tbuckley/cabot-search huggingface dataset:
Renal impairment impact on CPX-351 pharmacokinetics and safety.
Authors: Jeffrey E. Lancet, Eric Jay Feldman, Jonathan E. Kolitz, Helen S Pentikis, Lawrence Mayer, Arthur Chin Louie
Journal: Journal of Clinical Oncology (2015)

e13533 Background: A 300 patient randomized Phase 3 study comparing CPX-351 vs. 7+3 control is underway for newly diagnosed older patients (age 60-75) with secondary AML. Encapsulation of cytarabine (Ara-c) and daunorubicin (dauno) at a 5:1 molar ratio within stable low cholesterol liposomes (CPX-351) markedly alters the pharmacological characteristics of both drugs resulting in substantial increases in plasma half-life, AUC, and Cmax. Pharmacokinetic data (Phase 1, 100 and 134 units/m2) and safety data from a pair of randomized studies (Phase 2, 100 units/m2) were analyzed for the impact of renal function impairment on pharmacokinetics and safety to determine whether dose modifications would be necessary for patients with reduced renal function. Methods: See Feldman EJ, et al. J Clin Oncol 2011;29(8):979-85 (Phase 1); Lancet JE, et al., Blood 2014;123(21):3239-46 and Cortes JE, et al. Cancer 2015;121(2):234-42 (Phase 2) for details. Results: See Table. There was a proportional increase in the Cmax and AUC with increasing CPX-351 dose. Within each dose level there was little change in Cmax or AUC across the three renal function groups (≥90 vs. 60-89 vs. <60 mL/min GFR). Additional data for the safety of patients treated at 100 units/m2was reviewed without evidence of increased toxicity occurring in the presence of impaired renal function. Conclusions: Impaired renal function does not appear to significantly impact patient exposure to Ara-c or dauno or treatment safety following CPX-351 administration suggesting that dose modifications for renal impairment will not be necessary. This hypothesis is being tested in a Phase 3 study where CPX-351 dose is kept constant for all patients with baseline serum creatinine ≤2.0 mg/dL. Clinical trial information: NCT00389428.Impact of GFR on median drug exposure. CPX-351 Dose units/m2 GFR Group mL/min n Median CrCl mL/min Ara-c Dauno Cmax ng/mL AUC ng*hr/mL Cmax ng/mL AUC ng*hr/mL 101 ≥90 7 129.9 41,700 1,422,200 26,600 590,970 60-89 5 75.5 38,900 1,007,113 24,500 502,673 <60 1 53.3 41,500 1,166,425 25,000 556,153 134 ≥90 2 119.3 58,750 1,874,307 37,750 988,420 60-89 3 75.4 57,200 1,856,063 36,100 926,610 <60 1 27.5 67,900 2,114,600 44,400 1,114,750
Elderly patients with primary CNS lymphoma: Results from the G-PCNSL-SG-1 trial.
Authors: Patrick Roth, Peter Martus, Philipp M. Kiewe, Robert Moehle, Hermann A. Klasen, Michael Rauch, Alexander Roeth, Stephan Kaun, Eckhard Thiel, Agnieszka Korfel, Michael Weller
Journal: Journal of Clinical Oncology (2012)

