tbuckley/cabot-search huggingface dataset:
Effect of perioperative complications on recurrence and survival after resection of hepatic colorectal metastases: Analysis of data from a randomized controlled trial.
Authors: Camilo Correa-Gallego, Mithat Gonen, Mary Fischer, Florence Grant, Nancy E. Kemeny, T. Peter Kingham, Ronald P. DeMatteo, Yuman Fong, Peter J Allen, Michael Ian D'Angelica, William R. Jarnagin
Journal: Journal of Clinical Oncology (2012)

3620 Background: Perioperative outcomes such as blood loss, transfusions and morbidity have been associated with cancer specific survival, but this is unsupported by prospective data. Methods: Patients were derived from a previously reported prospective randomized trial of acute normovolemic hemodilution (ANH) versus standard management during major hepatectomy. Patients with metastatic colorectal cancer (mCRC) were selected for analysis. Chemotherapy and survival data were obtained from the medical record. Disease extent was measured using a clinical risk scoring (CRS) system. Log-rank test and Cox proportional hazard model were used to evaluate recurrence free (RFS) and overall survival (OS). Results: This trial enrolled 130 patients, 90 of whom had mCRC. Median follow up was 54 m; median age was 53 yr; 56% were men. The CRS was ≥3 in 55% of patients, and 57% had additional extrahepatic procedures. Morbidity and mortality were 33% and 3%. Chemotherapy was split before and after surgery in 70%; 10% received only preoperative and 19% only postoperative treatment, which was initiated after a median time of 6 wks (IQR = 4-7). RFS and OS were 29 and 59 m. On multivariate analysis, (+) resection margin, high CRS and perioperative complications predicted shorter RFS and OS. Delayed initiation of postoperative chemotherapy (≥ 8 wks) while most common in patients with complications (37 vs 12%; p: 0.01), was not a significant predictor of shorter RFS or OS. Randomization (ANH vs standard) was also not significant in this regard. (See Table.) Conclusions: In this prospective randomized cohort, perioperative morbidity was a highly significant independent predictor of cancer specific outcome, associated with but not entirely explained by delayed initiation of chemotherapy. [Table: see text]
Choosing wisely: Treatment recommendations from 36 Michigan Oncology Clinical Treatment Pathways practices.
Authors: Amy Hatfield Seung, Lauren M. Hamel, Philip J. Stella, Justin Frank Antoni Klamerus, Douglas W. Blayney
Journal: Journal of Clinical Oncology (2015)

6584 Background: ASCO identified ten low value, commonly used practices (Schnipper et al JCO 14:1715, 2012 and JCO 31:4362, 2013) as part of the “Choosing Wisely” (CW) campaign. Pathways is a statewide quality improvement program sponsored by Michigan BlueCross BlueShield. It measures and incentivizes adherence to locally defined treatment pathways (Fineberg et al JOP 8e32s, 2012). CARETSM, a web-based patient registry was developed to support this program. CARET allows providers to enter treatment data and patient characteristics, and to demonstrate pathway compliance. We report preliminary data for three CW items. Methods: CARET includes records entered by participating providers for medical anticancer treatment regimens. Provider-reported data is matched to insurance claims data. Three CW items were easily available for analysis, avoiding: 1) chemotherapy for patients with advanced incurable cancer, 2) unnecessary myeloid growth factors, and 3) unnecessary antiemetic drugs for chemotherapy with low or moderate risk of nausea or vomiting. Results: A total of 1060 anticancer regimens representing 937 unique patients were initiated in 2014. 114 physicians from 36 practices were included. 690 (65.1%) regimens required prophylactic myeloid growth factor and antiemetic pathways. Results by tumor type and by CW item are shown in the table. Conclusions: Pathways practices appear to CW for these three treatment measures. From our initial data, we cannot discern the role of incentives for pathway adherence; the effect of real-time, registry-based, decision support tools (CARET); support from payors; or other factors in CW. We plan to explore these reasons and analyze cost savings from CW. Regimens (n) Advanced disease with PS 3-4 receiving chemotherapy n (%) Regimens with supportive care (n) Antiemetic nonadherence n (%) Growth factor nonadherence n (%) Breast 442 7 (1.58%) 306 49 (16.1%) 38 (12.4%) Colon 133 1 (0.75%) 110 17 (15.5%) 4 (3.6%) Lung 201 6 (2.99%) 119 23 (19.3%) 15 (12.6%) Lymphoma 116 2 (1.72%) 87 16 (18.4%) 4 (4.6%) Multiple Myeloma 59 0 41 3 (7.3%) 2 (4.9%) Ovarian 46 0 16 3 (18.8%) 6 (37.5%) Prostate 59 1 (1.7%) 11 3 (27.3%) 2 (18.2%) Renal 4 0 0 - - Total 1060 17 (1.6%) 690 114 (16.5%) 71 (10.3%)
Epidermal growth factor receptor (EGFR) targeted photoimmunotherapy (PIT) for the treatment of EGFR expressing bladder cancer.
Authors: Reema Railkar, Spencer Krane, Q. Quentin Li, Thomas Sanford, Peter L. Choyke, Hisataka Kobayashi, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2017)

