tbuckley/cabot-search huggingface dataset:
Minibody imaging of prostate-specific membrane antigen (PSMA): From concept to clinic.
Authors: Tove Olafsen, Derek Bartlett, David Ho, Green Zhang, Michael Torgov, Jennifer Keppler, Christian Behrenbruch, Anna Wu, Neeta Pandit-Taskar, Michael J. Morris, Jason Stuart Lewis, Serge K. Lyashchenko, Jean M. Gudas
Journal: Journal of Clinical Oncology (2014)

e16057 Background: PSMA is an ideal target for imaging prostate cancer as it is highly expressed in a majority of lesions with low expression in normal prostate epithelium. This study describes the preclinical development of 89Zr-Df-IAB2M, an anti-PSMA minibody (Mb) conjugated with desferrioxamine (Df) and radiolabeled with 89Zr for imaging primary prostate cancer and soft tissue and bone metastases. Methods: In vitro binding analyses of IAB2M, an 80 kDa humanized Mb, included flow cytometry and ELISA. Serial PET imaging, tumor targeting, pharmacokinetics (PK) and tissue biodistribution of 89Zr-Df-IAB2M were evaluated in athymic male mice bearing 22Rv1 (PSMA+) and PC3 (PSMA-) subcutaneous tumors. Organ dosimetry was determined from PET scans of non-tumor bearing mice at 4, 24 and 48 h. A GLP toxicokinetic study evaluated two consecutive 10 and 25 mg/kg doses. Results: IAB2M, Df-IAB2M and Zr-Df-IAB2M bound to cell surface PSMA with high affinity (~0.06 nM). 89Zr-Df-IAB2M retained high (>90%) immunoreactivity and demonstrated specific tumor targeting that peaked at 24 h with 16.0±0.8% ID/g vs. 7.3±1.0% ID/g in positive and negative tumors, respectively, yielding high contrast PET images. Excess cold Mb reduced the tumor uptakes to 4.6±1.3% ID/g in the positive tumor at 24 hrs. The terminal half-life (t1/2β) of 89Zr-Df-IAB2M was 7.5 h. Biodistribution studies revealed highest uptakes in the liver followed by the kidney and heart. Intravenous administration of two consecutive doses of Zr-Df-IAB2M to male ICR mice followed by examination of tissues and organs on Days 3 and 16 showed no evidence of systemic toxicity. The protein t1/2 was between 8.0 and 9.4 hrs and the clearance rate 5.8 to 6.9 mL/h-kg. A phase I/IIa study in metastatic prostate cancer patients in progress at Memorial Sloan Kettering Cancer Institute has demonstrated targeting of 89Zr-Df-IAB2M to metastatic lesions. Conclusions: Pre-clinical testing demonstrated the binding specificity, tissue biodistribution and specific tumor localization by noninvasive microPET imaging as well as the PK and safety of 89Zr-Df-IAB2M in mice. These studies have enabled the Phase I/IIa clinical testing of this novel imaging agent for detecting prostate cancer metastases in patients.
Phase II trial of FOLFOX6, bevacizumab and cetuximab in patients with Colorectal Cancer
Authors: A. J. Ocean, K. O’Brien, J. Lee, N. Matthews, S. Holloway, P. Christos, T. S. Kung, A. Kaubisch, H. Chen, S. Wadler
Journal: Journal of Clinical Oncology (2007)

