tbuckley/cabot-search huggingface dataset:
Treatment of oxaliplatin-induced peripheral neuropathy with oxycodone and extension of FOLFOX in patients with advanced colorectal cancer.
Authors: M. Nagashima, M. Ooshiro, T. Kitahara, R. Takagi, A. Moriyama, T. Urita, Y. Yoshida, H. Tanaka, T. Oshiro, S. Okazumi, R. Katoh
Journal: Journal of Clinical Oncology (2011)

e19534 Background: FOLFOX is a combination chemotherapeutic regimen that incorporates folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX). FOLFOX is the standard adjuvant and metastatic therapy for advanced colorectal cancer. Peripheral neuropathy (PN) is the most frequent dose-limiting toxicity of oxaliplatin. It is crucial to prevent chemotherapy-induced PN or reduce its severity for optimal treatment delivery and prolongation of survival. We retrospectively evaluated the efficacy of oxycodone in patients with oxaliplatin-induced PN. Methods: The medical records of 56 eligible patients (range 48-74 y.o.) treated at Toho University Medical Center Sakura Hospital were reviewed; of these 56 patients, 27 received oxycodone (range 10-60 mg/day, average 17.8 mg) for oxaliplatin-induced PN (OXC (+) group). Treatment was continued until disease progression, unacceptable toxicity occurred, or until patient withdrawal. Results: One patient in the OXC (-) group showed Grade 3 PN (CTCAE v4.0), other patients showed Grade 1 or Grade 2 symptoms. Chemotherapy was suspended due to PN in 2 patients of the OXC (-) group, while it was not discontinued due to PN in any patient of the OXC (+) group. The number of mFOLFOX6 or mFOLFOX6+B-mab cycles was 15.6±1.5 (AVG±SE) (range 6-36 courses) in the OXC (+) group, and 7.4±0.5 (range 2-15 courses) in the OXC (-) group (P<0.05). The total dose of oxaliplatin was 1172.4±110.5 mg/m2 (range 408.7-2579.9 mg) in the OXC (+) group, and 537.9±43.5 mg/m2 (range 76.2-1235.9 mg) in the OXC (-) group (P<0.05). Conclusions: Treatment with oxycodone reduced the severity of oxaliplatin-induced peripheral neuropathy and contributed to the good performance status of patients receiving FOLFOX chemotherapy. Preventing oxaliplatin-induced PN with oxycodone made it possible to continue the FOLFOX regimen during its effective term and might improve the treatment outcome in patients with advanced colorectal cancer. Distribution of patients Total OXC(+) OXC(-) No. of patients 56 27 29 Stage III 16 3 13 Stage IV 40 24 16 mFOLFOX6 32 10 22 mFOLFOX6-B-mab 24 17 7
Comparative study of hormone receptor status and HER2 expression between primary and recurrent breast cancer.
Authors: N. Rokutanda, J. Horiguchi, D. Takata, R. Nagaoka, A. Sato, H. Odawara, H. Tokiniwa, K. Tozuka, I. Takeyoshi
Journal: Journal of Clinical Oncology (2011)

e21050 Background: Recent retrospective reviews suggest that the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) receptor may differ between the primary and recurrence or distant metastases. In these reports, the rate of discordance for ER, PR and HER2 status ranged between 10 and 30%. Methods: Primary and recurrent tumors from 42 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Results: The sites of biopsied recurrent/metastatic lesions are regional soft tissue (21.4%), lymph nodes (30.1%), lung (26.1%), bone (16.6%), brain (4.8%), and ovary (2.4%). Discordance for ER was 11% (n = 5). Among these, 7.1% (n = 3) patients had ER-positive primary tumor but ER-negative metastasis and 4.8% (n = 2) had ER-negative primary but ER-positive metastasis. Discordance for ER was 19% (n = 8). Among these, 14.3% (n = 6) had PR-positive primary but PR-negative metastasis and 4.8% (n = 2) had PR-negative primary and PR-positive metastasis. HER-2 status was known in both primary tumor and metastasis in 34 patients. Among these patients, 15.9% (n = 2) had discordant results. Among these discordant cases, two had negative primaries and positive metastasis and no cases had positive primaries and negative metastasis. Conclusions: As these discordant results make changes in treatment decision, a biopsy of the metastatic lesion could be recommended in patients with metastatic breast cancer.
Oral Contraceptive-Associated Thromboembolism. A Retrospective Analysis of Thrombophilic Work-out and Long Term Follow up in 57 Cases
Authors: Emmanouil Papadakis, Smaragda Efremidou, Haris Kartsios, Margarita Mpraimi, Kiriaki Kokoviadou, Konstantinos Loukidis, Georgia Papaioannou, Ioannis Korantzis
Journal: Blood (2008)
Evaluation of autophagy as a therapeutic target for DCIS.
Authors: Virginia A. Espina, Kirsten H. Edmiston, Lance A. Liotta
Journal: Journal of Clinical Oncology (2012)

189 Background: Survival of intraductal, preinvasive proliferating cells under stress may promote genetic instability and the selection of invasive carcinoma cells. Our analysis of the mechanisms used by DCIS cells to survive in the hypoxic, nutrient deprived intraductal niche has revealed autophagy as a therapeutic target. Methods: DCIS spheroid forming cells have been isolated and propagated from fresh human DCIS lesions. We characterized the DCIS cells by organ culture, xenograft transplantation, molecular cytogenetics (300,000 SNPs) and 59 signal pathway profiling endpoints (Reverse Phase Protein Microarray [RPMA]). Results: DCIS spheroid forming cells were tumorigenic in xenograft models. Autophagy is up-regulated in: human DCIS lesions, DCIS spheroid-forming cells, and the xenograft tumors they generate. Autophagy is a means for intraductal neoplastic cells, accumulating in the duct, to digest intracellular contents and generate energy to survive in the face of severe metabolic, oxidative, and hypoxic stress. Suppression of autophagy by chloroquine kills human DCIS spheroid forming cells in culture and prevents them from forming tumors in xenografts (p &lt; .0003). Based on these preclinical insights we have opened a neoadjuvant therapy trial for DCIS (NCT01023477 PINC Trial) to examine the safety and effectiveness of oral 30-day chloroquine for patients with any stage/grade DCIS. At the conclusion of treatment, all patients receive standard of care surgical therapy. MRI is performed before and after the treatment period. Endpoints compared before, versus after, therapy are lesion shrinkage, pathologic regression, disruption of lesion autophagy and proliferation (Ki67), induction of apoptosis, and suppression of xenograft tumorigenicity. Each patient serves as her own control because effectiveness is judged by comparing the patient’s DCIS lesion before and after oral therapy. Conclusions: We hypothesize that the intraductal pre-neoplastic cellular niche will be preferentially sensitive to a short term, anti-autophagy based prevention therapy which targets survival pathways used by pre-invasive carcinomas. Our unique trial design offers a means to functionally screen investigational agents that kill premalignant breast lesions.
Phase II trial of acai juice product in biochemically recurrent prostate cancer.
Authors: Elizabeth Riley Kessler, Lih-Jen Su, Xiaoping Yang, Xian Lu, Diana Morales, Mary Anduha, Nicole Chronister, Michael Wacker, Thomas W. Flaig, L. Michael Glode, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2013)