291 Background: There are limited treatment options for patients with non-muscle invasive bladder cancer (NMIBC) who fail intravesical bacillus Calmette-Guerin (BCG). The use of light as a means of therapy for bladder cancer (BC) has a long history but has been hampered by a lack of tumor specificity and toxicity. Monoclonal antibody (mAb)-conjugates represent an emerging therapeutic approach for malignancies that improves upon tumor specificity. The use of a mAb-photo-absorber (PA) conjugate is a more selective method of delivering light therapy and has been termed “photoimmunotherapy” (PIT). In this report, PIT is used to target the epidermal growth factor receptor (EGFR). EGFR is a good tumor-specific target as it is enriched in the basal molecular subtype of BC. In the present study, anti-EGFR antibody panitumumab (pan) was labeled with the PA, IRDye 700Dx (IR700), to create a pan IR700 mAb-PA conjugate which is activated by near-infrared radiation (NIR). Methods: BC tissue microarray (TMA) and BC cell lines were analyzed for expression of EGFR. Mechanism of PIT induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. Results: EGFR staining of TMAs showed that while most BCs have expression of EGFR to some degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Pan IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Pan alone, pan IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed towards cell death. NIR-PIT with pan IR700 reduced growth compared to only pan IR700 treated UMUC-5 xenograft tumors. Conclusions: PIT is a new targeted treatment for BC. Our data demonstrate that pan IR700-induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and hence warrants further studies in orthotopic models and in patients. We suspect that EGFR-directed therapy with PIT is a viable strategy for the basal molecular subtype of BC and will be testing this hypothesis in the future.
BK virus as a predictor of chronic kidney disease in hematopoietic stem cell recipients.
Authors: Ala Abudayyeh, Amir Hamdi, Maen Abdelrahim, Gabriela Rondon, Aimaz Afrough, Heather Lin, Elizabeth J. Shpall, Katy Rezvani
Journal: Journal of Clinical Oncology (2014)

7016 Background: Nephropathy from BK virus (BKV) infection is an evolving challenge in hematopoietic stem cell transplantation (HSCT) recipients. In contrast to kidney transplantation, where there are screening protocols for early detection and prevention of symptomatic BKV nephropathy, there is no such guideline in HSCT. We hypothesized that BKV infection is a marker of poor renal outcomes in the HSCT survivor population. Methods: We analyzed all engrafted patients undergoing first allogeneic HSCT at MD Anderson Cancer Center between January 2004 and December 2012, with normal kidney function at the time of HSCT. We evaluated the renal outcome and factors impacting poor renal outcome in these patients. BKV positivity was defined as BKV detection in urine by PCR testing. Renal outcome was determined as the time between HSCT to chronic kidney disease (CKD), defined by constant decrease of 25% or more in estimated glomerular filtration rate (eGFR) compare to the baseline at the time of transplant. Results: In a total of 2,477 SCT patients, BK viruria was manifested in 25% (n=629) of the patients. Conditioning regimen consisted of a myeloablative in 1,275 (52%), reduce intensity in 697 (28%), and non-myeloablative in 498 patients (20%). The source of stem-cells was peripheral blood in 1,575 (64%), bone marrow in 697 (28%), and cord blood in 205 (8%). In multivariate analysis, with the adjustment of age, gender, acute GVHD, chronic GVHD, preparative conditioning regimen, graft source, and tacrolimus serum level, BKV viruria showed significant association with renal outcome (Hazard Ratio (HR) (95% confidence interval (CI) = 1.706 (1.483, 1.964), P-Value <0 .0001). Additionally, BK viral load showed significant association with CKD (HR (95% CI) = 1.023 (1.017, 1.029) for one-fold increase, P-Value <0 .0001). Conclusions: To the best of our knowledge, this is the first study to identify BKV as a strong independent predictor of long-term renal outcome following HSCT. This study shed more light about the differences and similarities of BKV infection in HSCT and kidney transplant survivors and helps to formulate plans for more effective future prevention and treatment.
Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy
Authors: Denise Hilfiker‐Kleiner, Arash Haghikia, David Masuko, Justus Nonhoff, Dominik Held, Elena Libhaber, Mark C. Petrie, Niki L. Walker, Edith Podewski, Dominik Berliner, Johann Bauersachs, Karen Sliwa
Journal: European Journal of Heart Failure (2017)
Phase I study of NBTXR3 nanoparticles, in patients with advanced soft tissue sarcoma (STS).
Authors: Sylvie Bonvalot, Cecile Le Pechoux, Thierry De Baere, Xavier Buy, Antoine Italiano, Eberhard Stockle, Philippe Terrier, Nathalie Lassau, Axel Le Cesne, Paul Sargos, Mikael Antoine, Naima Lezghed, Fouzia Azzouz, Alejandro Goberna, Laurent Levy, Borghi Elsa, Mikaela Dimitriu, Jean-Charles Soria, Eric Deutsch
Journal: Journal of Clinical Oncology (2014)