4075 Background: Bevacizumab (B) + FOLFOX is widely accepted as a standard first-line therapy for metastatic colorectal cancer (mCRC). Recent treatment strategies have included the use of targeted therapies combined with chemotherapy to improve efficacy and to reduce chemotherapy-related toxicities. This Phase II study assesses first-line mFOLFOX6 + B + cetuximab (C), a monoclonal antibody approved for use in irinotecan-refractory mCRC. Methods: All pts had ECOG PS = 1, normal bone marrow, hepatic and renal function. Pts received mFOLFOX6 + B (5mg/kg) biweekly and C weekly (initially at 400 mg/m 2 , then subsequent doses at 250 mg/m 2 ). Tumor assessment by imaging was done every 8 weeks. Primary endpoints are response rate, progression free-survival (PFS), overall survival (OS), and safety. The regimen would be considered promising if there were = 32 responses, or if = 60% of pts were progression-free for at least 8 months. Results: 67 pts (37 males, 30 females) were enrolled from 12/04–11/06. Median age was 57. Toxicities included Grade 4: neutropenia (6%), thrombosis/embolism (5%). Grade 3: neutropenia (13%), rash (13%), fatigue (11%), diarrhea (11%), abdominal pain (6%), neuropathy (5%), infection with ≤ Grade 2 ANC (4.5%). There were 2 deaths, 1 due to neutropenia and diarrhea and 1 to pulmonary fibrosis. As of 12/06, 9 pts were too early to evaluate. Of the remaining 58 pts, there were 32 responses (55%; 95% CI: 42%, 68%), including 3 CRs and 29 PRs; Median PFS was 9.6 months (95% CI: 8.8, 13.9 months), 71% were progression-free for at least 8 months, and median OS was not reached after a median follow-up of 11.4 months (range 1.5–25.2 months). Conclusions: Treatment with mFOLFOX6+ B + C met the pre-specified criteria for objective response and PFS to be considered promising. This regimen is associated with an acceptable toxicity profile and merits further evaluation. Supported by N01-CA-62204. No significant financial relationships to disclose.
Bezlotoxumab Protects Against Recurrent <i>C difficile</i> Infections
Authors: Anita Slomski
Journal: JAMA (2017)

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The features and outcome of HIV-associated anal cancer in screened and unscreened populations.
Authors: Thomas Newsom-Davis, Paul Fox, Victoria Bradley, Alessia Dalla Pria, Mark Nelson, Mark Bower
Journal: Journal of Clinical Oncology (2012)

e14574 Background: The aims of screening for anal cancer are to prevent invasive anal cancer and/or to detect it at an early and hence more curable stage. We sought to evaluate differences in clinicopathological features and outcomes of HIV associated anal cancer between patients who were enrolled on a programme of high resolution anoscopy (HRA) surveillance and those who were not. Methods: A retrospective study of patients diagnosed with anal cancer was undertaken based on our HIV cancer registry. Results: Since 1989, 74 patients (73 male) have been diagnosed and treated for HIV-associated invasive anal cancer, including 7 patients who had been enrolled onto an HRA screening programme. The surveillance patients had undergone a total of 26 examinations starting a median of 3.8 years (range: 0.3-8.7) prior to cancer diagnosis. At anal cancer diagnosis, the screened patients were older (median age: 50 years, range: 45-61 vs 44, range: 28-75, p=0.04), had higher CD4 cell counts (median CD4: 575 /mm 3 , range: 390-842 vs 321, range: 16-1250, p=0.02), more had undetectable plasma HIV viral loads (100% vs 56%, p=0.04) and more were on HAART (100% vs 70% p=0.09). However, there were no differences in cancer stage (p=0.64), local tumour (T) stage (p=0.4), lymph node status (N) stage (p=0.47) or metastatic (M) disease (p=0.51). Similarly, there was no difference in tumour grade between screen and unscreened patients (p=0.19). Finally, there is no difference in the actuarial overall survival between the two groups (Log rank p=0.63). Conclusions: Despite enrolment onto an HRA screening programme and better immunological status at diagnosis, tumours detected in screened patients were neither earlier stage nor better differentiated and there was no improvement in survival. These findings in a relatively small number of patients may cast doubt on the validity of screening by HRA for anal cancer.
Correlating surrogate endpoints with overall survival at the individual patient level in BRAF-mutated metastatic melanoma patients treated with vemurafenib.
Authors: Emily Craig Zabor, Glenn Heller, Lawrence H. Schwartz, Paul B. Chapman
Journal: Journal of Clinical Oncology (2015)