2007 Background: Age is the most important therapy-independent prognostic factor in patients with primary central nervous system lymphoma (PCNSL). Here we aimed at providing an analysis of the impact of higher age on response to therapy, toxicity, and survival in the largest PCNSL trial ever performed to date. Methods: Response to therapy, toxicity and survival of PCNSL patients enrolled in the G-PCNSL-SG-1 trial evaluating the role of radiotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy were monitored. Subjects aged 70 or more were compared to younger patients. Results: Of all eligible patients (n=526), 126 (24%) were aged 70 or more. In the per protocol population, 66 of 318 patients (21%) were at least 70 years old. Among the eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly compared to 57% in the younger patients (p=0.016). A higher rate of grade III/IV leukopenia was observed in the elderly (34% versus 21%, p=0.007). Also, death on therapy was more frequent (18% versus 11%; p=0.027) in these patients. In contrast, there was no other major age-dependent toxicity. Survival analyses revealed shorter progression-free survival (PFS) (4.0 versus 7.7 months, p=0.014) and overall survival (OS) (12.5 versus 26.2 months, p&lt;0.001) in the elderly population. The PFS of CR patients was 35.0 months in younger patients compared to 16.1 in the elderly (p=0.024). Salvage therapy was used less commonly in elderly patients. When salvage WBRT was applied in patients who had failed on HD-MTX-based chemotherapy, there was no association between age and survival (p=0.633). Conclusions: Elderly PCNSL patients have a lower response rate and higher mortality on HD-MTX-based chemotherapy. Their PFS is shorter and they receive less salvage therapy which may contribute to the poor prognosis.
The impact of proton beam therapy on blood cell count nadir during neoadjuvant chemoradiation therapy for esophageal cancer.
Authors: Yutaka Shiraishi, Cai Xu, Juhee Song, Ritsuko Komaki, Brian P Hobbs, Steven H. Lin
Journal: Journal of Clinical Oncology (2017)

137 Background: To analyze the blood cell count nadir, particularly grade 4 hematologic toxicities, in patients with esophageal cancer who were treated with neoadjuvant chemoradiation (nCRT) with either Proton Beam Therapy (PBT) or Intensity Modulated Radiation Therapy (IMRT) in a propensity-matched pair analysis. Methods: Esophageal cancer patients (n = 480) treated from 2005-2016 with nCRT with (n = 167) or without (n = 313) induction chemotherapy (ICT) were analyzed. White blood cell, neutrophil, lymphocyte and platelet counts nadir during ICT and CRT were obtained, and graded according to the CTCAE v.4.0. Univariate and multivariable logistic regression models to identify factors associated with increased risk of grade 4 lymphopenia were fitted. By propensity score matching, 136 PBT cases and 136 propensity score matched IMRT controls were selected for comparison. Results: In the entire study cohort during CRT (n = 480), 2 (0.4%), 1 (0.2%), 159 (33%), and 2 (0.4%) patients experienced grade 4 leukopenia, neutropenia, lymphopenia and thrombocytopenia, respectively. This is not seen in patients who received ICT (n = 167), as only 0 (0%), 2 (1.2%), 1 (0.6%) and 0 (0%) patients experienced grade 4 leukopenia, neutropenia, lymphopenia and thrombocytopenia during the ICT phase. Multivariable analyses identified older age (p = 0.0139), larger planning tumor volume (PTV) (p = 0.0213), distal vs upper/mid tumor location (borderline significance, p = 0.0779) and IMRT vs PBT (p &lt; 0.0001) as factors associated with increased risk of grade 4 lymphopenia during CRT. Among the 272 propensity-matched patients treated with either PBT or IMRT, 24 (17.6 %) and 55 (40.4 %) patients experienced grade 4 lymphopenia, respectively (p &lt; 0.001). Grade 4 lymphopenia correlates with poorer survival (p = 0.0587), lower progression free survival (p = 0.0384) and distant metastatic recurrence (p = 0.0185). Conclusions: The use of PBT may be an important modifying factor in altering the incidence of grade 4 lymphopenia during CRT in esophageal cancer. The dosimetric factors that can modulate this risk is a subject of continued investigation.
5-FU/leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) induction followed by chemoXRT in borderline resectable pancreatic cancer.
Authors: Jordan Kharofa, Tracy R. Kelly, Paul S. Ritch, Ben George, Lauren Allison Wiebe, James P. Thomas, Kathleen K. Christians, Douglas B. Evans, Beth Erickson
Journal: Journal of Clinical Oncology (2012)

