tbuckley/cabot-search huggingface dataset:
Interrogating metastatic prostate cancer treatment switch decisions.
Authors: David Lorente, Praful Ravi, Niven Mehra, Carmel Jo Pezaro, Aurelius Gabriel Omlin, Miguel Miranda, Heather Payne, Emma Hall, Leon W M M Terstappen, Maarten J Ijzerman, Johann S. De Bono
Journal: Journal of Clinical Oncology (2016)

296 Background: Increased availability of treatment options in CRPC requires improved biomarkers to optimize decision making for therapeutic sequencing. Despite evidence for the value of CTCs in assessing prognosis and response to treatment, their use in clinical practice is not widely implemented. Clinicians rely on PCWG2 criteria based on PSA, clinical and radiological criteria although these are only inconsistently used in clinical practice. We evaluated the trends for clinical decision-making by physicians treating CRPC. Methods: An online questionnaire was distributed to physicians treating PC from the UK, Switzerland and Australia. Questions on clinical practice, familiarity with progression criteria, use of CTCs and clinical-decision making were formulated. Results: 111 participants replied. Most (84.7%) were oncologists treating ≥ 50 patients per year (65.3%). Although only 39.6% usually used PCWG2 in clinical practice, 74.5% considered PSA, bone scans and CT to be useful for monitoring disease. 55.6% considered PSA to be an important biomarker. A minority were able to identify PSA (41.4%) and bone scan (39.4%) progression criteria by PCWG2. On average, more physicians discontinued cabazitaxel (28%) than docetaxel (10.4%) before cycle 4. Similar number of cycles were given to bone only disease compared to RECIST evaluable patients. Clinical progression was most important for switching treatment for most physicians (90.5%), followed by RECIST (71.6%), bone scan (47.7%), CTC (23.2%) and PSA (21.1%). The main challenge associated with the use of CTCs was the access to technology (84.7%). Most respondents (92%) would not stop therapy with rising PSA but falling CTC counts; most (88.8%) would not stop with declining PSA but rising CTCs. Although 50% acknowledged the prognostic value of CTCs, only 33% would use them to guide decision-making. Conclusions: A significant number of physicians discontinue treatment before 12 weeks. Most physicians rely on clinical progression for decision-making. Knowledge of PCWG2 response and progression criteria is generally suboptimal. Greater physician awareness, access to technology and further evidence and will be required for the implementation of CTCs as a routine biomarker in CRPC.
NON-Peptidyl Small Molecule EPO Receptor Agonists Are Potent Pathway Selective Inducers of Erythropoiesis.
Authors: Reid P. Bissonnette, Deepa Rungta, Andrew R Hudson, Steven L Roach, Mei Hua Hong, Hong Sun, Junlian Hu, James N Ward, Wen Luo, Jen E Sanders, Peter M Syka, Daniela A Slavin, Lin Zhi, Keith B Marschke
Journal: Blood (2010)
Pilot phase II study with docetaxel in combination with curcuminoids in patients with hormone-resistant prostate cancer (HRPC).
Authors: H. Mahammedi, E. Planchat, H. Cure, C. Barthomeuf, M. Bayet-Robert, M. Mouret-Reynier, C. Abrial, E. Thivat, M. Atger, L. Savareux, L. Guy, J. Goyard, P. J. M. Chollet, J. Nabholtz, X. Durando, J. Eymard
Journal: Journal of Clinical Oncology (2011)