e20020 Background: Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib vs. dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2). Methods: De-identified tumor measurements and OS data from BRIM3 and BRIM2 were analyzed. Target and non-target tumor measurement data were available from pretreatment, weeks 6 and 12, and every 9 weeks thereafter. In BRIM3, associations of OS with both early tumor response (first 16 weeks) and time to progression (TTP) were assessed using a normalized concordance probability estimate and Kendall’s tau derived from the Clayton copula, respectively. Different definitions of response and progression were explored. Findings were validated using BRIM2. Results: Thresholds of early response were explored ranging from any degree to 100% tumor shrinkage. Correlation was weak at all tested thresholds. TTP, however, was more strongly correlated with OS. The strongest correlation was seen with progression defined as a ≥50% increase in the sum of tumor diameters from baseline or appearance of new tumors (Table). This was confirmed by similar analyses in BRIM2. Most patients who progressed on DTIC experienced growth of target lesions; in contrast, progression on vemurafenib was often due to appearance of new tumors. Conclusions: TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing tumor response with TTP or PFS as preferable surrogate endpoints. Correlation of progression defined by ≥ 50% relative increase in sum lesion size with OS. Without new lesions With new lesions # events Correlation (SE) # events Correlation (SE) BRIM3 (n=582) 104 0.675 (0.065) 376 0.588 (0.030) BRIM3 DTIC (n=257) 86 0.727 (0.073) 184 0.546 (0.048) BRIM3 vemurafenib (n=325) 18 NA 192 0.655 (0.034) BRIM2 (n=132) 8 NA 84 0.723 (0.037)
O 2 ⋅− and H 2 O 2 -Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate
Authors: Joshua D. Schoenfeld, Zita A. Sibenaller, Kranti A. Mapuskar, Brett A. Wagner, Kimberly L. Cramer-Morales, Muhammad Furqan, Sonia Sandhu, Thomas L. Carlisle, Mark C. Smith, Taher Abu Hejleh, Daniel J. Berg, Jun Zhang, John Keech, Kalpaj R. Parekh, Sudershan Bhatia, Varun Monga, Kellie L. Bodeker, Logan Ahmann, Sandy Vollstedt, Heather Brown, Erin P. Shanahan Kauffman, Mary E. Schall, Ray J. Hohl, Gerald H. Clamon, Jeremy D. Greenlee, Matthew A. Howard, Michael K. Schultz, Brian J. Smith, Dennis P. Riley, Frederick E. Domann, Joseph J. Cullen, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen
Journal: Cancer Cell (2017)
Impact of beta-blocker medication use on prostate cancer survival: Results from a single-institution cancer registry.
Authors: Manish Kohli, Debashis Nandy, Charlotte Haley, Winston Tan, Adam Lee, James Robert Cerhan, Donald J Tindall, Jyotishman Pathak, Matthew Breitenstein
Journal: Journal of Clinical Oncology (2014)

e16064 Background: Antihypertensive medication use may affect survival outcomes in specific malignancies although anti-tumor activity for this drug class in prostate cancer (PC) is unknown. We evaluated the effect of concomitant beta blocker use on survival in PC patients with high comorbid disease load who received treatment and follow up at a single academic institution that provides primary through tertiary care. Methods: Electronic health records (EHR) of PC patients treated at a single academic center from 1997-2013 were queried for beta blocker exposure (≥12 months) within 5 years of diagnosis, Charlson score and clinical outcomes using a combination of structured queries, natural language processing, and manual chart reviews. A cohort of patients with PC diagnosis and a high Charlson score was identified and followed till time to death due to PC. The association of beta blocker use with prostate cancer specific survival (PCSS) was estimated using hazard ratios (HRs) and 95% confidence intervals (CI) from a multivariate Cox model, accounting for age and stratified on Gleason score (GS) at initial diagnosis of PC. Results: Of 2,807 PC patients treated and followed at the institution, 552 patients had a high Charlson score (>4). In this analytic cohort 60 patients died from PC progression during follow up. The median age at PC diagnosis of the cohort was 64 years (range: 45–85). The cohort had a median follow-up of 83 months (range: 13–196). Use of ß blockers was associated with worse PCSS among patients with a GS ≤6 but not among PC patients with a GS ≥7 (Table). Conclusions: Beta blocker use in PC patients with GS ≤6 may have an adverse impact on PCSS. This observation needs further validation in multi-institutional settings because of its relevance on clinical impact in an elderly population who are often treated with beta blockers. GS Beta blocker use # of events/ # patients HR (95% CI) P-value ≤6 No Yes 117/190 73/190 1 (reference) 5.87 (1.15 – 29.99) 0.033 ≥7 No Yes 249/362 113/362 1 (reference) 0.65 (0.33 – 1.29) 0.228
Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment.
Authors: Shaji Kumar, William Bensinger, Todd M. Zimmerman, Craig B. Reeder, James R. Berenson, Deborah Berg, Ai-Min Hui, Neeraj Gupta, Alessandra Di Bacco, Jiang Yu, Yaping Shou, Ruben Niesvizky
Journal: Journal of Clinical Oncology (2013)