e14613 Background: FOLFIRINOX improves overall survival compared to gemcitabine in patients with metastatic PCa. We retrospectively evaluated the feasibility of using induction FOLFIRINOX followed by chemoXRT to improve resectability in borderline resectable PCa. Methods: All patients with borderline resectable, biopsy-proven PCa treated with the FOLFIRINOX between 1/2009 -11/2011 were reviewed. Borderline resectable PCa was defined by computerized tomography (CT) imaging as tumor-induced SMA abutment of &lt;180 degrees, SMV occlusion, or findings suspicious but not diagnostic for metastatic disease. CT imaging was obtained following induction chemotherapy and after chemoXRT prior to surgery. Results: Twelve patients with borderline resectable disease were treated with FOLFIRINOX induction (median of 4 cycles [range 3-8]). Chemotherapy details are listed in table 1. Tumors in 9 patients had SMA abutment or SMV occlusion and the median pre-treatment CA 19-9 was 297 U/ml (1-3432 U/ml ). Following induction chemotherapy, all patients proceeded to chemoXRT (50.4 Gy [1.8 Gy/fx] with concurrent gemcitabine [n=8] or capecitabine [n=4]). The median CA 19-9 reduction following systemic therapy alone was 58%. One patient did not complete chemoXRT due to infectious and hematologic toxicities. Following all neoadjuvant treatment, 7 (58%) of the 12 patients underwent successful PD. All 7 patients who underwent PD had an RO resection and only one patient had lymph node metastases. The median survival has not been met with median follow up of 13 months. Conclusions: In medically fit patients with borderline resectable PCa, induction FOLFIRINOX followed by chemoXRT is feasible and may facilitate a margin negative resection and histologic response in regional lymph nodes. [Table: see text]
The impact of treatment delay from diagnosis to prostatectomy on the biochemical recurrence rate.
Authors: Sudhir Isharwal, Joseph Zabell, Ryan Kent Berglund, Andrew J. Stephenson
Journal: Journal of Clinical Oncology (2017)

34 Background: In this study, we evaluate the impact of treatment delay on the biochemical recurrence (BCR) rate specifically in patients with NCCN intermediate to high-risk prostate cancer (PCa). Methods: We reviewed our institutional database of patients who underwent radical prostatectomy (RP) between 2004-2014. A validated preoperative nomogram was used to predict the 5-year BCR-free probability. We evaluated the actual risk of BCR (PSA&gt;0.2) stratified by time from diagnosis to treatment controlling for age and preoperative nomogram derived risk of BCR. We did subset analysis in the cohort of NCCN defined intermediate/high-risk categories. Results: A total of 3029 patients met the inclusion criteria. Median age for the entire cohort was 60 years. Median time from diagnosis to treatment was 77 days (IQR 54-110). Median overall follow-up time was 25 months. Group 1 (61.7%) experienced delay of less than 90 days, Group 2 (31.5%) 90-180 days, and Group 3 (6.7%) &gt;180 days. BCR occurred in 9.6%, 9.6%, and 4.9% of patients in Groups 1, 2, and 3 respectively (p=0.08). Out of the entire cohort, 1837 (60.6%) patients had NCCN intermediate or high-risk disease. On cox multivariable analysis, there was no significant difference in risk of BCR stratified by time to RP in the entire cohort as well in the patients with intermediate/high-risk disease (see table). Conclusions: In our cohort of patients, the delay in treatment did not have significant effect on the risk of BCR. While patients with high-risk pathology should receive prompt treatment, our data suggests that patients and urologists have time to obtain genomic or imaging information, seek second opinions or referral for surgery without significantly affecting the BCR. [Table: see text]
Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia
Authors: Maria L. Mace, Eva Gravesen, Anders Nordholm, Jacob Hofman-Bang, Thomas Secher, Klaus Olgaard, Ewa Lewin
Journal: Kidney International (2017)

Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone.
Matrix metalloproteinase-23 as a new immunotherapeutic checkpoint target in melanoma.
Authors: Duane Moogk, Michelle W. Ma, Ines Esteves Domingues Pires Da Silva, Erica Brooke Friedman, Eleazar Vega-Saenz de Miera, Farbod Darvishian, Arianne Perez-Garcia, Patrick Scanlon, Anna C. Pavlick, Nina Bhardwaj, Paul J. Christos, Iman Osman, Michelle Krogsgaard
Journal: Journal of Clinical Oncology (2014)

