tbuckley/cabot-search huggingface dataset:
Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 in patients (pts) with metastatic castration-resistant prostate cancer (metCRPC)
Authors: S. T. Tagawa, S. Parmar, J. Pena, K. Petrillo, D. Matulich, J. Selzer, S. Vallabhajosula, S. J. Goldsmith, N. H. Bander, D. M. Nanus
Journal: Journal of Clinical Oncology (2009)

e16004 Background: Reversible myelosuppression is the dose-limiting toxicity of radioimmunotherapy (RIT). Cases of marrow damage, including myelodysplasia and acute leukemia have been reported with the RIT most used to date (that targeting CD20 in Non- Hodgkin's lymphoma), though no statistically significant association exists. In addition, post-RIT chemotherapy (chemo) may theoretically be limited. We have treated metCRPC pts with anti-PSMA RIT since 2000 and analyzed post-therapy outcomes. Methods: Follow-up across 4 prospective phase I and II trials utilizing 177 Lu-J591 and 90 Y-J591 was performed. Quality of hematologic recovery from post-RIT myelosuppression was documented. Administration of pre- and post-RIT chemo was analyzed. Specific searches for subsequent myelodysplasia and/or leukemia were performed. Results: Median age of the 109 treated pts is 70 (range 47–88). Entry criteria for all trials included progressive metCRPC, PS &lt; 2, normal baseline neutrophil and platelet counts, and hemoglobin &gt; 10 g/dL. 80 received 177 Lu-J591 at cumulative doses ranging from 10–120 mCi/m 2 and 29 received 90 Y-J591 at cumulative doses of 5–40 mCi/m 2 . 43% received at least 1 line of pre-RIT chemo, 53% received at least 1 line of post-RIT chemo, and 20% have never received chemo to date. All pts with adequate performance status received chemo except per pt choice. Excluding re-treated pts, 98% and 87% of assessable pts had full recovery of neutrophils and platelets respectively. Of the remaining, all but 4 recovered to Gr 1 neutropenia and/or thrombocytopenia. The most common reason for lack of complete hematologic recovery was CRPC progression in bone marrow (16 pts with persistent or recurrent myelosuppression underwent bone marrow biopsy). No cases of post-RIT myelodysplasia and/or leukemia were discovered. Conclusions: Anti-PSMA radioimmunotherapy is well-tolerated with efficacy previously reported. While follow-up is ongoing, reports of irreversible bone marrow damage appear unfounded and all patients with intact performance status willing to undergo post-RIT chemotherapy are able to receive it. [Table: see text]
Phase II trial of capecitabine and cisplatin in advanced, persistent or recurrent carcinoma of the cervix
Authors: H. Errihanni, I. Elghissassi, H. M'rabti, Y. Sbitti, S. Boutayeb, S. Afqir, Y. Bensouda
Journal: Journal of Clinical Oncology (2008)

5574 Background: Platinum-based drugs are the most active agents in cervical carcinoma. The aim of this study was to assess the activity and toxicity of the association cisplatine and capecitabine as first-line treatment in patients with advanced, persistent or recurrent carcinoma of the cervix. Patients and Methods: Patients with histological proven primary carcinoma, presence of measurable tumors, age ≥ 18, performance status of 0 or 1, and adequate bone marrow, renal, and hepatic functions were potentially eligible for this trial. Prior chemotherapy was allowed only in the context of radiosensitization. Treatment consisted of cisplatin 50mg/m2 intravenously on day 1 with capecitabine 2,500 mg/m2/day orally (divided into two doses given every 12 h) days 1–14 in 21-day cycles. Responses were assessed using response evaluation criteria in solid tumors. Results: Between November 2004 and October 2007, twenty-two women were entered into the trial. Median age: 51 years (range 37–70). Histology: squamous cell carcinoma: 20, adenocarcinoma: 2. Dominant sites of disease: pelvis: 15, lung: 8, liver: 5, bone: 3 and vagina: 3. 17 patients had prior radiotherapy and 13 received a radiation sensitizer, while 2 patients underwent exclusively surgery and 3 patients had no prior treatment. A median of 5 cycles was administered (range 2–8). There was one septic death. Grade III and IV Fatigue, gastrointestinal, neutropenia, renal and hand-foot syndrome was seen in 31.8%, 22.7%, 9%, 9% and 9% patients, respectively. There were 1 complete response, and 6 partial responses, for an overall response rate of 31,8%. The overall response rate was 23,5% in patients with recurrent disease within the previous irradiated field and 60% in patients with tumor outside the irradiated field. Seven patients (31,8%) each had stable disease and eight showed progression. The median time to progression was 8 months with a median overall survival of 20 months. Conclusions: These results seem to suggest that capecitabine- cisplatin combination is safe, well tolerated, and moderately active in advanced, persistent or recurrent cervical carcinoma patients. Further evaluation of this drug combination may be warranted. No significant financial relationships to disclose.
Predictors of permanent menopause after chemotherapy for early-stage breast cancer in premenopausal women
Authors: H. C. Moore, J. Kim, C. Rodriguez, G. T. Budd, L. Rybicki
Journal: Journal of Clinical Oncology (2009)

