tbuckley/cabot-search huggingface dataset:
NCI 6896: A phase I trial of suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid in the treatment of patients with advanced renal cell carcinoma (RCC).
Authors: D. M. Nanus, S. T. Tagawa, J. P. Dutcher, N. H. Akhtar, A. Saran, M. Mazumdar, M. I. Milowsky, L. J. Gudas
Journal: Journal of Clinical Oncology (2011)

349 Background: Retinoid resistance in RCC inversely correlates with levels of intracellular retinol and retinyl esters suggesting that increasing intracellular levels of all-trans retinoic acid (RA) or enabling RA to become a more potent initiator of transcription will improve RA mediated anti-tumor effects. The combination of all-trans RA and a histone deacetylase (HDAC) inhibitor inhibited renal cancer cell proliferation and tumor growth in a xenograft model more than either drug alone. We performed a phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor SAHA (vorinostat) plus oral 13-cis RA (isotretinoin) in patients with advanced RCC. Secondary endpoints include analysis of peripheral blood samples to study the effects on retinoid metabolites and retinoid related genes. Methods: Patients (pts) with metastatic RCC (any histology) who have failed at least two lines of prior therapy were eligible. Vorinostat (300 mg bid x 3 consecutive days per week + isotretinoin co-administered at 0.25 mg/kg, 0.375 mg/kg, or 0.5 mg/kg PO bid x 3 days per week in cohorts using standard 3+3 dose escalation. Dose limiting toxicity (DLT) was defined as any grade &gt; 3 toxicity during the first cycle. Results: 14 pts have enrolled on the trial of which 12 are evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). One pt on dose-level 1 experienced a DLT (grade 3 depression). One patient experienced a partial response and 10 patients had stable disease lasting a median of 4 months (range 2–10 mos). Three patients progressed with brain metastases in the setting of stable systemic disease for at least 6 months. Pharmacokinetic and correlative studies examining expression of retinoid related genes are ongoing. Conclusions: The recommended phase II dose is vorinostat (300 mg bid) + isoretinoin (0.5 mg/kg PO bid) 3 days per week. The combination of vorinostat and isotretinoin was well tolerated, and there was evidence of antitumor activity in this heavily pretreated population of patients with refractory metastatic RCC. [Table: see text]
Reported patterns of utilization of intravesical therapy in non-muscle-invasive bladder cancer: Results from the BCAN/SUO/AUA/LUGPA electronic survey.
Authors: A. Smith, M. E. Nielsen, A. Manvar, J. Ferguson, R. Pruthi, E. Wallen, Y. Lotan
Journal: Journal of Clinical Oncology (2011)

267 Background: Guidelines recommend intravesical chemotherapy and immunotherapy in the management of non-muscle-invasive bladder cancer (NMIBC) to reduce the risks of recurrence and potentially progression. Nevertheless, recent claims-based analyses have suggested exceedingly low rates of utilization of some of these therapies in practice. In general, there is a paucity of data to inform our understanding of current patterns of care. Methods: An electronic survey was developed by the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported practices of utilization of intravesical chemo- and immuno-therapy for patients with NMIBC. The survey was circulated to urologists via the AUA, SUO and LUGPA distribution lists. 512 respondents completed the survey. Results: Overall, 63% of respondents reported routine administration of perioperative mitomycin-c (MMC) after TURBT [80% of SUO respondents vs. 55% of AUA/LUGPA respondents (p&lt;0.001)]. Whereas 5% of respondents reported routine induction therapy with all new low-grade (LG) diagnoses, 99% reported routinely doing so in new high-grade (HG) cases; most commonly with single- agent BCG (94%; vs. 9% BCG/IFN and 5% MMC). Reported induction therapy was higher in the setting of high-volume (77%) or frequently recurrent LG (44%) disease. 89% reported routinely using maintenance therapy for HG, vs. 29% for LG. Reduced strength BCG was most commonly endorsed only in the settings of poor tolerance of full strength (84%) or maintenance (11%), with only 3% endorsing routine use. Routine post-BCG biopsy, even with normal cystoscopy, was endorsed by 28% of respondents, and 64% of respondents used urine-based markers to assess response to intravesical therapy. Conclusions: Urologists report grade-specific patterns of utilization of intravesical therapy for NMIBC, at rates higher than suggested in some claims-based analyses. Variation exists in post-treatment followup practices. Further study is needed to rectify these self-reported patterns of care with results from claims-based analyses. No significant financial relationships to disclose.
MEDI-573 as a novel approach to IGF-1R and IR-A signaling inhibition by blocking IGF ligands: Phase I PK/PD, safety data, and disease linkage studies in breast cancer.
Authors: P. Haluska, J. Huang, B. Lam, M. Liang, W. Huang, P. LoRusso, M. E. Menefee, T. LaVallee, Y. Yao, J. Viner
Journal: Journal of Clinical Oncology (2011)