3030 Background: Matrix metalloproteinase-23 (MMP-23) can inhibit T cell activation by selectively blocking the voltage-gated potassium channel Kv1.3, and may also alter T cell activity and phenotype through cleavage of proteins affecting cytokine and chemokine signaling. We therefore tested the hypothesis that MMP-23 can negatively regulate the anti-tumor T cell response in human melanoma. Methods: We characterized MMP-23 expression in primary melanoma patients who received adjuvant immunotherapy. We examined the association of MMP-23 with the intrinsic anti-tumor immune response - as assessed by the prevalence of tumor-infiltrating lymphocytes and Foxp3+ regulatory T-cells. Further, we examined the association between MMP-23 expression and response to immunotherapy. Considering also an in trans mechanism, we examined the association of melanoma MMP-23 and melanoma Kv1.3 expression. Results: Our data revealed an inverse association between primary melanoma MMP-23 expression and the anti-tumor T-cell response, as demonstrated by decreased tumor-infiltrating lymphocytes (TIL) (P=0.05), in particular brisk TILs (P=0.04), and a trend towards an increased proportion of immunosuppressive Foxp3+ regulatory T-cells (P=0.07). High melanoma MMP-23 expression is also associated with recurrence in patients treated with immune biologics (P=0.037) but not in those treated with vaccines (P=0.64). Further, high melanoma MMP-23 expression is associated with shorter periods of progression-free survival for patients receiving immune biologics (P=0.025). On the other hand, there is no relationship between melanoma MMP-23 and melanoma Kv1.3 expression (P=0.27). Conclusions: Our data support a role for MMP-23 as a potential immune checkpoint blockade target in melanoma, as well as a possible biomarker for informing melanoma immunotherapies.
A phase II study of gemcitabine as adjuvant treatment for biliary tract cancer after surgical resection.
Authors: Sang Myung Woo, Kyong-Ah Yoon, Eun Kyung Hong, Weon Seo Park, Sung-Sik Han, Sang Jae Park, Jungnam Joo, Eun Young Park, Ju Hee Lee, Yun-Hee Kim, Tae Hyun Kim, Woo Jin Lee
Journal: Journal of Clinical Oncology (2017)

330 Background: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. Methods: This clinical phase II study was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patents received gemcitabine 1000 mg/m 2 as an intravenous 30-min infusion on day 1, 8, and 15 for every 28 days. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry and eight SNPs in the CDA, hENT1, dCK, hCNT3 and RRM1 genes were evaluated. The relationship of each with patients’ clinical outcomes was assessed. Results: From January 2010 to July 2014, a total of 72 BTC patients (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma) were enrolled. At a median follow-up was 38.09 months (range: 4.14-68.29), 2-year recur- free survival (RFS) was 43% (95% CI, 33% to 57%). The most common grade 3 and 4 toxicity was neutropenia, which occurred in 8 patients (11%). There was one treatment-related death from pneumonitis. The Cox proportion hazard model was performed with the following nine variables; gross type, degree of tumor differentiation. pathologic T factor, N stage, vascular invasion, perineural invasion, lymphatic invasion, dosage, and each protein expression. In the multivariable model, DCK expression, vascular invasion, and lymph node metastasis, were significantly associated with RFS. None of the tested SNPs was significantly associated with RFS or with any hematologic or non-hematologic toxicity. Conclusions: Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. Clinical trial information: NCT01043172.
Use of circulating tumor DNA levels to gauge necessity of surgery for patients undergoing trimodality therapy for esophageal cancer.
Authors: Nima Nabavizadeh, Patrick James McLaren, Daira Melendez, Carol Halsey, Charles D. Lopez, Sharlene D'Souza, Brintha Enestvedt, James P. Dolan, Charles R. Thomas, Paul Spellman
Journal: Journal of Clinical Oncology (2017)

