologically based scheduling of capecitabine and mitomycin C (MMC) in patients with gastrointestinal solid malignancies
Authors: Hill M. E. , Campbell A. , Kosuri K. , Thomas J. , Villalona M. , Bekaii-Saab T.
Published: March 2020

15154

Background: A principal determinant of the therapeutic index of capecitabine-based treatment is the grade of thymidine phosphorylase(dThdPase) activity in malignant tissues. MMC, an agent that is active in gastrointestinal malignancies, produces significant upregulation of the dTHdPase starting 4–6 days after treatment and persisting for at least 10 days. On the basis of the time-dependency and transience of this upregulation, we performed a phase I study of capecitabine in combination with MMC. The aim was to determine the maximally tolerated dose of this combination. Methods: In this ongoing study, patients with advanced gastrointestinal solid malignancies received MMC on day 1 and capecitabine twice daily on days 8 and 21, every 4 weeks. The MMC dose was fixed at 6mg/m2, whereas capecitabine was escalated in successive patient cohorts. Patients were allowed to have had a maximum of 2 prior therapies for metastatic disease. The total cumulative dose of MMC was capped at 36 mg/m^2 to reduce the risk of cumulative toxicity. Results: So far 23 patients with a median age of 62 received capecitabine doses from 1000 to 2000 mg/m^2/d. The majority of the patients had at least 1 prior treatment (86%). Four patients were considered non-evaluable. No dose-limiting toxicities were observed as we reached our final dose level. Toxicities were generally mild with only 7 patients experiencing grade 3 toxicities and two experiencing grade 4 toxicities. The most common toxicities were fatigue (67%), nausea (43%), diarrhea (33%), and anemia (29%), and all toxicities were reversible. There were no objective responses; however, 32% of evaluable patients had prolonged stable disease (43% colorectal, 29% pancreas, 14% esophageal, and 14% gastric). Conclusions: Capecitabine in combination with MMC in the proposed schedule is well tolerated and has promising preliminary activity in various gastrointestinal malignancies. Recommended doses for phase II studies are capecitabine 1000 mg/m^2 twice daily and MMC 6 mg/m^2. This study is ongoing with 2 more patients being entered at the recommended phase II dose.

No significant financial relationships to disclose.
BRCA1 and BRCA2 germline mutation carriers have a lower breast density compared to high risk women without such mutations
Authors: Sharma P. , Klemp J. R. , Kimler B. F. , Khan Q. J. , Smith E. J. , Fabian C. J.
Published: March 2020

1517

Background: High mammographic breast density, a known risk factor for breast cancer is influenced by both genetic and non genetic factors. It is not clear if there are differences in breast densities between BRCA1/2 mutation carriers and high-risk non carriers. The aim of this study was to compare breast density in high-risk women with and without BRCA1/2 mutation. Methods: Women at high risk for development of breast cancer (based on family history, prior precancerous disease or prior breast cancer) who underwent genetic testing at the University of Kansas Breast Cancer Prevention Center between 1998 and 2005 were identified under an IRB approved protocol. BRCA1/2 full sequencing was performed at Myriad Genetic Laboratories. The earliest digitized mammogram of these subjects was identified from a preexisting mammogram database. All mammograms had to be prior to/at least one year from any chemoprevention intervention. For subjects with prior breast cancer, mammogram of the uninvolved breast was used. Breast density was assessed on the left craniocaudal mammographic view by computer assisted method, Cumulus. Frequencies of categorical variables were assessed using chi-square analysis. Continuous variables were assessed using Mann-Whitney non parametric test. Multiple regression analysis was used to investigate whether differences are due to variables other than mutation status. Results: The study population consisted of 284 high-risk women who underwent BRCA1/2 testing and for whom a mammogram was available. 30 (11%) had BRCA1 and/or 2 deleterious mutation. There was no difference between mutation carriers and non-carriers for BMI, 5 year Gail risk, parity, menopausal status and HRT use. Mutation carriers were younger (median age 42 vs. 46, p=0.020) and more likely to have a positive family history (100% vs. 85%, p=0.020). Older age (p<0.001), higher BMI (p<0.001) and having a BRCA1/2 mutation (p=0.025) were significantly associated with a lower breast density. Conclusion: Among high risk women, possession of a deleterious BRCA1/2 mutation is associated with lower breast density after adjusting for factors known to affect breast density. This suggests that breast density may be governed by genetic factors other than BRCA1/2 mutation status.

No significant financial relationships to disclose.
Analysis of 94 patients with advanced biliary tract cancer
Authors: Andritzky B. , Adler S. , Burkholder I. , Thöm I. , Schuch G. , Görn M. , Schilling G. , Edler L. , Bokemeyer C. , Laack E.
Published: March 2020

15172

Background: Cholangiocarcinoma or gallbladder cancer are often diagnosed at an advanced stage with limited treatment options. Methods: Between 1994 and 2004, 94 patients (pts) (47 male, 47 female) with advanced biliary tract cancer were treated at the Department of Oncology and Hematology, University Hospital Hamburg-Eppendorf. Clinical and histopathological characteristics, response to chemotherapy, and survival were investigated in a retrospective analysis. Median age was 59 years (range 30–80) and median Karnofsky performance status was 90%. Predominant histologic type was adenocarcinoma (94.7%). Primary tumor sites were extrahepatic bile duct (29.9%), gallbladder (28.7%), intrahepatic bile duct (10.6%), ampulla of Vater (2.1%), not specified (28.7%). Predominant localizations of metastases were liver (73 pts (77.7%)), lymph nodes (49 pts (52.1%)) and the peritoneum (14 pts (14.9%)). 33 pts (35.1%) underwent surgery of the primary tumor at time of diagnosis. Results: 72 of 94 pts (76.6%) received a first-line chemotherapy, all together 10 different chemotherapy regimens were used. The median number of cycles was 2.5 (range 1 - 12). A single agent chemotherapy with gemcitabine was the most often adminstered regimen (23 pts (31.9%)), followed by carboplatin and etoposide plus whole body hyperthermia (12 pts (16.7%)) and 5- fluorouracil and folic acid (10 pts (13.9%)). The overall response rate was 8.3% (95% CI 3.1 - 17.3) (34.7% SD, 47.2% PD, 9.7% not evaluable). Second-line chemotherapy was given in 27 patients, which induced no tumor response, but a stable disease rate of 22.2%. Median time to follow- up was 44.8 months. Survival was calculated for all 94 pts since time of diagnosis. Median overall survival was 12.2 months and median progression-free survival 9.2 months. The median overall survival time for the 72 pts who were treated with chemotherapy was 14.0 months, and for the 22 pts who did not receive chemotherapy 10.7 months (p=0.2). Conclusions: Our analysis showed a poor prognosis for patients with advanced biliary tract cancer. Response rate to chemotherapy was low. Therefore, well tolerated cytotoxic agents should be used and new treatment strategies (including molecular targeted therapy) should be further investigated.

No significant financial relationships to disclose.
The risk of thrombotic events in patients with primary versus secondary hepatic malignancies who are undergoing surgical resection
Authors: Yates T. J. , Abouljoud M. , Lambing A. , Kuriakose P.
Published: March 2020

15178

Background: The increased risk of thromboses is well documented in patients with malignancies, and those undergoing abdominal surgery. Furthermore, patients requiring hepatic resection for underlying malignant disease have been reported to be at increased risk for thrombotic complications. However, guidelines for thromboprophylaxis in this patient population are still under investigation. A cursory review performed at our institution determined the incidence of thrombotic events to be comparable to that reported in the literature. We, therefore, went further to study if there was a difference in the risk of thromboses between those undergoing resection for primary hepatic cancer, versus metastatic disease. Methods: We performed a retrospective chart review of patients undergoing surgical resection for hepatic malignancies. The primary end point was to determine whether there was a difference in the incidence of thrombotic events between primary and secondary malignancies. Results: A total of 99 patients at our institution underwent surgical resection for either primary or secondary hepatic malignancies in the past 5 years. There were 7 patients who developed thrombotic events within three months of their resection. Of these patients, all 7 underwent resection for secondary hepatic malignancies. Based on the nature of this study, and its lack of standardized thromboprophylaxis, statistical analysis was not performed. Conclusions: Patients undergoing surgical resection of hepatic malignancies appear to be at increased risk of thrombotic events, and may require more specific standardization of their thromboprophylaxis. Furthermore, based on our observation it appears those associated with metastatic disease may derive an even greater benefit from this. Future prospective studies will be required to evaluate this difference in thromboses, and to better define the guidelines for thromboprophylaxis.

No significant financial relationships to disclose.
Gemcitabine for patients with chronic renal failure on hemodialysis
Authors: Matsuda M.
Published: March 2020

15189

Background: Numerous studies of gemcitabine (GEM) as an agent for advanced pancreatic carcinoma (APC) have been reported. Although significant and/or unexpected toxicities of GEM have been reported even at low doses in patients (pts) with impaired renal function, no dosing recommendations have been developed for chronic renal failure (CRF). Methods: In this report, we present five APC pts with CRF and discuss the use of GEM for pts on hemodialysis (HD). Results: CASE 1. A-74-year old man with CRF (not on HD) received GEM (800 mg) on days 1 and 8. Grade 3 hematological toxicity (neutropenia and thrombocytopenia) occurred on day 9, which recovered immediately after HD was performed. Ten courses of GEM (800 mg x q2w) with HD initiated 6 h after administration have since been administered without any side effects. CASE 2. A-48-year old man underwent Whipple’s operation and received GEM (1000 mg x3 q4w) as adjuvant chemotherapy. After 10 cycles, he developed hemolytic uremic syndrome (HUS), which recovered immediately after performance of HD. HD was initiated 24 h after GEM (1000 mg), and this sequence was repeated 53 times until recurrence occurred. CASE 3. A-78-year old woman with recurrent pancreatic carcinoma developed HUS after 29 cycles of GEM (800 mg x q2w). After remission of HUS by starting HD, GEM was commenced again (HD was initiated 24 h after GEM at 1000mg x q2w), and has been administered 18 times. Both CASE 4 (a 65-year- old woman) and CASE 5 (a 56-year-old man) are APC pts with a long history of HD. Although HD was initiated within 24 h after GEM (1000mg) administration, Grade 3 hematological toxicity (neutropenia and leukocytopenia) occurred in these pts and we had to give up GEM after several courses. Conclusions: GEM (800–1000 mg) can be administered safely to pts with CRF on HD, especially soon after commencing HD, as long as HD is initiated within 24 h after GEM administration. In pts with a long history of HD, however, GEM should be administered with caution.

No significant financial relationships to disclose.
Effect of familial breast cancer outcomes on health behaviors of relatives
Authors: Fisher S. G. , Mumby P. , Kohli S.
Published: March 2020

1521

Background: While the disease outcomes of breast cancer probands do not affect the objective risk of first degree relatives (FDR), the morbidity and mortality experience may impact their subsequent perceptions and health behaviors. This study examines the influence of a proband’s disease course on screening behaviors, perceived risk, self-efficacy, traumatic stress and related mood disturbances of FDR. Methods: A cross-sectional sample of 149 FDR was recruited (79% of respondents) by invitations distributed by 545 probands. Respondents were categorized into a ‘high impact’ group whose familial proband had expired, relapsed or undergone intensive chemotherapy (n=55), and a ‘low impact’ group whose proband was disease-free after surgery ± radiation (n=94). This sample provided a power of 84% for detection of a 1.5 unit difference in screening indices and a 10% difference in perceived risk between groups with a two-sided alpha level of 0.05. Parameters were measured by self-administered, mailed surveys of newly-developed and established instruments. Objective risk assessments were completed by a genetic counselor. Statistical analyses included parametric and non-parametric methods, as appropriate. Results: While the high impact group reported perceptions of greater familial proband suffering (8.6 vs.5.8) and greater anxiety and doubt regarding mammography benefits (11% vs. 1%) (p<0.01), there was no statistically significant difference between groups in screening behaviors or perceived risk. The high impact group experienced sleep disturbances (28%), emotional stress (52%), and mood swings (61%) more often than the comparison group (p<0.001). FDR with the highest objective risk had significantly higher scores on screening indices and perceived risk (p<0.01) but significantly lower knowledge regarding breast cancer (p=0.04). Conclusions: This study suggests that while morbidity and mortality of familial probands is not associated with screening practices of FDR, it does have a negative impact on their psychological well-being. Enhanced strategies to educate and support FDR regarding familial breast cancer risk and potential psychological repercussions of the proband’s experience are warranted.

No significant financial relationships to disclose.
Health-related quality of life among high-risk women in an MRI surveillance study
Authors: Bradbury A. R. , Cummings S. A. , Dignam J. J. , Patrick-Miller L. , Verp M. , White M. A. , Dudlicek L. , Newstead G. , Abe H. , Schmidt R. , Olopade O. I.
Published: March 2020

