Table S16 from High-Dose Intravenous Vitamin C Combined with Docetaxel in Men with Metastatic Castration-Resistant Prostate Cancer: A Randomized Placebo-Controlled Phase II Trial
Channing J. PallerMarianna ZahurakAdel MandlNicole A. MetriAliya LaljiElisabeth I. HeathWilliam K. KellyChristopher HoimesPedro C. BarataJason TakseyDominique A. GarrisonKartick PatraGinger L. MilneNicole M. AndersJulie M. NaurothJennifer N. DurhamCatherine H. MarshallMark C. MarkowskiMario A. EisenbergerEmmanuel S. AntonarakisMichael A. CarducciSamuel R. DenmeadeMark Levine
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<p>Table S16 shows Comparison of F2-Isoprostanes Control and Intervention Changes 60 minutes after Cycle 4</p>We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.
Prostate biopsy
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Docetaxel is an important anti-microtubule agent used to treat a variety of solid tumors, including breast cancer; notably, docetaxel-containing regimens improve outcomes for patients in metastatic, adjuvant, and neoadjuvant settings. However, the effectiveness of docetaxel in clinical practice can be compromised by suboptimal management of side effects. Here, we report two cases of docetaxel-based chemotherapy regimens in patients who exhibited invasive ductal breast cancer and underwent two different clinical treatment approaches. A 58-year-old postmenopausal female received salvage treatment with 8 cycles of docetaxel (67 mg/m2), and a 74-year-old female received 1 cycle of docetaxel (100 mg/m2). The two patients exhibited considerable hearing loss two days later. Of note, both patients had no hearing loss symptoms prior to docetaxel. Thus, ototoxicity may be a side effect of docetaxel that should be considered during treatment.
Ototoxicity
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62 歳，男性。4 型胃癌に対し胃全摘術を施行した。T 3， N 1， H 0， P 0， M 0， CYX であり，組織学的にはpoorly differentiated adenocarcinoma， ss， INF γ，ly2， v 2， n 2 であった。術後16 日目からTS-1 100mg/day を4 週投与2 週休薬を1 クールとして内服を開始，2 クールの投与を行った。投与終了ごろより腹部膨満感が出現し，CT を施行したところ著明な腹水の貯留を認めた。CEA は13.5ng/ml と上昇を示し，腹膜再発と診断した。外来にてdocetaxel40mg/body3 週投与1 週休薬を1 クールとして化学療法を開始した。CEA は6 クール目開始時には正常化した。CT でも腹水は消失しており，他の転移も認めなかったためCR と判定した。術後2 年，腹膜再発後1 年8 か月，10 クールのdocetaxel 投与終了後1 年経過した現在，無治療で観察中であるが再燃の徴候を認めていない。docetaxel の休薬や減量は不要であった。docetaxel のweekly 投与は安全に外来で施行可能なレジメンであり，胃癌領域でもその有効性が報告されている。本症例では胃癌に対して奏効率の高いTS-1 を投与中に発症した腹膜再発症例に対してdocetaxel が著効を示した。TS-1 無効例に対する治療についての検討は少ないが，FU 系の薬剤とは作用機序が異なることもあり，docetaxel のweekly 投与は有用な治療法となり得ると思われた。
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Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.