575 Background: Optimal choice of endocrine therapy for early-stage breast cancer differs with menopausal status. While amenorrhea is common during adjuvant chemotherapy, there is currently no available test to establish when menopause is permanent. The aim of this study was to determine the age cutoff after which resumption of menses is unlikely following chemotherapy and to assess what additional risk factors may predict for persistent menopause at 5 years after initiation of chemotherapy. Methods: One hundred patients treated with chemotherapy for early-stage premenopausal breast cancer and who remained alive and free of recurrence at least 5 years from the start of treatment were enrolled. Participants were evaluated for current menstrual status and for baseline potential risk factors for menopause: age at start of chemotherapy, race, BMI, smoking history, age at menarche, irregular menses prior to chemotherapy, presence of menses during chemotherapy, type of chemotherapy regimen, hormonal therapy, ovarian protection during chemotherapy, and number of doses of alkylating agent (cyclophosphamide). Recursive partitioning analysis (RPA) was used to identify the age cutoff that best predicts permanent menopause; additional risk factors were assessed using logistic regression analysis. Results: Median age at start of chemotherapy was 43 (range 26–49). RPA identified age &gt;42 at the start of chemotherapy as a significant predictor of permanent menopause (p &lt; 0.001). Cessation of menses during chemotherapy was also associated with permanent menopause (p &lt; 0.001). Both variables remained significant in multivariate analysis (p &lt; 0.001), with the combination of these factors being associated with a 95.4% chance of permanent menopause. Conclusions: In this series, fewer than 5% of premenopausal patients who were at least 42 years old and who experienced cessation of menses during chemotherapy experienced any return of menses over at least 5 years. Upfront use of aromatase inhibitors as adjuvant endocrine therapy for premenopausal hormone-receptor positive breast cancer warrants further investigation for those who are at least 42 years of age and who experience amenorrhea with chemotherapy. No significant financial relationships to disclose.
The ultra-low molecular weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in patients with cancer receiving chemotherapy: SAVE ONCO study.
Authors: G. Agnelli, D. J. George, W. Fisher, A. K. Kakkar, M. R. Lassen, P. Mismetti, P. Mouret, U. Chaudhari, A. G. G. Turpie
Journal: Journal of Clinical Oncology (2011)