230 Background: There are conflicting data as to the benefit of treating patients with biochemically recurrent prostate cancer (PCa). Plant derivatives, called “nutraceuticals” such as grape seed extract or milk thistle, have been studied as therapies for PCa based on their purported anti-inflammatory and anti-oxidant properties and low toxicities. Acai is a fruit rich in bioflavinoids shown to induce apoptosis in preclinical studies of PCa, leukemia and esophageal cancer. Anecdotal experience of two patients with falling prostate specific antigen (PSA) values while consuming acai juice prompted us to evaluate its efficacy in a clinical trial. Methods: This was a phase II Simon two-stage open-label single-arm single-institution study of the efficacy of Acai Juice Product in asymptomatic PCa patients with a rising PSA. Eligibility included lack of current hormone therapy, hormone sensitivity, and a PSA doubling time of &gt;4 weeks. Patients consumed 2 oz of Acai Juice Product twice daily for 30 weeks, with a primary endpoint of PSA response. Secondary endpoints included PSA doubling time, PSA velocity, and duration of PSA response. Progression was defined as a rise of 25% from baseline PSA with absolute rise of 2ng/dL. Results: 21 patients were enrolled in the first stage of the trial. Median baseline PSA was 2.74 (range 0.38-36.88). Eighteen patients have completed therapy with 1 PSA response. In the one responder, the patient entered with a doubling time of 4 months and a PSA of 12.57, which was 2.15 at 36 weeks suggesting a prolonged and continued response. PSA either decreased or doubling time prolonged from baseline in 18 patients. PSA velocity was a negative rate of change per month in 4 patients. Conclusions: Acai juice did not produce enough PSA responses in this patient population to proceed beyond the first stage of this trial. However, PSA doubling time did slow in 85.7% of patients, and the one observed PSA response was sustained over at least 36 weeks at the time of data cutoff. Thus, we will analyze potential cellular signals through an M30 Apotosense ELISA assay and Human Cytokine 10-plex panel on patient samples with data available for presentation at the meeting. Clinical trial information: NCT01521949.
Hematopoietic Progenitors in Myelodysplastic Syndrome (MDS) Demonstrate Cell Cycle Arrest, Mitotic Failure, and DNA Damage.
Authors: David R. Head, James W. Jacobberger, Madan H. Jagasia, Stacey A. Goodman, Leanne Flye, Sara A. McClintock-Treep, Fouad I. Boulos, Fen Jiang, Greg Stelzer, Robert C. Briggs, Keith Shults
Journal: Blood (2004)
Effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure (OF) due to adjuvant chemotherapy (AdC): First results from CALGB trial 7980
Authors: C. L. Shapiro, S. Halabi, G. Gibson, D. J. Weckstein, J. Kirshner, W. M. Sikov, E. P. Winer, C. A. Hudis, C. Isaacs, D. Weckstein, R. L. Schilsky, E. Paskett
Journal: Journal of Clinical Oncology (2008)

512 Background: OF causes accelerated bone loss in premenopausal women receiving AdC of greater magnitude than natural menopause or aromatase inhibitor therapy in postmenopausal women. CALGB 79809 compared the effect of early ZA (with AdC) or late (one year after AdC) on change in BMD in the lumbar spine (LS). We report the effect of early ZA versus no ZA (Control) at 12 months after randomization. Methods: Eligible women (≥ 40 years; stages I-III breast cancer; and last menstrual period ≤ 6 months prior to entry) were randomized to either ZA 4 mg IV every 3 months beginning 1–3 months (Arm A) after the start of AdC or no ZA. BMD of LS, serum FSH, estradiol, and β-HCG were performed at baseline (≤ 28 days prior to randomization) and repeated at 12 months. OF was prospectively defined at the 12 month study visit as ≥ 3 months of amenorrhea with an FSH ≥ 30. All women were told to take 1,000 mg of calcium and 400 IU of vitamin D and compliance (by self-report) and toxicity were assessed every 3 months. Assuming an attrition rate of 20% and that only 50% of women would develop OF, a sample size of 200 per arm was required to have 80% power to detect a mean difference of 0.09 g/cm2 in LS BMD at 12 months with at a two-sided significance level of 0.05. A prespecified boundary for early stopping for superiority was crossed at the first interim analysis. Results: From 12/01 to 12/06, 439 women enrolled and 166 (38%) met the criteria for OF at 12 months. Median age was 47 years (range 40–58); white-92%; performance status 0–91%; stage I-25%; and stage II- 56%. Compliance with calcium and vitamin D was nearly 100%. The majority of ZA-related toxicities were grades 1 or 2; grade 3 included fever- 3%, fatigue-2%, and pain-3%. There was 1(0.5%) woman with possible jaw osteonecrosis after trauma to the jaw and 2 doses of ZA. The results are described in the Table. Conclusions: ZA adds minimal toxicity and prevents the accelerated bone loss that occurs in women who develop OF receiving AdC. Arm A (n=81) Control (n=85) p Mean Percent Change in LS BMD (SD) +2.6 (6.4) −6.4 (6.7) <0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Smarter radiation oncology.
Authors: Louis Potters, Ajay Kapur
Journal: Journal of Clinical Oncology (2014)