Carboplatin
Vinorelbine
Taxane
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e20595 Background: Docetaxel is currently approved in non-small cell lung Cancer (NSCLC) after a failure of first line chemotherapy. However, docetaxel has an unfavorable toxicity profile that limits its use. A docetaxel-containing regimen with an improved safety profile would therefore be attractive. Plinabulin, a first-in-class small molecule vascular disruptive agent with potent immuno-oncology effects, is being developed in combination with docetaxel to address this need. Methods: We conducted a Phase 2 study comparing the safety and efficacy of the plinabulin /docetaxel combination (n=90) with docetaxel alone (n=73) in patients with NSCLC entering 2nd or 3rd line therapy. Plinabulin was given intravenously at 20 mg/m2 (n= 40) or 30 mg/m2 (n=50) and docetaxel at 75 mg/m2(n=73). Results: Efficacy results of this study were presented at ASCO 2014. Baseline characteristics for age, gender, ECOG performance score, histology and disease status were comparable between groups. The plinabulin/docetaxel combination improved overall survival, in a subset of patients with large tumors (> 3 cm; HR=0.758, p =0.36), and also had duration of response benefit over docetaxel alone (12.7 vs 1.5 months; P<0.05). We are reporting on the safety profile of plinabulin/ docetaxel combination. Conclusions: In this Phase 2 study, the plinabulin/docetaxel combination mitigated some of the docetaxel toxicities. Most importantly it improved docetaxel dose intensity. The neutropenia benefit was likely due to plinabulin-induced release of cytokines such as IL-1 and IL-6 (data obtained in in-vitro plinabulin studies), which are known to increase neutrophil count. In addition, preliminary results indicated a potential efficacy benefit of the plinabulin/docetaxel combination over docetaxel alone. A global Phase 3 trial with the plinabulin/docetaxel combination vs docetaxel alone is currently underway in the US, China, Australia and New Zealand. Clinical trial information: NCT00630110.Adverse events. Plinabulin/Docetaxel Docetaxel Grade 3/4 Neutropenia * 7 % 25 % Use of G-CSF * 14 % 29 % Sepsis 0 % 3.6 % Severe infections 0 % 3.6 % Asthenia * 13 % 28 % Docetaxel dose reduction due to toxicity * 6 % 20 % *p<0.01; Plinabulin/docetaxel combination vs docetaxel alone.
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To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx).We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated.Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion.The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.
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Taxane
Clinical Practice
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Objective To investigate the expressions of mitosis regulative factor STK-15 in prostate cancer and the relationship between STK-15 and the biological behavior of prostate cancer.Methods The expressions of STK-15 were examined by using immunohistochemical staining on 63 cases of prostate cancer and 16 cases of normal prostate tissues.And the expressions of STK-15 mRNA were detected by using RT-PCR in 14 cases of prostate cancer,BPH,and normal prostate tissues respectively.Results The STK15 protein was expressed in 98%(62/63) of prostate cancer tissue and in 19%(3/16) of normal prostate tissues.The difference between these expression rates was significant(P0.001).Meanwhile,the positive expression rates of STK-15 mRNA in prostate cancer,BPH,and normal prostate tissue were 93%(13/14),21%(3/14) and 14%(2/14) respectively.Compared with those in BPH and normal prostate tissue,the STK-15 mRNA expression rate in prostate cancer was significantly high(P0.001).Meanwhile,there was no significant difference between those in BPH and normal prostate tissue(P0.05).Conclusion The expressions of STK-15 increase in prostate cancer tissues which may contribute to the prostate carcinogenesis.
Prostate Diseases
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Abstract Background We assessed the effect of biopsy location on the prostate cancer detection and clinically significant prostate cancer. Methods A total of 2774 patients with 12‐core prostate transrectal ultrasound‐guided prostate biopsy were included for per core analysis. Multivariate Cox regression analysis was performed to evaluate the effect of the location of biopsy on the prostate cancer and clinically significant prostate cancer detection. Results Prostate cancer was found in 775 patients (27.9%) and 576 prostate cancer patients (20.8%) were found to be clinically significant. The core length ( P = .043), tumor length ( P < .001), and % tumor length ( P < .001) were significantly different according to the biopsy location. The detection rates for prostate cancer and clinically significant prostate cancer differed significantly according to the location of biopsy. Multivariate analysis revealed that the apical core was significantly related with increased detection of prostate cancer and clinically significant prostate cancer. The lateral core, in addition to apical core, was found to be significantly related with increased detection rates of prostate cancer and clinically significant prostate cancer in men with prostate‐specific antigen <10 ng/mL. Conclusions More in‐depth discussions on the location of standard 12‐core prostate biopsy are considered necessary. Apical core and lateral core biopsies may be helpful, especially in patients with prostate‐specific antigen ˂10 ng/mL if additional biopsies are planned following findings of no target lesions on imaging studies.
Prostate biopsy
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