TPS214 Background: Up to 40% of patients receiving neoadjuvant esophageal chemoradiotherapy (CRT) are found to have no evidence of malignancy post-operatively. Given this, a sensitive and specific biomarker is needed, as reliable identification of complete responders may spare patients the morbidity and mortality of esophagectomies. Recent work with circulating tumor DNA (ctDNA) collected from the plasma of cancer patients indicates tumors routinely shed large amounts of DNA into the blood. This ctDNA can be systematically analyzed, quantification of which has been correlated with local and systemic disease burden. To further increase the specificity of analysis, the somatic mutations that arose in the tumor can be detected in ctDNA via targeted and whole genome sequencing. However, information on the feasibility of using ctDNA quantification as a biomarker for neoadjuvant response assessment is lacking. We hypothesize that quantification of ctDNA throughout trimodality therapy can be of practical use in the non-invasive monitoring of treatment response. The overall goal of this pilot project is to assess the feasibility and predictive utility of incorporating a sensitive, patient and tumor specific, plasma ctDNA quantification assay to more reliably identify complete responders following CRT. The long-term goal of this proposal is to apply these methods into prospective clinical trials for personalization of therapy by identifying neoadjuvant complete responders who may benefit from non-operative therapy. Methods: Pilot/feasibility study to evaluate the correlation between plasma ctDNA levels and pathologic treatment response. Plasma samples at different treatment time points (pre-CRT, during CRT, immediately pre-op and post-op) will be collected from 28 patients receiving pre-operative CRT followed by surgery for esophageal cancer. Patient-specific mutations will be identified through whole exome sequencing of paraffin-embedded pre-treatment biopsies. SafeSeqS PCR primers will be designed per patient for targeting of tumor mutations. Plasma-derived ctDNA will be assayed using the patient-specific SafeSeqS approach for each time point in triplicate.
Performance of 18FDG-PET in the management of non-metastatic HIV+ anal squamous cell carcinoma (ASCC).
Authors: Nabil Baba Hamed, Gael Deplanque, Raid Kassis, Michel Gatineau, Lionel Staudacher, Imene Chaiba, Francesco Savinelli, Robert Sverdlin, Oumou Maiga, Jean Luc Marin, Vincent de Parades, Nicolas Lemarchand, Olivier Marty, Damien Levoir, Jerome Loriau, Eric Zerbib, Marc Zins, Isabelle Boulay, Eric Raymond
Journal: Journal of Clinical Oncology (2017)

541 Background: ASCC remains rare, but the incidence has been increasing over the last decade, especially in patients with HIV infection (HIV+). A recent meta-analysis demonstrated the usefulness of 18FDG-PET in initial staging and response assessment in ASCC. HIV+ patients may develop opportunistic infections which can cause false positives lymph nodes on PET scanning and, therefore, our objective was to evaluate performance of 18FDG-PET in HIV+ patients. Methods: Retrospective analysis of consecutive patients with non-metastatic ASCC, treated in our institution during six years. HIV+ patients were analyzed separately in two groups according to their lymph nodes status, group 1 (Gr 1): N0, group 2 (Gr 2): N1, N2, N3. Results: A total of 87 patients with ASCC were analyzed, including 24 HIV+ patients (21 males, median age was 53 for male and 50 for women). There were 15 patients in Gr 1 and 9 in Gr 2. All patients performed conventional imaging (MRI and CT-scan). In Gr 1, 12/15 patients had 18FDG-PET, it resulted in upstaging nodal disease in 2 patients. In Gr 2, 6/9 patients had 18FDG-PET, it resulted in upstaging nodal disease in 1 patient and downstaging nodal disease in 2 patients. Both of sensibility and specificity of FDG-PET were 83% in our HIV+ population. All patients underwent Mitomycine C and 5FU based chemoradiation or exclusive radiation therapy. Mean radiation dose received was 63.3Gy in G1 and 63.9Gy in G2. 18FDG-PET drives a modification in treatment strategy in only 1 patient in both of groups. Post-treatment 18FDG-PET was performed 4 months after treatment completion. Among patients who had post-treatment 18FDG-PET, a metabolic complete response was observed in 6/11 patients in Gr 1 and 3/5 patients in Gr 2. Survival at 5 years was 89% and 75% in Gr 1 and Gr 2, respectively. Conclusions: Based on our experience, 18FDG-PET drives substantial changes neither in staging nor in therapeutic strategy for ASCC HIV+ patients, however, it may be useful for radiation therapy planning.