10563 Background: Functionalized hafnium oxide nanoparticles (NBTXR3) have been developed as selective radioenhancers, which may represent a breakthrough approach for the local treatment of solid tumors. This is a unique approach where crystalline nanomaterials with high electron density when exposed to radiotherapy, can allow penetrate into the cell and make feasible the absorption/deposition of a high energy dose within the tumor cell. A phase I/II trial was implemented in patients with locally advanced STS. Methods: Patients (pts)received a single intratumor (IT) injection of NBTXR3, volume escalated, followed by 50Gy RTx (see Table). Primary endpoints include feasibility of the IT implantation and safety. Secondary endpoints focus on efficacy such as pathological and RECIST response, IT residency of NBTXR3 over all the RTx period and operability. Results: Enrollment was completed for volume 1, 2, and 3 (15 pts). Feasibility of the IT injection was confirmed. The treatment was safe with no SAE, no early DLT and allowed the pts for completion of the planned RTx schedule. No grade 3-4 toxicity occurred, main grade 1-2 toxicities related to NBTXR3 were injection pain/reaction (4 pts), pyrexia (2 pts), abdominal pain (1 pt), pruritus (1 pt) and paresthesia (1 pt). Results demonstrated that a single injection of NBTXR3 provides adequate bioavailability of NBTXR3 IT over five weeks of radiotherapy. No leakage of NBTXR3 to the adjoining healthy tissues was observed. Further, NBTXR3 persistence was established by CT scan before surgery. Conclusions: Injection of NBTXR3 was well tolerated. All pts received the planned radiotherapy (50 Gy/25 fractions/ 5 weeks) followed by wide surgical resection of the sarcoma. NBTXR3 with RTx showed a very good safety profile. Encouraging signs of antitumor activity were observed in different sarcoma subtypes, such as undifferentiated sarcoma, rhabdomyosarcoma, and synovial sarcoma, which constitutes a promising feature for this subset of pts whose primary tumor is locally advanced and has an important risk of relapse. Clinical trial information: NCT01433068. Volume level Pts Tumor volume cc Injected volume mL 1 6 55-1,814 (503) 1.4-45 (12) 2 6 85-3,682 (1127) 4.2-184 (56) 3 3 360-885 (590) 36-100.5 (60) 4 Screening
Evaluation of the pattern of SOX2 expression in non-small cell lung cancer (NSCLC) and correlation with clinicopathologic (CP) features and prognosis.
Authors: Vamsidhar Velcheti, Huan Cheng, Xiaopan Yao, Yanhong Deng, Scott N. Gettinger, David Rimm
Journal: Journal of Clinical Oncology (2012)

e21106 Background: SOX2 is an embryonic stem cell transcription factor that plays a crucial role in differentiation and maintaining pluripotency. We examine the pattern of SOX2 expression and assess correlation with CP features in NSCLC. Methods: Using the AQUA method of automated quantitative immunofluorescence we measured SOX2 expression in two cohorts (in a tissue microarray format), from Yale New Haven Hospital (YTMA 79) and an independent cohort from Patras University Hospital in Greece (YTMA 140) (196 and 342 cases, respectively). YTMA 140 had high percentage of Squamous cell carcinoma (SCC) (48.8%) as opposed to 17.9% in YTMA 79. There were more stage III &amp; IV pts in YTMA 140 (41.3%) compared to YTMA79 (30.6%). 88% of pts in the YTMA 140 were male compared to 52.5% in YTMA79. Survival analysis was done using Kaplan-Meier analysis with log-rank test. The associations between SOX2 expression level and CP features were evaluated by using non-parametric Kruskal-Wallis test. Results: In both cohorts, we found significantly higher SOX2 expression in SCC compared to adenocarcinoma. There was no correlation with gender or stage. Using the threshold of specific signal detection as the cut point, we divided the cohorts into expressers and non-expressers. YTMA 140 cohort which is enriched in SCC showed that 28/161(17.3%) pts with SCC were SOX2 non-expressers. Pts who were SOX2 non-expressers had a worse median overall survival (15 months) compared to pts who were SOX2 expressers (23.5 months) (p=0.015). Conclusions: Our data reveals that pts who have SCC have significantly higher expression of SOX2 and higher SOX2 expression correlates with better outcome. Further studies to define the molecular characteristics of SCC may elucidate more effective markers and effective classification for NSCLC.
Phase lb/ll study of the PI3Kα inhibitor BYL719 in combination with cetuximab in recurrent/metastatic squamous cell cancer of the head and neck (SCCHN).
Authors: Albiruni R. A. Razak, Myung-Ju Ahn, Chia-Jui Yen, Benjamin J. Solomon, Se-Hoon Lee, Hung-Ming Wang, Pamela N. Munster, Carla M.L.- Van Herpen, Jill Gilbert, Rupam Ranjan Pal, Lars Blumenstein, Belen Gomez-Carrillo, Christina Marie Coughlin, Wan-Teck Lim
Journal: Journal of Clinical Oncology (2014)

6044 Background: Preclinical data suggest that simultaneous inhibition of PI3K and EGFR leads to synergistic antitumor activity in SCCHN. BYL719 is a potent, oral inhibitor of the α-isoform of class I PI3K. The Phase Ib dose-escalation part of this study used a Bayesian model to identify the recommended Phase II dose (RP2D) of BYL719 combined with standard weekly doses of cetuximab (EGFR inhibitor) in patients (pts) with platinum-resistant, recurrent/metastatic SCCHN (NCT01602315). Methods: BYL719 was administered QD in 28-day cycles using two methods: (1) as whole tablets (Arm A) or (2) as a drinkable suspension (crushed tablets) for pts with swallowing dysfunction (Arm B). Results: As of Oct 28, 2013, 32 pts were treated with either BYL719 300 mg QD (n=15) or 400 mg QD (n=5) in Arm A or BYL719 300 mg QD (n=12) in Arm B. At 300 mg (Arms A+B), 4 out of 27 pts had dose-limiting toxicities (DLTs; 2 mucositis, 1 hyperglycemia, and 1 PEG tube site infection). At 400 mg (Arm A), 2 out of 5 pts had DLTs (1 fatal tumor lysis syndrome and 1 esophageal ulcer). Other frequent drug-related AEs (any grade >15%) were similar across arms and included hyperglycemia (55%; G3/4, 20%), acneiform dermatitis (40%; G3/4, 5%), stomatitis (40%; G3/4, 5%), dry skin (25%; G3/4, 0%), hypomagnesemia (25%; G3/4, 5%), decreased appetite (20%; G3/4, 5%), diarrhea (20%; G3/4, 0%), fatigue (20%; G3/4, 10%), and paronychia (20%; G3/4, 0%) in Arm A. Exposures (AUC) and maximal concentrations (Cmax) were similar across arms and were consistent with the PK profile of single-agent BYL719. Best overall response per RECIST v1.1 in Arm A was 1 partial response, 3 unconfirmed partial responses, 5 stable diseases (SDs), and 1 unknown at 300 mg (10 evaluable pts); 1 pt had progressive disease (PD) and 1 pt had SD (2 evaluable pts) at 400 mg.No responses were observed in Arm B. The primary reason for discontinuation was PD (28%). The RP2D of BYL719 in combination with cetuximab was declared as 300 mg QD (whole tablets). Conclusions: Combined inhibition of PI3K-a and EGFR by BYL719 and cetuximab was tolerated and demonstrated encouraging antitumor activity. The Phase II part of the study comparing this combination with cetuximab alone is ongoing. Clinical trial information: NCT01602315.
Targeted pancreatic cancer drug-delivery utilizing sigma-2 ligand/receptor internalization is energy-dependent.
Authors: Linda X Jin, Suwanna Vangveravong, Darren R Cullinan, Peter S. Goedegebuure, Andrew J Loza, Robert H Mach, Dirk Spitzer, William G. Hawkins
Journal: Journal of Clinical Oncology (2017)

