tbuckley/cabot-search huggingface dataset:
First-, second-, third-line therapy for metastatic renal cell carcinoma (mRCC): Benchmarks for trials design from the International mRCC Database Consortium (IMDC).
Authors: Daniel Yick Chin Heng, Brian I. Rini, Jae-Lyun Lee, Nils Kroeger, Sandy Srinivas, Lauren Christine Harshman, Jennifer J. Knox, Georg A. Bjarnason, Mary J. MacKenzie, Lori Wood, Ulka N. Vaishampayan, Neeraj Agarwal, Sumanta Kumar Pal, Min-Han Tan, Sun Young Rha, Takeshi Yuasa, Frede Donskov, Aristotelis Bamias, Scott A. North, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

4586 Background: Limited data exists on outcomes for mRCC patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counseling and clinical trial design. Methods: Outcomes of mRCC patients from the IMDC treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared and adjusted by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) benchmarks were calculated using different population inclusion criteria. OS and PFS are calculated from the line of therapy under consideration unless otherwise specified. Results: 2,705 patients were treated with TT of which 1,533 (57%) received only 1st-line TT, 734 (27%) received 2 lines of TT, and 438 (16%) received 3+ lines of TT. The median OS of patients that received 1, 2 or 3+ lines of TT starting from initial TT was 14.9, 21.0, and 39.2 months, respectively (p&lt;0.0001). On multivariable analysis adjusting for baseline Heng prognostic factors, the use of 2nd-line and 3rd-line therapy were each independently associated with better OS (HR=0.738 and 0.626, respectively, both p&lt;0.0001). Survival benchmarks derived from patients in the IMDC using selected inclusion criteria as seen in contemporary mRCC clinical trials are shown below. Conclusions: Patients that are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing new clinical trials. [Table: see text]
ETS1 Phosphorylation at Threonine-38 Is a Marker of B Cell Receptor Activation, Associating with Cell of Origin and Outcome in Diffuse Large B Cell Lymphoma
Authors: Elaine Y Chung, Maurilio Ponzoni, Zijun Yidan Xu-Monette, Valdemar Priebe, Luciano Cascione, Eugenio Gaudio, Emanuele Zucca, Davide Rossi, Ken H. Young, Francesco Bertoni
Journal: Blood (2016)
Prognostic factors in extrapulmonary small cell carcinomas.
Authors: Ryan Ying Cong Tan, Chau Hsien Matthew Ng, Joanne YY Ngeow
Journal: Journal of Clinical Oncology (2015)

e15196 Background: Extra-pulmonary small cell carcinomas (EPSCC) are a heterogeneous group of cancers whose clinicopathological features of EPSCC remain poorly defined. Methods: A retrospective study of 140 patients with a histological diagnosis of EPSCC made between 1984 and 2008 and treated at the National Cancer Centre of Singapore. Clinical characteristics were evaluated in relation to primary site and extent of disease. Results: Out of a total of 140 patients, 48% had limited disease and 52% extensive disease, with a median age of 57.2 years. The commonest sites of occurrence of EPSCC were the gastrointestinal (31%) and gynaecological (31%), followed by head and neck (21%). The overall median survival for EPSCCs was 16months with the medial survival being 47% at 1 year, 27% at 2 years, 9% at 5 years and 5% at 10years. Patients with gastrointestinal EPSCC had a particularly poor prognosis. They were four times as likely to present with extensive disease compared to those with non-gastrointestinal EPSCC (OR 3.97, 95% Confidence Interval 1.79-8.79). They also had a shorter median survival of 15months and overall survival of 47% at 1year, 19% at 2 years, 2% at 5years and 10years. The pancreas was commonest site involved (35%), followed by oesophagus/stomach (26%). In contrast, EPSCC of the head, eyes, ears, nose and throat (HEENT) appear to have better prognosis. In our study, 60% of HEENT EPSCC patients were found to have limited stage disease. The median survival was 46 months and overall survival was 64% at 1 year, 54% at 2 years, 25% at 5 years and 10.7% at 10years. The sinonasal cavity was the commonest site (37%) followed by the larynx (17%). Gynaecological EPSCCs in our study also predominantly had limited disease (60%), however median survival was only 11 months. The cervix was the most common site (73%), followed by the ovary (7%). Conclusions: EPSCC is a unique class of tumours that is becoming more recognised. This is one of few studies from an Asian cohort of patients. Primary site and extent of disease significantly affect survival with gastrointestinal EPSCC carrying a poor prognosis.
Phase I, open-label, multi-ascending dose trial of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors.
Authors: Kohei Shitara, Yasuhide Yamada, Kiyotaka Yoh, Yoichi Naito, Satoru Iwasa, Noboru Yamamoto, Anja von Heydebreck, Hiroyuki Achiwa, Toshihiko Doi
Journal: Journal of Clinical Oncology (2015)

3023 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in phase I/II trials. Here we report on the safety and tolerability of avelumab in a phase I dose escalation study (NCT01943461) in Japanese patients (pts) with advanced solid tumors. Methods: Dose escalation (3+3 design) was performed for 3 dose levels (DL 3, 10, and 20 mg/kg). The dose limiting toxicity (DLT) evaluation period was 3 weeks. Results: A total of 17 pts (4 gastric, 4 melanoma, 3 NSCLC, 2 CRC, 2 GIST, 1 esophageal, 1 MBC) were enrolled, with 5, 6, and 6 pts treated with avelumab at 3, 10, and 20 mg/kg, Q2W, respectively. