bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II trial of nemorubicin hydrochloride in combination with cisplatin is supported by new preclinical evidences of its mechanism of action
Authors: Pacciarini M. A. , Geroni C. , Sabatino M. A. , Ciomei M. , Valota O. , Ballinari D. , Capolongo L. , Broggini M. 
Published: March 2020

14116 Background: Nemorubicin hydrochloride (nemorubicin) is a non-conventional anthracycline in Phase II evaluation in hepatocellular carcinoma (HCC). Its mechanism of action is not fully elucidated. Although structurally related to doxorubicin, nemorubicin is a topoisomerase I inhibitor, overcomes anthracyclines resistance, is minimally cardiotoxic and is biotransformed by hepatic CYP3A4 into hundred times more cytotoxic metabolite. Phase I and II trials were conducted in Europe and China to test nemorubicin by hepatic intra-arterial (IHA) infusion in HCC patients (pts). The drug was well tolerated up to 600 mcg/m2 q4–6w; DLT was transient liver transaminase elevations. Overall, 57 HCC pts were evaluable for efficacy, with 11/57 confirmed liver CR/PRs (RR = 19.3%; 95% ci 10–31.9%) lasting 1–54+ months. Stable disease ≥ 3 months was observed in 17/57 (29.8%) pts, most with AJCC Stage III, IIIA and IVA. These data supported new trials of nemorubicin in HCC. Methods: To further characterize the mechanism of action of the drug, we generated cells (L1210) resistant to nemorubicin. Since resistant cells were more sensitive than the parental ones to UV irradiation, we reasoned that the nucleotide excision repair (NER) system might be involved in mediating the activity of nemorubicin. To test this hypothesis we used isogenic CHO cells proficient or deficient in excision repair cross-complementing (ERCC) genes, namely ERCC1 and ERCC6 genes. Results: In contrast with what is observed for most DNA damaging drugs that show resistance in the presence of high NER activity, nemorubicin is more cytotoxic in NER proficient than in deficient cells. This suggests that NER pathway plays a role in the cytotoxic effect of nemorubicin. Also, cells resistant to nemorubicin are NER-deficient and are highly sensitive to platinum derivatives and alkylating agents and synergism was found combining cisplatin with nemorubicin. Conclusions: Nemorubicin has a peculiar mechanism of action through the NER system providing the rationale for clinical combination studies with platinum derivatives. A Phase I/II trial of nemorubicin with cisplatin in HCC patients started in Italy at the end of 2005. No significant financial relationships to disclose.
Chemoradiotherapy in anal carcinoma using cisplatin and 5FU
Authors: Calderillo G. , Cano C. , Ruiz J. M. , Zamora J. , Lopez H. , Martinez J. , Gallardo D. 
Published: March 2020

14128 Background: Chemoradiation (CRT) is now established as the primary treatment for anal carcinoma. The original combination was 5Fu and mitomycin C, but the cisplatin may offer better local control than the standar of MMC with toxicity more tolerable. Methods: Between March 2000 and January 2005, 25 patients with anal carcinoma advanced with non pre-treated were enrolled. Eligible patients had an ECOG PS 0–2. They received cisplatin 80–100 mg/m2 day 1 and 5FU 800–1000 mg/m2 day 1–4 every 4 weeks and radiotherapy >45 Gys. Results: 25 patients, 12 male and 13 female, median age 63 (range 36–83 y). 22 with squamous cell carcinoma and 3 adenocarcinoma. (A) 11 patients recieved QT concurrente with RT, median cycles 2 and median of RT 50 Gys and (B) 14 patients recieved QT follow QT-RT concurrent, median cycles 3.5 and median of RT 48 Gys. The toxicity 3–4 were: neutropenia 23%, anaemia 4%, trombocytopenia 8%, diarrhea 15%, vomiting and nausea 19%. The evaluation: (RC) (64%), (RP) (28%) and PD (8%). The median survival 15.5 m (9–42 m), 12 m group A vs 16 m group B. Conclusions: The combination RT-QT with cisplatin and 5FU is feasible and tolerable, and may offer more the secuencie QT follow CRT. No significant financial relationships to disclose.
The mechanisms of apoptosis induced by artistical composition of Chinese medicinal herbs in gastric cancer metastasis
Authors: Li J. , Sun G. 
Published: March 2020

14147 Background: In China, gastric cancer has been treated by Chinese medicinal herbs to prevent relapse and metastasis for decades. The purpose of this study is to investigate the effectiveness and the mechanism of artistical composition of Chinese medicinal herbs (YWKL) in preventing gastric cancer metastasis. Methods: The herbs, after decoction, were administered by feeding 615 mice, which is a proventriculus cancer (FC) transplanted model, the rate of its lung metastasis rate is 70–80%. The inhibitory effect of artistical composition of Chinese medicinal herbs on FC spontaneous lung metastasis was evaluated by histological classification method. Apoptosis were determined through TUNEL technique. The expression of apoptosis relative gene was determined by immunohistochemical methods. Results: It has been found that YWKL can significantly decrease the tumorous node numbers in the lung, while increase the apoptosis cell index (AI) of tumor cell metastasizing to lung. We found the expression of Fas,Bax were much higher than that of control group, FasL and Bcl2 were no significantly different between the two groups. Conclusions: The oral application of the herbs after decoction was demonstrated to prevent gastric cancer metastasis mice model. The mechanism of YWKL-induced apoptosis in FC cancer cell might through regulating the expression of Fas and Bax genes. No significant financial relationships to disclose.
The importance of etoposide dose intensity in the management of metastatic germ cell tumours and the role of paclitaxel in salvage treatment of relapsing patients
Authors: North S. A. , Marwaha S. , Venner P. M. 
Published: March 2020

14502 Background: The primary objective was to evaluate the effect of etoposide dose intensity in the standard cisplatin/etoposide/bleomycin (PEB) regimen on progression free (PFS) and overall survival (OS). Secondary objectives were and to determine how the addition of paclitaxel in salvage regimens impacts OS and to compare the risk distribution of germ cell patients seen at a tertiary care centre to that quoted in the International Germ Cell Consensus Classification (IGCCC). Methods: A retrospective chart review of all 302 germ cell patients requiring cisplatin-based chemotherapy between January 1980 and December 2004 was conducted. Data collected on initial treatment included the dose of etoposide: 500 mg/m2/cycle (E500) or 360 mg/m2/cycle (E360) and whether the salvage treatment contained paclitaxel or not. PFS and OS were calculated. Patients were risk stratified as per IGCCC variables. Results: In the PEB regimen, E500 is superior to E360 as it results in a relapse rate of only 3% and an overall survival of 97% compared to a relapse rate and survival of 29% and 80% respectively. The addition of paclitaxel to salvage chemotherapy regimens for patients relapsing results in 1/5 (20%) of patients dying compared to 26/39 (67%) for those receiving a non-paclitaxel based salvage regimen. The distribution of seminoma patients was similar to the IGCCC (90% good risk, 10% intermediate risk). Non-seminoma (NS) patients were skewed to the good-risk category: 71% good risk, 10% intermediate risk and 18% poor risk as compared to 56%, 28% and 16% respectively as reported by the IGCCC. 5-year PFS and OS were comparable to those documented by the IGCCC with the exception of the intermediate risk NS patients where our 5 year PFS was 48% compared to 75% expected but 5 year OS was similar in these patients (75% Vs. 80%). Conclusions: This review demonstrates that PEB treatment containing higher dose etoposide is superior in terms of PFS and OS. Although the sample size is small it appears that Paclitaxel containing salvage regimens results in superior outcomes compared to previously used salvage regimens. Our centre has a similar risk distribution of patients as that quoted by the IGCCC. No significant financial relationships to disclose.
National study of patients, caregivers and physicians reveals pain associated with advanced prostate cancer as the primary concern
Authors: Moyad M. A. , Kirk T. A. 
Published: March 2020