LBA9014 Background: Patients receiving chemotherapy for cancer are at increased risk for VTE; large randomized controlled trials (RCT) are needed to demonstrate benefit of antithrombotic prophylaxis. Semuloparin is a novel ULMWH with high anti-factor Xa and residual anti-factor IIa activities. We performed a multinational RCT to assess the efficacy and safety of semuloparin for VTE prevention in cancer patients receiving chemotherapy (SAVE-ONCO). Methods: This was a double-blind study in patients with metastatic or locally advanced cancer of lung, colon-rectum, stomach, ovary, pancreas, or bladder, initiating a new chemotherapy course. Patients were randomized to receive subcutaneous semuloparin, 20 mg od, or placebo, until change of chemotherapy. The primary efficacy outcome was the composite of any symptomatic deep vein thrombosis (DVT), non fatal pulmonary embolism (PE) and VTE-related death. Clinically relevant bleeding was the main safety outcome. Outcomes were adjudicated by an independent Committee. Results: Of 3,212 randomized patients, 68% had metastatic cancer; the majority had lung (37%) or colon-rectum (29%) cancer. Median treatment duration was ~3.5 months. Twenty of the 1,608 patients treated with semuloparin (1.2%) and 55 of the 1,604 patients treated with placebo (3.4%) had a thromboembolic event, representing a 64% risk reduction in such event rate (hazard ratio [HR]=0.36, 95% confidence interval [CI] 0.21–0.60, p&lt;0.0001, intent-to-treat analysis). Treatment effect was consistent for DVT and PE, with a 59% risk reduction in PE rate (odds ratio 0.41, 95%CI 0.19–0.85). No heterogeneity in the benefit was observed for cancer type or stage. Nineteen of 1,589 patients (1.2%) in the semuloparin and 18 of the 1,583 patients (1.1%) in the placebo group had a major bleeding (HR=1.05, 95%CI 0.55 to 1.99). The rate of clinically relevant bleeding was 2.8% with semuloparin vs 2.0% with placebo (HR=1.40, 95%CI 0.89–2.21). Conclusions: We have demonstrated the benefit of thromboprophylaxis with semuloparin in patients receiving chemotherapy without increase in major bleeding. Such patients should be considered for thromboprophylaxis.
Monochemotherapy vs. doublet vs. triplet chemotherapy (CTX) with predefined sequence for 2<sup>nd</sup>-line therapy in stage IIIb and IV NSCLC: A randomised phase III trial
Authors: T. H. Fink, J. R. Fischer, E. Jäger, U. Seifart, L. J. Müller, P. Schiller, C. Klose, M. Wolf
Journal: Journal of Clinical Oncology (2008)

19008 Background: The optimal intensity of CTX for palliative treatment in stage IIIb/IV NSCLC is still unclear. We initiated a prospective, randomised phase III trial comparing mono vs. doublet vs. triplet CTX given in both 1st- and 2nd-line therapy. Methods: 280 patients with advanced stage IIIB/IV NSCLC were randomized to Arm A: Gemcitabine (Gem) 1g/m2, d1,8, q3w followed by 2nd-line Vinorelbine (Vin) 30 mg/m2, d1,8, q4w or Arm B: Gem, d1,8 + Carboplatin (Cbp) AUC 5, d1, q3w followed by 2nd line Vin 25 mg/m2, d1,8, + Mitomycin (Myc) 8 mg/m2, d1, q4w or Arm C: Gem, d1,8, + Cbp, d1, + Vin 25 mg/m2, d1,8, q3w followed by 2nd-line Myc 6 mg/m2, d1 + Ifosfamide 3 g/m2, d1, + Cisplatin 50 mg/m2, d1, q4w. 1st-line CTX was given for 6 cycles or until PD, 2nd-line until PD. A stratified log rank test of differences in overall survival between study arms was performed modified to the final recruitment of 280 pts. Results: Accrual per arm was A=94, B=93 and C=93 patients. Follow-up was 9 months. Median survival was 8.3 (A), 7.5 (B) and 9.5 months (C), respectively (p=0.1546). No statistically significant differences were observed, however, there was a trend to better survival for arm C vs. A or B. Hematologic toxicity was higher in 1st-line doublet or triplet CTX. Severe toxicities (%) in arms A/B/C were: Leucopenia (<1.000): 0/0/16.1; anemia (Hb<9): 10.2/44.6/53.4; thrombocytopenia (<50.000): 6.8/52.2/58.0. Nonhematological toxicities were not substantially different between arms. Conclusions: A trend to better survival was observed for triplet CTX with lack of statistical significance. Pronounced hematotoxicity was observed in combination arms, most prominent in triplet CTX. No significant financial relationships to disclose.
JS-K, a GST-Activated Nitric Oxide Generator, Induces Apoptosis and Overcomes In Vitro Drug Resistance in Multiple Myeloma Cells.
Authors: Tanyel Kiziltepe, Kenji Ishitsuka, Teru Hideshima, Noopur Raje, Norihiko Shiraishi, Hiroshi Yasui, Laurence Catley, Dharminder Chauhan, Joseph E. Saavedra, Larry K. Keefer, Paul J. Shami, Kenneth C. Anderson
Journal: Blood (2005)
Effect of aprepitant for the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized double-blind trial in 866 patients
Authors: D. G. Warr, P. Eisenberg, P. J. Hesketh, R. J. Gralla, H. Muss, H. Raftopolous, M. Gabriel, A. Rodgers, C. M. Hustad, F. Skobieranda
Journal: Journal of Clinical Oncology (2004)