32 Background: The evolution of radiation oncology (RO) has established granular and detailed CPT codes that define the process of care for patients receiving radiation services. And while each of these codes are legitimately and carefully crafted within the relative value system, they nonetheless serve as surrogates for treatment. As health care moves into a value based future, RO is uniquely situated to offer high-value and affordable cancer care. In addition, ASTRO’s ‘safety is no accident’ and other authoritative articles show a high emphasis of structure, a ‘learning curve’ in process but a dearth of direction on outcomes. A truly integrated practice standard for RO has therefore not yet been realized. Methods: Over the last 5-yrs, based on learning from incidents reported in our department and a risk mitigation study, we have reshaped our practice to be based on three measurable aspects – evidence based and consensus driven care pathways, patient experience and quality. By assimilating the cost perspective into this three-tiered matrix, we believe we have created a model for RO that is predictive of value. We summarize facets of this model that embrace structure, process and outcomes aspects of quality that we believe add most value to the care we provide. Results: The elements of Smarter Radiation Oncology (SRO) were determined to be process mapping, standardization of treatment pathways and toxicity grading, incident reporting, pre-treatment peer review planning contour rounds, our no-fly policy, the Kaizen approach to overhead mitigation, an electronic whiteboard for process co-ordination, survivorship, patient perception of care and the Z-score for measuring operational efficiencies. Conclusions: SRO has shown a sustained and substantial level of improvement in many aspects of the care we provide. And while it is designed to allow for the unencumbered freedom to practice RO, we are often times limited by payers who refuse care based on the artificial and differential aspects of complex therapy. We plan to present how SRO improves value by offering less expensive care that can be used as a foundation for a new episodic payment system based on cost. If adopted, the decision process of therapy becomes agnostic of technology and patient focused.
Testosterone kinetics after proton therapy for low- and intermediate-risk prostate cancer.
Authors: Romaine Charles Nichols, Christopher G. Morris, Bradford S. Hoppe, Randal H. Henderson, William M. Mendenhall, Zuofeng Li, Christopher R Williams, Joseph A Costa, Stephanie Harris, Nancy Price Mendenhall
Journal: Journal of Clinical Oncology (2013)

237 Background: Evaluate long term changes in serum testosterone levels in patients with low and intermediate risk prostate cancer treated with proton therapy (PT) on two prospective clinical trials. Methods: Between August, 2006 and October, 2007, 171 patients with low and intermediate risk prostate cancer were enrolled and treated on the University of Florida Proton Therapy Institute institutional review board (IRB) approved PR01 and PR02 protocols. Of the 171 patients, 20 were excluded for having received hormonal therapy prior to PT. The pretreatment serum testosterone level was available for 149 of the remaining 151 patients. These 149 patients were included in the present study. Proton doses ranged from 78 Cobalt Gray Equivalent (CGE) to 82 CGE to the prostate using passively scattered protons. No patient underwent pelvic nodal irradiation. Results: The median baseline serum testosterone level was 358ng/dL (range 112 to 791ng/dL). Immediately after completion of PT, median serum testosterone was 365ng/dL which was not significantly different from the pre-PT level (p=0.2039). Subsequent median testosterone levels with associate P-Values are shown in the Table. At no point in the 60 month follow up period was the median serum testosterone value significantly different from the baseline value. Conclusions: Conformal proton therapy to the prostate, as delivered using the University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect serum testosterone levels within 60 months after PT. [Table: see text]
Early tumor shrinkage as a predictor of favorable outcomes in patients (pts) with advanced pancreatic cancer treated with FOLFIRINOX.
Authors: Yasuhiro Kaga, Yu Sunakawa, Yutaro Kubota, Teppei Tagawa, Taikan Yamamoto, Toshikazu Ikusue, Yu Uto, Yu Kitahara, Hirokazu Toshima, Kouji Kobayashi, Atsushi Hisamatsu, Wataru Ichikawa, Takashi Sekikawa, Ken Shimada, Yasutsuna Sasaki
Journal: Journal of Clinical Oncology (2016)