1522

Background: The quality of life (QOL) and psychological impact of incorporating MRI into breast cancer screening programs for high-risk women (HRW) has not been well studied. Psychological and biological risk factors, e.g. cancer history, BRCA mutation, imaging recall, generalized anxiety or clinical depression may mediate QOL outcomes. Methods: 100 HRW undergoing intensive surveillance including yearly mammography, semiannual breast ultrasound and breast MRI have completed QOL (SF-36), anxiety (STAI) and depression (Beck) questionnaires at semi-annual visits. 56 HRW have completed 3 screenings. Differences in QOL measures over time were evaluated using longitudinal regression models. Differences between participants and population norms (PN), women with/without a history of cancer and with/without a BRCA mutation were assessed using t-tests. Results: QOL scores increased over time and were statistically significant for the general health (GH) subscale (p=0.016). All QOL subscales were higher than PN at baseline and were significantly higher than PN at 12 months. Mean GH score at 12 months = 80.0, PN 72.7 (SD14.2, p<0.01). Mean mental health score at 12 months = 78.9, PN 73.4 (SD14.9, p<0.01). At baseline, BRCA carriers had lower QOL scores than non-carriers and women with a history of cancer had higher QOL scores than unaffected participants, although these differences were not statistically significant. Conclusions: These data suggest that intensive breast cancer screening incorporating breast MRI may have a positive effect among HRW. Continued enrollment will allow for multi-variate characterization of psychological and biological predictors of change in QOL and psychological well-being among high-risk women undergoing intensive screening.

No significant financial relationships to disclose.
Effect of coronary heart disease (CHD) risk factors and medications on invasive breast cancer risk in the Raloxifene Use for The Heart (RUTH) trial
Authors: Mershon J. , Geiger M. , Barrett-Connor E. , Collins P. , Kornitzer M. , Dowsett S. , Zheng S. , Song J. , Wenger N.
Published: March 2020

1530

Background: RUTH enrolled 10,101 postmenopausal women at increased risk for major coronary events. Women were not enrolled based on their risk for breast cancer. The incidence of invasive breast cancer in the placebo group was low for this older population of women (mean age 67.5 years). The aim of this analysis was to determine whether CHD risk factors and selected cardiac medications were protective against invasive breast cancer in this population at increased risk for coronary events. Methods: Covariates assessed were baseline factors that are known CHD risk factors and selected medications ( Table ). Univariate analyses were performed for all covariates using placebo data. Results: The effect of baseline CHD risk factors and selected cardiac medications on the incidence of invasive breast cancer in women receiving placebo in RUTH (N=5057) Conclusions: In these postmenopausal women at increased risk for major coronary events, baseline CHD risk factors and selected cardiac medications assessed individually did not protect against invasive breast cancer. The low incidence of invasive breast cancer in the RUTH population does not appear to be due to the presence of CHD risk factors or use of cardiac medications.

[Table: see text]

[Table: see text]
Gene expression as a predictive marker of outcome for high-risk transitional-cell carcinoma (TCC) of the bladder in patients (pts) randomized to adjuvant chemotherapy with cisplatin-gemcitabine (PG) or observation (OBS) after radical cystectomy
Authors: Pollera C. F. , Pessina G. , Nelli F. , Felici A. , Moscetti L. , Ruggeri E. , Mottolese M. , Gallucci M. , Sperduti I. , Cognetti F.
Published: March 2020

15502

Background: A randomized phase III trial comparing PG vs OBS in muscle-invasive TTC of the bladder is currently ongoing. ERCC1 and RRM1 genes are involved in the nucleotide excision repair pathways, and their up-regulation by tumor has been clearly related to resistance of cisplatin and gemcitabine, respectively. Preliminary correlations in patients with bladder cancer randomized to PG were already presented (Proc ASCO 2005, Abstract No: 4589). In the present study, we have examined the predictive value of ERCC1 and RRM1 as markers of tumor progression, as well as their potential correlation with other known prognostic factors also in patients randomized to OBS. Methods: Thirty-nine paraffin-embedded TTC samples of a subset of patients entered the trial were collected. The characteristics were: pT2 23%, pT3 54%, pT4a 23%, pN1–2 46%; G3–4 98%; M/F 10%/90%, median age: 65 years (range 53–74); PG/OBS: 49%/51%. Analysis consisted of real time RT-PCR quantification of mRNA levels of ERCC1 and RRM1. Results: After a median follow-up of 25 months (range 12–51), 17 patients relapsed and 10 deceased. A good correlation was found between mRNA expression levels of both genes. Three-year disease-free survival (DFS) was 74% vs 33% for patients with low and high ERCC1 expression (p=0.03), and 64% vs 22% for those with low and high RRM1 expression (p=0.26), respectively. Comparable result in favour of patients showing lower ERCC1 mRNA levels was found in both groups of patients randomized to PG or obs. Multivariate analysis demonstrated that only the presence of N1–2 and low expression level of ERCC1 were significant prognostic factor for better DFS (HR 4.358, 2.775 and p value = 0.006 and 0.046, respectively). Conclusions: Determination of ERCC1 mRNA expression level in muscle-invasive bladder cancer can make a contribution as an independent predictor of DFS after radical cystectomy. It’s still unclear if quantification of ERCC1 gene expression level could interact with adjuvant chemotherapy. Longer follow-up will help to address this issue (Supported by CNR-MIUR grants 02.00447, 03.00387-ST97).