8007 Background: A regimen containing aprepitant (APR), a neurokinin-1 receptor antagonist (NK1RA), has been proven to be effective for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). This is the first phase III study in which aprepitant has been evaluated for the prevention of CINV with non-cisplatin-based moderately emetogenic chemotherapy (MEC). Methods: This was a worldwide, multicenter, randomized, double-blind, parallel-group study funded by Merck & Co., Inc. Eligible breast cancer patients were naïve to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomized to either an Aprepitant Regimen (Day 1: APR 125mg, ondansetron (OND) 8mg, and dexamethasone (dex) 12mg before chemotherapy and OND 8mg 8 hours later; Days 2–3: APR 80 qd) or a Standard Regimen (Day 1: OND 8mg and dex 20mg before chemotherapy and OND 8mg 8 hours later; Days 2–3: OND 8mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy endpoint was the proportion of patients with complete response in the 120 hours after initiation of chemotherapy, defined as no vomiting and no use of rescue therapy, in cycle 1. Safety was also assessed.Results: Of 866 patients randomized, 857 (99%) were evaluable; 99% were women, and 99% received both an anthracycline and cyclophosphamide. Overall complete response was greater with the aprepitant regimen than with the standard regimen (50.8% vs. 42.5%, p=0.015). More patients taking aprepitant reported no vomiting (75.7% vs. 58.7%, p<0.001). Reports of no use of rescue therapy were similar (58.7% vs. 56.2%). More patients taking aprepitant achieved a complete response during both acute (75.7% vs. 69.0%, p=0.034) and delayed (55.4% vs. 49.1%, p=0.064) phases. Both treatments were generally well tolerated. Conclusions: The aprepitant regimen is more effective than the standard regimen for the prevention of CINV in patients receiving non-cisplatin-based moderately emetogenic chemotherapy. These and previous similar results for cisplatin-based HEC demonstrate the utility of the aprepitant regimen for the prevention of CINV across the range of emetogenic chemotherapies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc. Helsimm; Merck & Co., Inc.; MGI Pharma Merck & Co., Inc. Merck & Co., Inc.; Merck Frosst Canada Merck & Co., Inc.
Outcomes of second line chemotherapy (II-LC) in platinum resistant non small cell lung cancer (NSCLC)
Authors: D. Tassinari, C. Santelmo, E. Tamburini, C. Possenti, L. Lazzari Agli
Journal: Journal of Clinical Oncology (2008)