8514 Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820). Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m 2 (dose-escalation phase) and at the MTD, 2.97 mg/m 2 , in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria. Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m 2 ). PK data were similar across expansion cohorts. Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz. Clinical trial information: NCT00963820.
Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.
Authors: Miguel Aracil Avila, Antonio Nieto, Adnan Tanovic, Bradley J. Monk, Stanley B. Kaye, Andres Poveda, Thomas J. Herzog, Trilok V. Parekh, Nadia Badri, Carlos Galmarini
Journal: Journal of Clinical Oncology (2013)

5566 Background: Nibrin (p95/NBS1) is a protein with an essential function in DNA double-strand break repair by homologous recombination. Therefore, we have investigated its value as a possible biomarker in patients with AOC by immunohistochemistry (IHC). Methods: IHC staining was performed in 138 samples from a subset of patients that have participated in the phase III OVA-301 trial, in which the combination of trabectedin plus pegylated liposomal doxorubicin (PLD) or PLD alone were randomly administered for advanced disease after failure of platinum-based chemotherapy (Monk 2010; Monk 2012). A computerized image analysis system was used to calculate the total percentage of nibrin-positive cells. Nibrin expression was considered as a continuous variable. The analysis of overall response rate (ORR) and progression-free survival (PFS) was based on independent oncologist assessment. Overall survival (OS) was defined from randomization to death/last contact. All the comparisons had an exploratory nature; an alpha cut-off value of 0.05 (two-sided) was established as statistically significant. Results: For PFS, there was a statistically significant correlation between high levels of nibrin and short PFS (HR = 1.014, 95% CI: 1.004-1.024, p=0.0047). Similarly, for OS, there was a statistically significant correlation between high levels of nibrin and worse OS (HR = 1.009, 95% CI: 1.001-1.017, p = 0.0295). A multivariate analysis showed that high levels of nibrin were independently correlated to a worse PFS (HR = 1.012, 95% CI: 1.002-1.022, p = 0.0147) and to a worse OS (HR = 1.010, 95% CI: 1.002-1.018, p=0.0192). After stratification according to platinum-sensitivity, high nibrin showed a significant correlation with lower ORR (ORR = 1.02, 95% CI: 1.01-1.03, p=0.0009), short PFS and OS values only in the platinum-sensitive patients. Conclusions: The results point out the potential importance of nibrin expression in the clinical outcome of patients with AOC. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted. Clinical trial information: NCT00113607.
Retrospective analysis of salvage percutaneous cryoablation of hepatocellular cancer (HCC) in liver
Authors: J. R. Daniels, M. D. Katz, M. Hart, T. Fong, J. A. Donovan, A. B. El-Khoueiry, M. A. Wallman
Journal: Journal of Clinical Oncology (2009)