e15069 Background: Prostate cancer is the most frequent tumor in men from developed countries. A previous phase I study showed the feasability of curcuminoids in association with docetaxel for advanced breast cancers. Despite several analogies, HRPC has a lower sensitivity to chemotherapy than breast cancer. Docetaxel (first-line reference treatment in HRPC) induces a PSA response in 45% of treated patients. However, the objective tumor response is limited to 12%. A pilot phase II study was conducted to assess the response of HRPC to docetaxel/curcuminoids combination. Methods: Docetaxel was given (75mg/m² + prednisolone, every 3 weeks for 6 cycles) in combination with curcuminoids orally at the dose of 6g/day according to previous phase I schedule (7 days/cycle: d-4 to d+2). The primary endpoint was the response rate assessed by clinical, biological and paraclinical examinations. The secondary endpoints included safety, time to progression (TTP) and compliance. Results: Among the 30 patients included (october 2009 to november 2010), data are available for 25 patients with a mean age of 69 years (range 58-83). Of 139 cycles, 122 (88%) were completed with perfect compliance. Twenty one patients received the 6 courses and 4 withdrew prematurely. No patient withdrew for toxicity. The most common grade-3-4 hematological toxicity was neutropenia and 2 patients presented with grade-2 anemia. For non-hematological toxicity, 4 grade-3 and 23 grade-2 adverse events were observed: mainly asthenia, diarrhea and ungueal toxicity. A PSA response was observed in 14 of the 24 evaluable patients (59%). The responses were complete (3 patients) or partial (11 patients) and were observed rapidly (before the 3rd cycle) in 12 patients. Fourteen of 25 patients had measurable or evaluable lesions (RECIST criteria), with 5 (36%) partial responses; 8 (57%) stable disease, 1 (7%) progressive disease. The median PSA TTP was 5.85 months (TTP on targets are not yet available). Conclusions: In HRPC patients, combination with curcuminoids tends to improve the response rate of docetaxel in terms of both PSA level and objective responses. This justify further randomized trials.
Mechanistic added value of a trans-Sulfonamide-Platinum-Complex in human melanoma cell lines and synergism with cis-Platin
Authors: Alba Agudo-López, Elena Prieto-García, José Alemán, Carlos Pérez, C. Vanesa Díaz-García, Lucía Parrilla-Rubio, Silvia Cabrera, Carmen Navarro-Ranninger, Hernán Cortés-Funes, José A. López-Martín, M. Teresa Agulló-Ortuño
Journal: Molecular Cancer (2017)

Cisplatin is a potent antitumor agent. However, toxicity and primary and secondary resistance are major limitations of cisplatin-based chemotherapy, leading to therapeutic failure. We have previously reported that mono-sulfonamide platinum complexes have good antitumor activity against different tumoral cell lines and with a different and better cytotoxic profile than cisplatin. Besides, N-sulfonamides have been used extensively in medicinal chemistry as bactericides, anticonvulsant, inhibitors of the carbonic anhydrase, inhibitors of histone deacetylases, and inhibitors of microtubule polymerization, among others. We aimed to compare the cytotoxic effects of cisplatin and a trans-sulfonamide-platinum-complex (TSPC), in two human melanoma cell lines that differ in their TP53 status: SK-MEL-5, TP53 wild type, and SK-MEL-28, TP53 mutated. We performed cytotoxicity assays with both drugs, alone and in combination, cell cycle analyses, western blotting and immunoprecipitation, and fluorescence immunocytochemistry. TSPC had similar antiproliferative activity than cisplatin against SK-MEL-5 (3.24 ± 1.08 vs 2.89 ± 1.12 μM) and higher against SK-MEL-28 cells (5.83 ± 1.06 vs 10.17 ± 1.29 μM). Combination of both drugs inhibited proliferation in both cell lines, being especially important in SK-MEL-28, and showing a synergistic effect. In contrast to cisplatin, TSPC caused G1 instead G2/M arrest in both cell lines. Our present findings indicate that the G1 arrest is associated with the induction of CDKN1A and CDKN1B proteins, and that this response is also present in melanoma cells containing TP53 mutated. Also, strong accumulation of CDKN1A and CDKN1B in cells nuclei was seen upon TSPC treatment in both cell lines. Overall, these findings provide a new promising TSPC compound with in vitro antitumor activity against melanoma cell lines, and with a different mechanism of action from that of cisplatin. Besides, TSPC synergism with cisplatin facilitates its potential use for co-treatment to reduce toxicity and resistance against cisplatin. TSPC remains a promising lead compound for the generation of novel antineoplastic agent and to explore its synergism with other DNA damaging agents.
Factors associated with mortality in an inpatient acute palliative care unit at a comprehensive cancer center
Authors: A. F. Elsayem, M. Mori, H. A. Parsons, M. Munsell, N. A. Fadul, D. Hui, M. O. Delgado-Guay, T. Paraskevopoulos, E. Bruera
Journal: Journal of Clinical Oncology (2008)