19058 Background: To assess the outcomes of II-LC in platinum-resistant NSCLC. Methods: A systematic review of literature in the MEDLINE and EMBASE data bases from 2000 to 2007 was performed independently by two authors (DT and ET). 3-weekly docetaxel (3WD) was considered the gold standard chemotherapy on the basis of the TAX317 trial. All the randomized phase III trials comparing 3WD with other schedules were considered eligible and included into the analysis. 1-year survival rate (1YSR) was the primary outcome of the analysis; response rate (RR) and time to progression (TTP) the secondary ones. Moreover, a sub-analysis including the trials comparing 3WD and weekly docetaxel (WD) was secondarily performed. Heterogeneity between the trials was analysed using the Mantel-Haenszel test; the outcome analysis was performed using a random effects model and an alpha error lower than 5%. Results: 8 trials met the selection criteria and were included into the analysis. The outcomes of 2671 patients (1292 treated with 3WD, 283 with pemetrexed, 468 with WD, 214 with vinorelbine and 414 with topotecan) were compared in the pooled analysis. 1YSR and RR were reported in all the selected trials, and TTP in 3 ones. A significant heterogeneity was documented between the trials (p<0.0001). No significant differences between the treatments were observed respectively for 1YSR (Odds Ratio=0.85, p=0.42), RR (Odds Ratio=0.80, p=0.337) and TTP (Odds Ratio=0.82, p=0.129). 4 trials (enrolling 843 patients) compared 3WD (375 patients) with WD (468 patients). 1YSR and RR were the outcomes reported in the trials. No significant heterogeneity was documented between the trials (p=0.164). No significant differences between the treatments were observed respectively for 1YSR (Odds Ratio=1.29, p=0.22), and RR (Odds Ratio=1.01, p=0.97). Conclusions: Till today no evidences exist supporting a superiority of alternative schedules to 3WD. A comparative analysis of quality of life, side effects, patient’s preferences and comprehensive costs is probably needed to better define the actual gold standard in the treatment of platinum- resistant NSCLC. No significant financial relationships to disclose.
Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria
Authors: Sébastien Wielgoss, Tobias Bergmiller, Anna M. Bischofberger, Alex R. Hall
Journal: Molecular Biology and Evolution (2015)

Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.
Clinical relevance of a novel EGF pathway directly linked to E2F3a in ovarian cancer
Authors: D. U. Reimer, M. Hubalek, A. Wiedmair, V. Porto, D. Auer, E. Mueller-Holzner, C. Marth, A. G. Zeimet
Journal: Journal of Clinical Oncology (2008)

5588 Background: Over the last decade the retinoblastoma protein and its down-stream effectors have been shown to be involved in tumorigenesis and progression in various cancer entities. Especially the E2F family of transcription factors, are regarded to be fundamental players in the deregulation of the cell cycle control. Proliferation-promoting E2F1 to E2F3a are responsible for promoting the cell cycle at the G1/S phase checkpoint, E2F3b to E2F8 seem to act as inhibitors of cell proliferation. By our knowledge, there are no data considering a direct interplay between the EGF-R dependent pathways and the E2F family. Methods: The functional relationship between E2F3 isoforms and EGF-R was evaluated in EGF stimulated ovarian cancer cell lines by the use of RT-PCR. Protein expression was estimated by immunoblot analyses. In vitro data and expression of miRNA-34a were confirmed in a collective of 128 ovarian cancer patients. Results: Herein we show that in ovarian cancer cell lines EGF and TGF-alpha treatment selectively increase the transcription of E2F3a, whereas all other members of the E2F-family remain unaffected upon EGF-R stimulation. E2F3a transcription was completely abolished by simultaneous treatment with EGF-R inhibitors such as Cetuximab, Erlotinib and Lapatinib. Furthermore, the E2F3a peak observed after 3 to 12 hrs after EGF treatment was associated with the initiation of cell proliferation. In addition, our investigations reveal, that EGF treatment also reduced the transcription of miRNA-34a, a specific negative epigenetic regulator of E2F3a, in ovarian cancer cells. E2F3a and E2F3b expression are shown to be elevated in 128 ovarian cancer tissue samples compared to healthy controls. Both isoforms were significantly associated with FIGO stage and histological grading. However, only the proliferation-promoting E2F3a was associated with immunohistochemically demonstrated phosphorylated EGF-R and turned out to be an independent prognosticator for progression free and overall survival. In line with this, E2F3a was also the only member of the E2F-family which was constitutively up-regulated in platinum resistant ovarian cancer cell lines. Conclusion: Taken together, this so far un-described EGF-E2F3a axis seems to play a pivotal role in the tumor biology of ovarian cancer. No significant financial relationships to disclose.