14505 Background: Over 50,000 men developed hormone refractory prostate cancer (HRPC) in 2005 (CancerMetrics 2005). The objective of this study is to compare attitudes of patients, caregivers and physicians on the effects of advancing disease on patients. Methods: Respondents indicated attitudes towards 18 PC symptoms. Responses were analyzed by a division of Yankelovich. Grant funding from Abbott.Us TOO International conducted an online survey of HRPC patients, caregivers, and physicians in 2005. Patients and caregivers were recruited from NexCura’s database of users of the Treatment Profiler Options Tool for PC and links from PC websites (UsTOO, PCRI, PCF and PAACT). Board certified physicians who treat HRPC were recruited by J. Reckner & Associates. Respondents indicated their attitudes towards 18 symptoms of advancing PC. Responses were analyzed by TSC, a division of Yankelovich. Results: 409 HRPC patients (P), 236 caregivers (C), and 204 physicians (MD) (100 urologists/104 oncologists) participated in the study. Mean patient age was 65.7 and age at diagnosis was 60.2. Patients were identified as non-metastatic (M0) or metastatic (M+). 46% of patients were M+; 60% of caregivers are caring for M+ patients. 51% of M+ patients and 74% of M+ caregivers’ patients experienced bone pain. The most common symptom concerns were bone pain, other pain and mental changes. Conclusions: Over half of the M+ patients experienced bone pain related to PC in this survey. Once HRPC becomes M+, bone pain significantly affects the quality of life of patients and caregivers. It is the highest rated concern of patients, caregivers and physicians. Bone pain significantly alters the lives of those with advancing HRPC. New options are needed for patients with advancing PC. [Table: see text] [Table: see text]
Mifepristone (RU-486) in androgen independent prostate cancer
Authors: Hayes J. H. , Oh W. K. , Kantoff P. W. , Manola J. B. , Smith M. R. , Gelmann E. P. , Bubley G. , Balk S. P. , Taplin M. 
Published: March 2020

14508 Background: The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, and available antiandrogens do not turn off AR transcription completely. Mifepristone (RU-486) is a potent inhibitor of AR and acts by both competing with dihydrotestosterone (DHT) and binding with the AR co-repressor nuclear receptor co-repressor (NCoR), converting AR from a transcriptional activator to a transcriptional repressor. Methods: 22 patients with AIPC, PSA ≥5 ng/mL, and documented bone metastases were treated with mifepristone 200 mg PO QD until disease progression. Correlative studies include measurement of testosterone, cortisol, androstenedione, DHT, DHEA (dehydroepiandrosterone), and DHEA sulfate levels at baseline and during therapy. Results: Patients were treated a median of 84 days (range 10–182 d). Median PSA at time of enrollment was 41.9 ng/mL (range 5.2–1930.9 ng/mL). No patients demonstrated a PSA response. 13 patients have discontinued treatment, 12 for progressive disease (11 PSA progression and 1 bony progression) and 1 for grade 3 toxicity (GI bleed after 10 d on treatment). 6 patients are still on therapy with stable disease after a median 98 d. In 11 patients, baseline testosterone levels were mean 28.4 ng/dL (range <20–49 ng/dL). After one month of therapy, testosterone increased to mean 66.6 ng/dL (range 16–104 ng/dL) (p = 0.001). Compared to baseline, one month androstenedione and DHEAS levels were elevated in the majority of patients. Conclusions: Mifepristone demonstrated limited activity in AIPC patients. Potential efficacy was most likely limited by a rapid elevation in testosterone levels. We hypothesize that inhibition of glucocorticoid receptor led to an increase in ACTH with subsequent elevation of adrenal androgens and conversion to DHT. These preliminary data suggest that even moderate increases in systemic testosterone levels may stimulate tumor growth. These data also emphasize the continued importance of adrenal androgens and AR transcription in prostate cancer biology. No significant financial relationships to disclose.
Role of prognostic factors in patients with metastatic renal cell carcinoma (MRCC) eligible for treatment with interleukin (IL2)
Authors: Muniswamy H. , Dutcher J. P. , Mannam P. , Malik S. , Rusciano V. , Paul L. , Wiernik P. H. 
Published: March 2020

14514 Background: Motzer (JCO1999) defined 5 factors that predict for poor survival of patients with MRCC: low Karnofsky scale (<80%), high LDH (>1.5 times upper limit), low Hb (<lower limit of normal), elevated corrected calcium (10 mg/dl) and absence of nephrectomy. Method: We retrospectively evaluated 124 patients with MRCC (81 male/43 female, median age 54 years, range (R) 27 to 79 years) treated in our center from 10/98–12/05 with IL2 based therapy. Patients eligible for IL2 study were included. Patients were categorized into favorable (F - 0 risk factors), intermediate (I - 1–2 risk factors) and poor (P - 3 or more risk factors) groups. 89 patients had high dose (HD) IL2 (600,000 u/kg/dose every 8 hours up to 14 doses), and 35 patients had moderate dose (MD) IL2 (5 mu/m2/day for 5 days continuous infusion or 72,000 u/kg every 8h up to 14 doses). 26 patients had prior treatment. Prognostic factors were identified at the start of IL2 therapy. Primary endpoint was survival time defined as the time from initiation of IL2 treatment to time of death or December 2005 as the last follow up for all patients. Results: Analyzed using Kaplan-Meier method. Conclusions: 1. These prognostic factors apply to IL2 treated patients and separate them into prognostic groups. 2. HD IL2 treated patients have ≥ 6 months greater survival compared to MD IL2 treated patients or historical data. [Table: see text] No significant financial relationships to disclose.
Phase II trial of motexafin gadolinium (MGd) for treatment of metastatic renal cell carcinoma (MRCC)
Authors: Misellati A. , Phan S. , Amato R. J. 
Published: March 2020