20756 Background: Predicting inpatient mortality has clinical and financial implications and helps improve the care of advanced cancer patients and their families. Models are available for mortality prediction in intensive care units with excellent validity and reliability. The purpose of this study was to determine factors associated with increased likelihood of mortality in an acute palliative care unit (PCU). Methods: We reviewed the medical records of 357 patients admitted to the PCU and collected information regarding demographic factors, tumor type, hospital length of stay, source of admission, and insurance type. Symptom intensity, vital signs, relevant laboratory tests and presence/absence of delirium were obtained from the palliative care consultation preceding PCU admission. Univariate and multivariate analyses were conducted to compare factors in patients who died in the PCU vs. those who were discharged alive. Results: 93 (26%) patients died in the PCU. The results for univariate and multivariate analyses are described in the table. Surprisingly, no statistically significant association was found between inpatient death and delirium or low lymphocyte percentage. Borderline association was found between inpatient death and high bilirubin, high LDH, elevated white blood cell counts and also with hematologic malignancy. Conclusion: We have observed significant association of certain factors with increased likelihood of PCU death in advanced cancer patients. These findings need to be validated in a larger prospective study to develop a model predicting PCU mortality for advanced cancer patients. Factor Univariate Analysis Multivariate Analysis OR p OR p Medicare/Medicaid vs. Private or Self pay 0.59 0.044 Age ≥ 65 vs. < 65 0.49 0.010 0.36 0.001 Consultation team referral vs. Emergency Center 2.54 0.114 1.74 0.380 Consultation team referral vs. outpatient center 4.03 0.005 3.93 0.009 Low platelets (<140.000) 2.15 0.003 Low sodium (<135) 1.81 0.021 2.75 0.001 High sodium (>147) 3.67 0.047 3.05 0.110 Low CO2 (<23) 2.29 0.004 High BUN (>20) 1.93 0.014 High heart rate (≥101) 2.07 0.006 High respiratory rate (≥21) 1.88 0.010 1.80 0.036 Supplemental O2 use 2.80 < 0.001 2.35 0.003 Dyspnea * 1.16 0.002 * Not included in the multivariate model. No significant financial relationships to disclose.
Relationship between survival and lymph node assessment from a population-based study of colorectal cancer patients.
Authors: R. Urquhart, J. Bu, G. A. Porter, R. Dewar, R. Moineddin, E. Grunfeld
Journal: Journal of Clinical Oncology (2010)

6125 Background: Within a 5-year population-based cohort of colorectal cancer (CRC) patients with Collaborative Stage in Nova Scotia (NS), Canada, survival curves showed that stage IIIA patients had better 1-year overall survival (OS) than stage I patients and better 5-year OS than stage II patients. We hypothesize that the Collaborative Staging system, which uses clinical data in the absence of pathology data, may be partially responsible for this finding. Thus, the objective of this study is to further explore the relationship between lymph node (LN) assessment and OS in CRC patients. Methods: All CRC patients diagnosed between 2001-2005 were identified through the NS Cancer Registry (n = 3501). Linkage with vital statistics data allowed for determination of survival to March 31, 2008. The Kaplan-Meier method was used to estimate stage-specific 1- year and 5-year OS. Cox Regression was used to examine the relationship between LN assessment and OS for stage I and II patients. Results: Controlling for age and comorbidity, compared with stage III patients, the adjusted OS for stage I patients with assessed LN (HR = 0.36, p < 0.0001) and without assessed LN (HR = 0.626, p < 0.0001) were higher. Compared with stage III patients, the adjusted OS for stage II patients with assessed LN (HR = 0.6, p < 0.0001) was higher and without assessed LN (HR = 2.3, p < 0.0001) was lower. Conclusions: The lower OS for stage II patients appears to be related to LN assessment. Reasons for not pathologically assessing LN in CRC patients include not undergoing a resection or undergoing a resection for rectal cancer that does not involve LN removal. Further analyses are warranted to explore the impact of pathologically unassessed LN on stage misclassification and ultimately survival, particularly in the setting of Collaborative Staging where patients with pathologically unassessed LN may be classified as stage I or II patients. No significant financial relationships to disclose.
The role of relative lymphocyte count as a new biomarker for the effect of catumaxomab on overall survival in patients with malignant ascites: Follow-up results from a phase ll/lll study.
Authors: M. M. Heiss, M. A. Ströhlein, C. Bokemeyer, D. Arnold, S. L. Parsons, M. G. Ott, E. Schulze, H. Lindhofer, D. Seimetz, M. Hennig
Journal: Journal of Clinical Oncology (2011)