e15649 Background: We report our initial experience with percutaneous cryoablation of HCC in liver. Prior published series are limited. Methods: We treated 30 lesions in 23 patients (pts): Child-Pugh class A, 13 pts; B, 8 pts.; C, 2 pts Candidate pts had residual disease after intra-arterial chemotherapy. Probe placement (2.4 mm, Endocare) occurred under general anesthesia with restricted tidal volume to facilitate computer tomographic (CT) localization. An average 2.7 probes (range 1- 5) achieved an estimated margin of 0.5 cm visualizing the ice ball after two 10 min freeze cycles. Median follow-up was 342 days (range 30–947) Results: Tumors ranged from 1.3 to 5.8 cm. Three pts died within 30 days: 2 following intra-peritoneal hemorrhage despite control of bleeding and 1 from ischemic liver injury following a TIPSS for hydrothorax in a pt with refractory ascites. Two additional pts had hemorrhage with recovery. Risk of bleeding was associated with ascites (P = 0.013). One pt had cutaneous needle tract tumor seeding caused by needle repositioning prior to freezing. Survivors remained clinically stable at the 2–3 month follow-up. At the 2 month evaluation 29 lesions had no residual enhancement by CT. One lesion required a second cryoablation procedure.There were no recurrences in any target lesion (30–947 days). Thirteen pts are alive without recurrence of whom 6 had liver transplant with no (4) or &lt; 5% (2) residual disease. Three pts have had recurrence in non-target liver and have died. Multiple tumors at baseline predicts for hepatic recurrence. Two pts have died from complications of cirrhosis, and 2 are lost to follow-up. Conclusions: Percutaneous cryoablation effectively manages selected hepatic HCC tumors. Cirrhotic pts with ascites have significant risk for hemorrhage. We recommend peri-procedure paracentesis and an immediate post-procedure CT. [Table: see text]
Patterns of chemotherapy administration in soft tissue sarcoma (STS) and impact on overall survival (OS): A National Cancer Database (NCDB) analysis.
Authors: Sujana Movva, Elizabeth Handorf, Eric A Ross, Margaret von Mehren
Journal: Journal of Clinical Oncology (2014)

10566 Background: Patients with AJCC stage III STS (large, deep, high grade) have an expected OS of approximately 50% at 5 years. A meta-analysis of adjuvant chemotherapy in STS showed an absolute benefit in OS for the chemotherapy group. Despite these results, patterns of care and opinions with regard to adjuvant chemotherapy vary. Our aims were to identify factors associated with receipt/non-receipt of chemotherapy, and their impact on OS in patients with high risk STS. Methods: Individuals diagnosed with stage III STS between 1998-2010 were identified from the NCDB. Excluded from the analysis were patients who did not undergo surgery for the primary tumor and histologies considered resistant to chemotherapy. Chi-square tests and multivariate logistic regression were used to compare sociodemographic and tumor factors between the groups receiving and not receiving chemotherapy. All-cause mortality was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. The survival analysis cohort was limited to patients diagnosed between 2003-2005 based on availability of survival and comorbidity data. Results: 12,198 individuals with stage III STS were identified. 29% of patients received chemotherapy. Patients who were <40, privately insured, earned a higher income, had no comorbidities, had synovial histology, and whose tumors were > 10 cm were more likely to receive chemotherapy on both univariate and multivariate analysis. Race, education level and type of treating facility were not significantly associated with receipt of chemotherapy. Median unadjusted OS in the chemotherapy and non-chemotherapy groups were 83.9 and 48.5 months respectively (P<0.0001). The benefit for chemotherapy was also seen on adjusted analysis, (HR 0.77; P<0.0001), when controlling for sociodemographic and tumor factors (15 total factors including age, comorbid conditions, race and insurance status). Conclusions: Our analysis demonstrates an OS benefit for chemotherapy in stage III STS after adjusting for comorbidities. To our knowledge this is the first retrospective OS analysis restricted to stage III patients that also adjusts for socioeconomic status.
Stereotactic Ablative Radiotherapy Induces Peripheral T-Cell Activation in Patients with Early-Stage Lung Cancer
Authors: Pauline L. de Goeje, Egbert F. Smit, Cynthia Waasdorp, Merel T. B. Schram, Margaretha E. H. Kaijen-Lambers, Koen Bezemer, Mark de Mol, Koen J. Hartemink, Joost J. M. E. Nuyttens, Alexander P. W. M. Maat, Joost P. J. J. Hegmans, Rudi W. Hendriks, Suresh Senan, Joachim G. J. V. Aerts
Journal: American Journal of Respiratory and Critical Care Medicine (2017)