No significant financial relationships to disclose.
Romidepsin (FK228), a histone deacetylase inhibitor: Final results of a phase II study in metastatic hormone refractory prostate cancer (HRPC)
Authors: Parker C. , Molife R. , Karavasilis V. , Reid A. , Patterson S. G. , Riggs C. , Higano C. , Stadler W. M. , McCulloch W. , de Bono J. S.
Published: March 2020

15507

Background: Romidepsin is a bicyclic depsipeptide that inhibits histone deacetylase (HDAC). Translocations fusing TMPRSS2 gene and ERG oncogenic factor is associated with elevated HDAC-1 expression. HDAC inhibition results in accumulation of hyperacetylated histone proteins resulting in G1 and G2/M arrest, differentiation of transformed cells and apoptosis. Romidepsin can also inhibit HSP90, ablating androgen receptor expression. This is the 1st study to report activity of an HDAC inhibitor in HRPC. Methods: Romidepsin was administered intravenously at 13mg/m2 on days 1, 8 and 15 of a 28-day schedule. A 2-stage design was used. Eligibility criteria included: no prior chemotherapy, metastatic disease, QTcB <470msec, Karnofsky PS =80. The primary endpoint was to determine rate of disease control (complete response [CR], partial response [PR], stable disease [SD] for 6 months). Secondary endpoints were PSA response rate (RR), time to PSA and objective disease progression, safety profile, effect on disease related symptoms and pharmacokinetics (PK) of romidepsin. Results: Thirty-one patients were enrolled. Median age: 64 years (range 43–82). Twenty-one patients are evaluable for radiological and PSA response: 1 patient achieved a confirmed radiological PR lasting >6 months (m), and 2 confirmed SD for 6m. Four patients had SD lasting 5m (n=2) and 4m (n=2). The PSA RR was 7%. A 3rd patient had a 40% fall in PSA lasting 5m. The most common drug related adverse events were (all grades, %): nausea (84%), fatigue (77%), vomiting (65%), anorexia (61%), constipation (45%), dysguesia (35%), diarrhea (32%), thrombocytopaenia (32%), anemia (28%) and neutropenia (25%). There were no grade 4 events. Non-specific asymptomatic ST segment changes on ECG were seen in 15 % of patients; there was no evidence of significant QTc prolongation on ECG confirmed by manual calculation. Conclusions: Treatment with single agent romidepsin is associated with a disease control rate of 14% and a PSA RR of 7%. Constitutional toxicities are prominent, no grade 4 events have been observed and only minimal cardiac toxicity has been reported. Further investigation in combination with other active agents in HRPC is warranted.

[Table: see text]
Identification of occult prostate malignancy using a stereotactic transperineal prostate biopsy technique
Authors: Moran B. J. , Braccioforte M. H.
Published: March 2020

15520

Background: This study investigates the detection rate of non-palpable, isoechoic occult prostate malignancy using a stereotactic transperineal prostate biopsy (STPB) technique in patients with previously negative transrectal ultrasound-guided prostate biopsy. Methods: 327 consecutive patients with continued rising total prostate specific antigen (PSA) with a minimum of 1 prior benign transrectal prostate biopsy (range 1–8), underwent STPB at a single out-patient institution between 05/2004 and 11/2006. Median patient age, total PSA and prostate volume and number of specimens obtained were 62 years, 8.3 ng/ml, 46.1 cm3 and 40 specimens, respectively. Similar to a prostate brachytherapy procedure, the prostate was positioned on the implant grid. Specimens were obtained according to x, y, and z coordinates from eight equal octants with pathology reported accordingly. A greater number of specimens were obtained from the apical half than the basilar half of the prostate; this was attributed to smaller glands in which the apical specimens sufficiently sampled the anterior curvature of the gland. Results: STPB yielded adenocarcinoma in 125/327 (38%) patients. The number of biopsy cores obtained per patient approximated the prostate gland volume in cm3. Multivariate analysis (paired samples t-tests) demonstrated there was a significant difference in detection rates with the apex having a higher incidence of malignancy than the base of the prostate gland (p=.000). Furthermore, the anterior apex harbored significantly more adenocarcinoma when compared to the posterior apex (p=.026) ( Table 1 ). Conclusions: STPB is efficacious for diagnosis of non-palpable, isoechoic occult prostate malignancy. A possible explanation for the significant finding in this study that occult malignancies occupy a higher percentage of apical biopsies using STPB may be related to difficulty and limitations of apical sampling using a standard transrectal biopsy approach.

[Table: see text]

No significant financial relationships to disclose.