271 Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis. Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers. Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer. Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.
Number needed to treat and treatment cost per fracture avoided with denosumab compared with zoledronic acid in patients with breast cancer with bone metastases.
Authors: E. Q. Wu, J. Xie, J. Signorovitch, M. Diener, R. Sorg, M. Namjoshi
Journal: Journal of Clinical Oncology (2011)

151 Background: Pathologic fractures (PF) are a common and expensive-to-treat skeletal-related event (SRE), which affect over two-thirds of metastatic breast cancer (MBC) patients, and cost $26,936 (2009 US dollars) per event on average for inpatient treatment. In a phase III trial ( NCT20050136 ), MBC patients randomized to denosumab (Dmab; n=1,026) demonstrated longer time to SRE, but comparable rates of survival and disease progression relative to those randomized to zoledronic acid (ZOL; n=1,020). We calculated the number needed to treat (NNT) to avoid one PF and the treatment cost per PF avoided with Dmab vs. ZOL in MBC patients. Methods: Phase III trial results from the Dmab product label were used to determine the rate of PFs and SREs in MBC patients treated with Dmab vs. ZOL. Treatment cost included only the wholesale acquisition cost of Dmab and ZOL, and assumed 12 months of treatment. The NNT calculated the number of patients who would need to be treated with Dmab vs. ZOL to avoid one additional PF. Sensitivity analyses included expanding the treatment outcome from PFs to SREs and adding drug administration costs for Dmab and ZOL, and, renal monitoring costs only for ZOL. Results: Based on the estimated differences in PF risk of 2.7%, 37.4 patients would need to be treated with Dmab vs. ZOL to avoid one additional PF, resulting in a treatment cost per PF avoided of $346,911. The lower 95% confidence limit for the cost per PF avoided with Dmab vs. ZOL was $148,114, which is significantly greater than the mean inpatient cost of treating a PF event. Including drug administration and renal monitoring costs led to a cost per PF avoided of $323,069. Expanding the treatment outcome from PFs to SREs showed that 17.3 patients would need to be treated with Dmab vs. ZOL to avoid one additional SRE (95% CI: 10.2 to 59.7; absolute risk reduction 5.8%), resulting in a treatment cost of $160,595 per SRE avoided. Conclusions: PFs have a debilitating effect on patients, and treatment with Dmab compared to ZOL was associated with a treatment cost per PF avoided that exceeded 12 times the mean inpatient cost of a PF. Decision makers need to consider the high costs associated with Dmab prior to formulary inclusion.
Comparing Eras: Assessing Treatment Trends before and after Ruxolitinib Approval
Authors: Andrew Kuykendall, Chetasi Talati, Najla Al Ali, Eric Padron, David Sallman, Jeffrey E. Lancet, Kendra L. Sweet, Alan F. List, Kenneth S. Zuckerman, Rami S. Komrokji
Journal: Blood (2016)
Thrombotic Complications Are Associated with Phlebotomy Therapy in Patients with Chuvash Polycythemia
Authors: Adelina Sergueeva, Galina Miasnikova, Ekaterina Lisina, Mehdi Nouraie, Sergei A. Nekhai, Tatiana Ammosova, Josef T. Prchal, Xu Zhang, Victor R. Gordeuk
Journal: Blood (2015)
No Evidence of Association between Borrelia burgdorferi and Primary Cutaneous B-Cell Lymphomas in Marche Region, in Italy.
Authors: Gaia Goteri, Roberta Capretti, Serena Rupoli, Renzo Ranaldi, Stefano Menso, Stefano Pulini, Angela Tassetti, Doriana Morichetti, Anna Rita Scortechini, Simonetta Mulattieri, Andrea Stronati, Massimiliano Nicolini, Elio Grilli Cicilioni, Stefano Serresi, Anna Maria Offidani, Pietro Leoni
Journal: Blood (2006)
Cardiovascular events and clinical responses in prostate cancer patients treated with transcutaneous estrogen patches compared with LHRH analogues: Results from a randomized phase II trial (MRC PR09 PATCH).
Authors: P. D. Abel, S. K. Sundaram, H. G. Kynaston, N. Clarke, A. A. Alhasso, S. D. Rosen, R. C. Jinks, P. Pollock, F. Cafferty, R. E. Langley
Journal: Journal of Clinical Oncology (2011)

201 Background: Androgen-deprivation therapy (ADT) with a luteinising hormone-releasing hormone analogue (LHRHa) is widely used in the management of prostate cancer. LHRHa suppresses testosterone to castrate levels but can lead to long term toxicities including osteoporosis, adverse metabolic effects and cardiovascular (CV) complications. Transcutaneous oestrogen is an attractive potential alternative to ADT. This approach circumvents first-pass hepatic metabolism and so should avoid the CV effects previously reported with oral oestrogen in men with prostate cancer. Castrate levels of testosterone, and hence prostate cancer outcomes, are expected to be equivalent but the side-effects associated with ADT will potentially be avoided. Methods: PATCH is a multi-centre phase II randomized study of 254 men with locally advanced or metastatic prostate cancer assigned (2:1) to either oestrogen patches (Merck FemSeven 100mcg/24hr; 4 patches changed twice-weekly, reducing to 3 after 4 weeks) or LHRHa. The primary outcome is CV morbidity and mortality, including arterial and venous thromboembolic events, acute coronary syndrome and heart failure. These have been assessed by an independent committee, blind to the treatment arm. Secondary outcome measures include PSA response, serum testosterone and also toxicities. Results: Baseline data on the 254 men will be presented including age, cardiovascular risk factors (smoking history, lipid levels and family history), and stage/grade of tumour at presentation and randomisation. CV events will be presented by randomisation arm and by treatment at the time of the event. Data relating to rates of castrate levels of hormones, PSA responses, sexual dysfunction, other toxicities (including gynaecomastia, hot flushes, anaemia and bone fractures) and compliance will also be available. Conclusions: Providing the data demonstrate that the patches are a safe and potentially efficacious therapy we propose to recruit a further 410 patients with progression-free survival as the primary outcome. CV events will continue to be closely monitored, alongside other outcomes. [Table: see text]
Increased Clearance of Storage-Damaged Red Blood Cells Induces an Acute Phase Response in Critically-Ill Children
Authors: Camilla L'Acqua, Gary M. Brittenham, Sheila Bandyopadhyay, Richard O. Francis, Donald McMahon, Boguslaw S. Wojczyk, Steven G Kernie, Steven L. Spitalnik, Eldad A. Hod
Journal: Blood (2014)
Maintenance therapy with capecitabine in patients with resected pancreatic adenocarcinoma after adjuvant therapy.
Authors: Xuezhong Yang, Christina Sing-Ying Wu, Jimmy J. Hwang, Benjamin Weinberg, Michael J. Pishvaian, Aiwu Ruth He, John Marshall
Journal: Journal of Clinical Oncology (2012)

333 Background: The 5-year disease free survival of pancreatic adenocarcinoma (PAC) with surgery alone is below 10%, and adjuvant chemotherapy increases that to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not chemoradiation. This hypothesis has not been tested since that trial. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our patient (pts) who were treated with maintenance capecitabine (cape). Methods: Pts in the Georgetown University Hospital/Lombardi Cancer Center electronic medical record database since Oct 2007 were sought for PAC that were resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation, and received maintenance cape for at least 2 months. Results: Among 214 PAC pts that have been treated at our institution in this time, 21 pts met these criteria. Among the 21 pts, 1 was lost to follow up after moving overseas, and 20 pts were eligible for this analysis. 13 of the 20 pts had lymph node involvement at resection. Cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, most often two years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median followup duration was 33 months (16 to 78 months). The median overall survival (OS) for the 20 analyzed patients was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea respectively. Conclusions: Cape maintenance therapy following adjuvant chemotherapy in resected PAC is associated with a promising higher overall survival and PFS compared to historical data, and this approach should be further studied in a randomized controlled study.
Excellent Response to 177Lu-PSMA-617 Radioligand Therapy in a Patient With Advanced Metastatic Castration Resistant Prostate Cancer Evaluated by 68Ga-PSMA PET/CT
Authors: Wolfgang Roll, Axel Bode, Matthias Weckesser, Martin Bögemann, Kambiz Rahbar
Journal: Clinical Nuclear Medicine (2016)