237 Background: Results from the phase III PRODIGE 4/ACCORD 11 trial provided one of current standard regimens for advanced pancreatic cancer (PC), consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX), which has superior response rate (RR) and survival benefit even with severe toxicity (Thierry C, et al. N Engl J Med 2011;364:1817-1825). There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in PC. We therefore analyzed retrospectively whether the ETS will predict outcomes in pts with PC treated with FOLFIRINOX therapy. Methods: Advanced PC pts with ECOG PS of 0 or 1, who received FOLFIRINOX as 1st- or 2nd-line treatment between November 2012 and July 2015 in 3 institutes of Showa University were included in this analysis. ETS was defined as a reduction ≥ 20% of target lesions’ diameters measured at 8 weeks from treatment start. We evaluated the association of ETS with progression-free survival (PFS) and overall survival (OS) but also addressed the correlation between outcomes and DpR, which was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Results: Fifty-nine PC pts with median age of 63 (range 34-76) years and males of 68% were enrolled: 80% of pts had metastatic disease. In the population, RR, median PFS, and OS were 28%, 5.4 months, and 10.7 months, respectively. Among 46 (78%) evaluable pts for the ETS, 12 (26%) pts experienced ETS. The PFS was significantly longer in pts with ETS compared to pts with no ETS (9.0 vs. 4.2 months, HR 0.43, 95%CI 0.17-0.96, log-rank P= 0.045). Moreover, pts with ETS had a better OS although no statistical significance (HR 0.53, log-rank P= 0.25). Median DpR was 11.1% (from -75.7 to 100), and the correlation of DpR with clinical outcome was observed (P= 0.024 for PFS, P= 0.22 for OS). Conclusions: This retrospective analysis suggests that the early response to FOLFIRINOX treatment may predict better outcomes in pts with advanced PC. The ETS may serve as a novel predictor of prolonged survival time in PC pts treated with FOLFIRINOX.
Understanding the role of carbonyl reductase polymorphisms on doxorubicin-induced cardiotoxicity with population pharmacokinetics (PK).
Authors: G. J. Fetterly, K. E. Thudium, J. Kalabus, M. Murphy, P. D. Zagst, J. Prey, E. Kittleman, A. A. Adjei, T. L. O'Connor, J. G. Blanco
Journal: Journal of Clinical Oncology (2011)

2606 Background: Single nucleotide polymorphisms (SNPs) in carbonyl reductase 3 (CBR3V244M and CBR3C4Y), may impact the variable pharmacodynamics of anthracyclines. For example, homozygosis for the CBR3 V allele (G) is associated with an 8-fold increased risk for anthracycline-related heart failure. The aim was to develop a population pharmacokinetic model to characterize the metabolism of doxorubicin and explore the influence of CBR3V244M and CBR3C4Y genotype status on the formation of doxorubicinol, a major contributor to doxorubicin-induced cardiotoxocity. Methods: Advanced breast cancer patients received 60mg/m2 of doxorubicin. Blood was collected over three time windows to capture the PK profile. Doxorubicin and doxorubicinol was measured by UPLC. S-ADAPT-TRAN (v1.56) was used to co-model parent and metabolite data. For simplicity, a single metabolic pathway for doxorubicin was considered. Covariates including age, weight, BSA, and influence of CBR3V244M and CBR3C4Y were explored. Results: A total of 34 female patients (79.4% White, 17.6% Black, and 2.9% Native American) were evaluated. Patient demographics including mean (sd) weight, BSA, and age were 81.9kg (20.8), 1.87m2 (0.25), and 51.8 yrs (10.4), respectively. A 4-compartment model best characterized the bi-exponential decay of doxorubicin and doxorubicinol compared to a 3-compartment model (p<0.0033). Model estimated PK parameters were similar to those reported in the literature. The mean (sd) half-life of doxorubicin was estimated as 25.0hr (0.06). CBR3V244M and CBR3C4Y genotype status were similar in Black and White patients (α<0.05). Thus, analysis was conducted without stratifying by geographical ancestry/ethnicity. Patients with homozygous CBR3V244M G genotype status showed greater exposure to doxorubicin (AUC0-inf ) with one (G/A) or two (G/G) copies of the variant allele (p=0.0003). Conclusions: Successful model development characterized the pharmacokinetics of doxorubicin and may further elucidate the role of polymorphic CBRs during anthracycline metabolism. Further analyses are ongoing to investigate the influence of age, weight, BSA, CBR3V244M and CBR3C4Y on PK parameters.