14518 Background: MGd inhibits thioredoxin reductase. Thioredoxin is implicated in activation of hypoxia-inducible factor-1 alpha, which is overexpressed in >85% of renal cell carcinomas (RCC). We evaluated anti-tumor and safety activity of MGd in patients (pts) with progressive MRCC. Methods: Eligibility included: measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤2, life expectancy ≥12 weeks, ≤2 prior therapies and no active CNS involvement. MGd was infused intravenously over 30 minutes at 5mg/kg on days 1–5 and 15–19 of each 28-day cycle. Evaluation was performed after every 3 cycles. RECIST criteria were utilized to determine response rate. Time to progression (TTP) is determined from time of study entry. Results: 25 evaluable pts were enrolled 19 male/6 female, median age 63 years (range 38–76). All pts had histologic confirmed RCC; 9 pts had clear cell carcinoma, 9 pts with predominant clear cell carcinoma component, 2 pts with papillary and 1 pt with collecting duct. 23 pts received prior systemic therapy, median 2 treatments. 16 pts had ZPS of 0, 8 pts had ZPS of 1, and 1 pt had ZPS of 2. All pts had progressive MRCC. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 6 pts had 2 and 12 pts had 3 or more. 20 pts have completed at least 12 weeks of therapy. 5 pts progressed within 3 months. 1 pt had a complete response of lung metastasis but progressed in the CNS. Median TTP is 12 weeks (3–69). Median overall survival is 10.1+ months (1–19+). Grade 1/2 toxicity consisted of: skin discoloration, fatigue, nausea, and headache. Grade 3/4 toxicity consisted of: blisters of the digits and hypophosphatemia. Conclusions: MGd was well tolerated and stabilization of disease was observed in pts with progressive disease. These results show promise for MGd in the previously treated MRCC population and potentially can be used in combination with other MRCC agents. [Table: see text]
Burden of illness analysis of renal cell carcinoma
Authors: Lang K. , Danchenko N. , Gondek K. , Schwartz B. , Thompson D. 
Published: March 2020

14548 Background: There were over 36,000 new cases of kidney cancer reported in the US in 2004, the most common being renal cell carcinoma (RCC). RCC patients have limited treatment options and low survival rates, particularly for advanced-staged patients. Despite the growing importance of RCC, data on its economic burden are limited. Methods: A prevalence-based approach was used to estimate the aggregate annual cost burden from a societal perspective, including costs of medical treatment and lost productivity, due to RCC in the U.S. Key relationships represented in the model include the annual number of patients treated for RCC by age group and cancer stage; utilization of cancer specific treatments; unit costs of these treatments; work-days missed by these patients, and wage rates. Data sources included the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the Bureau of Labor Statistics, and the published literature. Results: The annual prevalence of RCC in the US was estimated to be 109,500 cases. The associated annual burden of RCC (US $2005) was approximately $4.8 billion ($43,749 per patient). Healthcare costs and lost productivity accounted for 84.9% ($4.1 billion) and 15.1% ($726 million) of the total, respectively. Reflecting its higher prevalence, the total cost associated with localized RCC accounted for the greatest share (78.2%) followed by regional, distant and unstaged RCC, which accounted for 18.3%, 2.8% and 0.7%, respectively. Sensitivity analyses resulted in a range in the estimated annual burden from $3.9 to $5.2 billion. Focusing only on newly diagnosed RCC cases (approximately 25,000 per year), the annual burden was estimated at $1.5 billion, with a per-patient cost of $62,340. Conclusions: The economic burden of RCC in the US is substantial. New therapies for RCC have the potential to yield considerable economic and societal benefits. [Table: see text]
The treatment of primary and metastatic renal cell carcinoma (RCC) with stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS)
Authors: Teh B. S. , Bloch C. , Paulino A. C. , Doh L. , Chiang S. , Shen S. , Baskin D. , Jac J. , Amato R. J. 
Published: March 2020