Recently radiolabeled ligands targeting prostate specific membrane antigen (PSMA) have been introduced for diagnostics and treatment of prostate cancer. Labeled with 177Lutetium, PSMA radioligand therapy (RLT) is one of the most promising new treatments of metastatic castration refractory prostate cancer. We present images of 68Ga-PSMA PET/CT and parameters of response of a 75-year-old heavily pretreated metastatic castration refractory prostate cancer patient with extended bone metastases, showing an extraordinary biochemical response in PSA-levels concordant to SUV decline in bone metastases. Furthermore, this case shows that CT is of no use in assessing response in bone metastases of prostate cancer.
Outcomes of patients diagnosed with DCIS with isolated tumor cells or micrometastases on sentinel lymph node biopsy.
Authors: G. Moscol, M. S. Morginstin
Journal: Journal of Clinical Oncology (2011)

133 Background: Ductal carcinoma in situ of the breast (DCIS) is considered a precancerous condition. Nevertheless, 6 to 13% of cases will present cancerous cells in the sentinel lymph node biopsy (SNB) when analyzed using immunohistochemistry (IHC). Current guidelines do not specify if patients with isolated tumor cells (ITC, staged as N0[i+] for clusters &lt;0.2mm) or with micrometastases (micromets, staged as N1mic for clusters between 0.2mm and 2 mm) would benefit from radiation or systemic therapy. We compared the clinical outcomes of patients diagnosed with DCIS and found to have ITC or micromets on SNB to those of patients diagnosed with DCIS without SNB analysis. Methods: Retrospective study. Medical records from patients diagnosed with DCIS at the Cancer Center of AEMC between 01/01/97 and 12/31/08 were reviewed and the SNB status assessed. Other pertinent data (receptor status, type of recurrence and time to recurrence) was collected. The primary outcomes were recurrence/distant metastasis rate (RR) confirmed by biopsy and the time to recurrence (TTR). Descriptive statistics, chi-square and Mann-Whitney U tests were used to analyze the data. Results: Of the patients diagnosed with DCIS between 1997 and 2008 (N=743), 145 were lost to follow up; 598 charts were analyzed. Only 22% of patients had a SNB. Those that underwent the SNB showed a higher RR as compared to those w/o a SNB (9.2% vs 3.6%, p=0.018). The average TTR between groups showed a wide distribution and no statistically significant difference (SNB mean= 2163 days, S.D=1664; w/o SNB mean= 1300 days, S.D. =819, p=0.180). Subgroup analysis in the SNB group showed that patients w/o IHC exam showed the highest rate of recurrence (6 cases, 13.6%), as compared to those with negative findings (5 cases, 7.6%), those with isolated tumor cells (1 case, 5.9%) and those with micromets (0 cases) (p=0.597). Conclusions: Patients with SNB had a higher RR when compared to those w/o SNB. Among patients with SNB, those w/o IHC had a higher RR as compared to those with SNB and IHC (although p &gt; 0.05), possibly due to unidentified ITC/micromets. These results are limited due to the small number of cases with SNB and short follow up interval for patients with SNB and performed IHC.
Effect of a therapeutic sphingosine 1-phosphate antibody on intratumoral hypoxia and sensitivity to standard chemotherapy in prostate cancer animal model.
Authors: O. Cuvillier, I. Ader, P. Bouquerel, B. Malavaud, R. A. Sabbadini
Journal: Journal of Clinical Oncology (2011)

24 Background: Hypoxia promotes neovascularization, metastasis, growth and resistance to treatments. The activation of HIF-1α has been identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is up-regulated under hypoxia, may help normalizing the tumor microenvironment and increase sensitivity to chemotherapy, in the broader concept of normalization of tumor vessels as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009). Methods: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of fluorescent HRPC cells. Results: We provide in vitro evidence that inhibiting the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia and modifies vessel architecture within 5 days of treatment. Third, we demonstrate that an anti-S1P strategy sensitizes to docetaxel, the “gold standard” treatment for HRPC. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibodytogether withdocetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel alone, but also significantly reduced the occurrence and number of metastases. Conclusions: These data establish the proof-of-concept that blocking the exogenous action of S1P reduces intratumoral hypoxia and sensitizes to chemotherapy in prostate cancer animal model. [Table: see text]
Clinical Outcome of Hypomethylating Agents in Hypocellular MDS: Mayo Clinic Experience
Authors: Sonia Cerquozzi, Hassan B Alkhateeb, Moritz Binder, Darci Zblewski, Shahrukh K Hashmi, Mrinal M Patnaik, William J. Hogan, Mark R. Litzow, Aref Al-Kali
Journal: Blood (2015)
Costs of Inpatient Medications: Do Dispensing and Nursing Fees Lead to Overestimates?—Reply
Authors: Emily G. McDonald, Todd C. Lee
Journal: JAMA Internal Medicine (2016)

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