331 Background: Pancreatic cancer is a devastating disease that is poorly responsive to traditional systemic therapies. Cancer-selective drug delivery can improve survival and reduce systemic toxicities. We have developed a pancreatic cancer drug delivery platform based on sigma-2 receptor ligands conjugated to small molecule drug cargos, which improves delivery and efficacy through efficient drug internalization. However, the mechanism of drug internalization via the sigma-2 receptor/ligand interaction remains unclear. Methods: Uptake of fluorescently conjugated sigma-2 ligand SW120 was studied in ASPC-1 human pancreatic cancer cells. Uptake was measured at 37C, 4C, after competitive inhibition with sigma-2 ligand SW43, and after pretreatment with Pitstop 2 (Abcam), an inhibiter of clathrin-mediated endocytosis. Uptake was visualized using live-cell imaging using A1Rsi confocal laser scanning microscope (Nikon). Image analysis was performed using FIJI (NIH) and Matlab (Mathworks). Results: SW120 (10 nM) was rapidly internalized into ASPC-1 cells at 37C with maximal fluorescence at 12 minutes. As a negative control, incubation of ASPC-1 cells with the unconjugated flourophore NBD Cl demonstrated no uptake after 15 minutes, indicating that uptake of SW120 depends on the specific sigma-2 receptor/ligand interaction. Fluorescence at 15 minutes was reduced by 85% in ASPC-1 cells incubated at 4C, indicating uptake of SW120 into cells is an energy dependent process. Pretreatment of cells with Pitstop 2 decreased total flourescence at 15 minutes by 76%, suggesting an important role of clathrin-mediated endocytosis in sigma-2 receptor uptake, while pretreatment with competitive inhibitor SW43 reduced uptake by 84%, suggesting that sigma-2 ligands are internalized via a specific receptor capable of saturation. Conclusions: Sigma-2 receptor ligands are rapidly internalized into pancreatic cancer cells via a specific, targetable, energy-dependent pathway that appears to rely on clathrin-mediated endocytosis. Further understanding of sigma-2 mediated drug internalization can help optimize targeted drug development and delivery for pancreatic cancer patients.
Effect of sunlight exposure on survival in patients with lymphoma: Results from the prospective Singapore Lymphoma Study.
Authors: Yin Leng Lee, Kevin Tay, Soon Thye Lim, Soo Yong Tan, Miriam Tao, Richard Hong Hui Quek, Leonard Tan, Tam Cam Ha
Journal: Journal of Clinical Oncology (2012)

1593 Background: Recently, several studies evaluating the effect of ultraviolet light exposure on the risk of developing lymphoma have yielded conflicting results, in part due to seasonal and latitude variation. Further, most of these studies also lack long term follow up and could not systemically address the influence of sunlight exposure on survival. In this prospective, epidemiological study, we explored the relationship between past sunlight exposure and survival in lymphoma patients in tropical Singapore, where sunlight exposure is constant throughout the year. Methods: Singapore Lymphoma Study was established in 2005. A total of 384 patients with histologically confirmed lymphoma were followed from date of diagnosis through November 2011. Interviewers were trained to conduct in-person interviews to collect detailed information, including every occupational period that lasted at least 1 year and number of hours worked outdoor from 9am to 5pm using a structured questionnaire. Descriptive, multivariate and survival analysis (Kaplan Meier; age, gender, race and education level adjusted) were performed. Results: Among all lymphoma subtypes, the most prevalent was diffuse large B cell lymphoma, 47.7%, followed by Hodgkin lymphoma, 14.6%, follicular lymphoma, 12.2% and T cell lymphoma, 6.5%. 97.1% had black or brown eye color and 49.6% had fair skin. Overall survival of lymphoma and NHL subtype decreased significantly with increasing lifetime occupational hours (ptrend=0.01 and 0.03). Chinese was associated with longer survival with increasing daily sunlight exposure during childhood and adolescent years, whether at school or outdoor leisure (ptrend=0.04) and there were no evidence for non-Chinese (Malays or Indians). Patients with lighter eye color results in shorter survival (HR=2.91, 95% CI: 1.15-7.34, p=0.02). Conclusions: We found leisure sunlight exposure during childhood and adolescent years to be beneficial to the survival of Chinese lymphoma patients and increasing lifetime cumulative occupational exposure is associated with increasing risk of death. This data contributes to the growing research on the effects of sunlight exposure on lymphoma patients.