2512 Background: Catumaxomab (anti-EpCAM x anti-CD3) is approved in the EU for the intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas. Here we report the follow-up overall survival (OS) results including long-term survival for the pivotal phase II/III randomized study in patients with malignant ascites due to different epithelial cancers. In addition, the impact of relative lymphocyte count (RLC) as a new biomarker for the efficacy of catumaxomab therapy was tested on the basis of a separate small hypothesis-generating study. Methods: Survival analyses were performed for the safety set of the pivotal trial (paracentesis + catumaxomab [catumaxomab]: n=157; paracentesis alone [control]: n=88). In order to identify patients with pronounced OS benefit, the impact of treatment and RLC was evaluated using the Cox model. For group comparisons, the Kaplan-Meier method and log-rank test were applied. Results: Follow-up results showed a statistically significant benefit in OS for catumaxomab-treated patients compared with controls (p=0.0219, HR=0.649). The 6-month OS rate in these patients was 28.9% compared with 6.7% for the control group. In addition, elevation of RLC had a positive impact on OS (p<0.0001). In patients with a RLC >13% (n=159: 100 catumaxomab; 59 control), catumaxomab treatment was associated with a pronounced beneficial effect on OS vs controls (p=0.0072, HR=0.518), with a median/mean OS benefit of 41/131 days and an increased 6-month survival rate of 37.0% vs 5.2% in the control group. The time to first paracentesis was significantly prolonged by catumaxomab treatment for patients with a RLC below (p<0.0001, HR=0.159) and above (p<0.0001, HR=0.182) the threshold of 13%. Conclusions: Intraperitoneal treatment with catumaxomab significantly improved OS in patients with malignant ascites due to EpCAM-positive carcinomas. A RLC >13% at start of treatment was a significant biomarker for a prolonged OS outcome with catumaxomab therapy and should lead to further investigation into the immunology of this clinical observation.
Chemosensitivity and endocrine sensitivity prediction by MammaPrint and BluePrint in the Neoadjuvant Breast Registry Symphony Trial (NBRST).
Authors: Pat W. Whitworth, Mark Gittleman, Stephanie Akbari, Lisette Stork, Femke De Snoo, Sarah Untch, Peter D. Beitsch
Journal: Journal of Clinical Oncology (2014)

29 Background: Classification into molecular subtypes is important for the selection of therapy for patients with breast cancer. Previous analyses demonstrated that breast cancer subtypes have distinct clinical outcome (Gluck, BCRT 2013). The aim of the prospective NBRST study is to measure chemosensitivity as defined by pathologic complete response (pCR), or endocrine sensitivity as defined by partial response (PR) and metastasis-free survival in molecular subgroups. Methods: The study includes women aged 18 to 90 with histologically proven breast cancer, who are scheduled to start neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy (NET), and who provide written informed consent. Additional inclusion criteria include no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment is at the discretion of the physician adhering to NCCN approved regimens. Results: Of 336 patients, T1-4 N0-3, had definitive surgery and the overall pCR rate was 24%. 32/167 (19%) IHC/FISH ERPR+/Her2- patients were reclassified by BluePrint (31 Basal). 43/95 (45%) IHC/FISH Her2+ patients were reclassified by BluePrint (25 Luminal and 18 Basal). 3/74 (3%) IHC/FISH triple-negative patients were not Basal by BluePrint. Of 45 (13%) patients classified as Luminal A 32 received NCT; one patient (3%) had a pCR; 13 patients received NET and 9 (70%) had a PR. Of 116 (35%) patients classified as Luminal B, 111 received NCT and seven (6%) had a pCR. The pCR rate (17/149 (11%)) in IHC/FISH ERPR+/HER2- patients was higher. Fifty-five (16%) are BluePrint HER2 and received NCT (51 plus trastuzumab); 27 (49%) had a pCR compared to 35/95 (37%) in IHC/FISH HER2+ patients. One-hundred twenty (36%) are BluePrint Basal and received NCT; 46 (38%) had a pCR, similar to the pCR percentage seen in the 74 patients designated triple-negative by IHC/FISH. Conclusions: Molecular subtyping using MammaPrint and BluePrint leads to a reclassification of 23% (78/336) of tumors. BluePrint reclassification resulted in better grouping of patients into expected response groups compared to local surrogate subtyping with immunostains.
Different effects of sunitinib, sorafenib, and pazopanib on inducing cancer cell death: The role of autophagy.
Authors: Matteo Santoni, Consuelo Amantini, Maria Beatrice Morelli, Valerio Farfariello, Massimo Nabissi, Sonia Liberati, Laura Bonfili, Matteo Mozzicafreddo, Anna Maria Eleuteri, Luciano Burattini, Rossana Berardi, Stefano Cascinu, Giorgio Santoni
Journal: Journal of Clinical Oncology (2013)