14572 Background: RCC is often regarded as a radio-resistant tumor. However, brain metastases from RCC have been successful treated with SRS. Therefore, metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high dose radiation in a few fractions. We report our experience with SRS/SBRT in the management of primary and metastatic RCC. Methods: The image-guided Novalis radiation therapy system was used. Thirty patients with brain metastases were treated with SRS (16–22 Gy in a single fraction). Five of these patients underwent resection of their metastatic lesions after SRS and their pathology were reviewed. Twenty patients with extra-cranial metastatic lesions (orbits, head and neck, lung, mediatinum, sternum, clavicle, scapula, humerus, rib, spine, abdomen) and 2 patients with biopsy proven primary RCC (not surgical candidates), were treated with SBRT (24–32 Gy in 3–4 fractions over 1–2 weeks). All patients were immobilized in body cast and image-guidance was used for all fractions. 4D-CT was utilized in the treatment planning to assess tumor motion. Results: Of the 30 patients who received SRS to brain metastases, 25 showed decreasing or stable lesion size. Five patients showed an increase in size and underwent resection. Their pathology revealed necrosis in >99% of the specimen, with no viable RCC. Nineteen patients who received SBRT to extra-cranial metastases achieved symptom relief. One patient had local progression, yielding a local control rate of 95%. In the 2 patients with primary RCC, tumor size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There was no significant treatment related side-effect. Conclusions: Precise high dose radiation can cause significant tumor cell death in “radio-resistant” metastases from RCC. It also offers excellent local control and symptom palliation, without significant toxicity. Therefore, SBRT may represent a novel non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC. A prospective clinical trial using SBRT for primary and metastatic RCC is on-going. No significant financial relationships to disclose.
Phase II trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive bladder cancer: Preliminary results
Authors: Dienstmann R. , Herchenhorn D. , Peixoto F. A. , Campos F. , Santos V. O. , Moreira D. M. , Moreira D. M. , Small I. A. , Cardoso H. , Ferreira C. G. 
Published: March 2020

14590 Background: Gemcitabine and cisplatin (GC) is an active and well tolerated combination in the treatment of metastatic bladder cancer (BC). Studies of neoadjuvant chemotherapy in BC suggest improved survival, especially for patients with complete pathologic response. We have prospectively analyzed the tolerability and efficacy of GC as neoadjuvant treatment of invasive BC. Methods: in this single-institution, one-stage phase II trial, patients (pts) with histologically verified muscle-invasive transitional cell carcinoma received 3 cycles of gemcitabine 1200 mg/m2 on days 1 and 8 with cisplatin 75 mg/m2 on day 1 prior to surgery. Radiologic response was evaluated with computed tomography and magnetic resonance imaging. Planned accrual was 35 pts. Primary endpoint was clinical and pathological response rate. Results: between Jun 2002 and Mar 2005, 22 pts (19 males) were enrolled. Accrual was poor due to a higher percentage of superficial tumors than expected. Median age was 61 years. All pts had Performance Status 0 or 1. Initial stage was II (T2) in 11 and III (T3–4) in 11 pts. Chemotherapy was well tolerated with infrequent grade III/ IV toxicity (nausea/ vomiting in 27%, neutropenia in 23% and neutropenic fever in 1 patient). Median follow-up is 26 months (6–40). Partial radiologic response rate was documented in 15 out of 19 assessable pts (79%). One patient was excluded due to renal toxicity in the first chemotherapy cycle and other had sarcomatoid carcinoma at definitive pathologic examination. By Dec 2005, 14 pts underwent radical cystectomy, 4 pts pelvic radiotherapy, 1 is waiting surgery and 1 had systemic progression before surgery. Nine out of 20 pts (45%) relapsed (8 systemic and 1 local) and 4 (20%) are dead (3 with confirmed disease progression). Complete pathologic response was observed in 3 pts (21.5% of 14) and local progression during chemotherapy in another 3 pts. Median estimated progression-free survival by Kaplan-Meier is 27 months (CI 95% 20.5–33.5) with median overall survival not reached. Conclusions: the combination of gemcitabine and cisplatin is effective and tolerable when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact in the overall survival of these pts. [Table: see text]