270 Background: Tyrosine kinase inhibitors (TKI), such as sunitinib, sorafenib and pazopanib, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). However, their use in sequential or combined strategies is limited by the lack of evidences on the ability of TKIs to induce cell death in cancer cells. Aim of our study was to evaluate the different mechanisms responsible of the cytotoxic effects induced in vitro by µM doses of sunitinib, sorafenib and pazopanib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with the anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Necrosis and apoptosis, (ΔΨ m ) dissipation and ROS generation were determined by Annexin-V/PI, JC-1 and DCFDA staining, respectively and cytofluorimetric analysis. The cathepsin B activity was evaluated by ELISA. Finally, by mRNA estraction and RT-PCR array the pazopanib-induced gene profile expression was evaluated. Results: We found that treatment of 5637 and J82 BC cells with the three TKI agents markedly reduced cell viability. Treatment for 24 h with sunitinib and sorafenib at 20 µM dose, triggers an incomplete autophagy of BC cells. In addition, inhibition of autophagy induced by sunitinib and sorafenib triggers cell death of BC cells. Thus, sunitinib by imparing the cathepsin B activity induces lysosomal-dependent necrosis. Similarly, sorafenib by defective lysosomial degradation triggers ROS- and mitochondrial-dependent apoptosis. As regard to pazopanib, we first demonstrate that treatment of BC cells for 72 hrs (20 µM) induces autophagic Type II cell death, which was markedly reversed in a dose-dependent manner by 3MA and chloroquine autophagic inhibitors. Finally, pazopanib upregulates the mRNA expression of α-glucosidase (GAA) and TP73 belonging to the p53 tumor suppressor genes. Conclusions: Overall, our results showing different TKI-induced cell death mechanisms provide the rationale for the sequential use of these agents and the biological basis for novel molecularly targeted approaches.
Tesetaxel, an advanced-generation oral taxane, as first-line treatment in women with metastatic breast cancer.
Authors: L. S. Schwartzberg, M. Beeram, A. Patnaik, A. W. Tolcher, L. Itri, A. L. Olson, A. D. Seidman
Journal: Journal of Clinical Oncology (2011)

TPS123 Background: Taxanes such as docetaxel and paclitaxel are among the most active agents in metastatic breast cancer (MBC). Tesetaxel is an active novel taxoid that overcomes disadvantages of these standard agents. Among other features, the drug is taken by mouth as an oral capsule. Tesetaxel is not a substrate for P-glycoprotein, a major cause of taxane resistance. The drug is not associated with hypersensitivity reactions, thus obviating the need for both premedications and extended medical/nursing observation. Preclinical studies in human tumor xenografts show activity in taxane-resistant BC as well as reduced peripheral neuropathy. In dose-ranging studies, 8 of 13 evaluable patients (pts) (62%) with MBC achieved prolonged stable disease (SD) (i.e., up to 24 cycles) when the drug was administered once every 3 weeks (wks). A phase II trial of tesetaxel (27-35 mg/m2 p.o. Q3 wks) showed a 38% partial response (PR) rate among 34 pts who had progressed after an anthracycline-containing regimen. Based on these favorable data, we have initiated a multicenter study to assess the efficacy and safety of tesetaxel as 1st-line therapy in MBC. Methods: Eligible patients have: Stage IV, HER2-negative MBC; ECOG PS 0-1; adequate organ function; no prior chemotherapy for MBC, although 1 adjuvant regimen is allowed. Tesetaxel is administered Q3 wks at a starting dose of 27 mg/m2 p.o., which can be increased to 35 mg/m2 depending on tolerability. A Simon mini-max two-stage design is being used. Target accrual is 25 pts. Response rate, per RECIST 1.1 criteria, is the primary endpoint. Other objectives include progression-free survival and safety. Assuming initial results are favorable, we will examine a weekly dosing schedule in a second pt cohort.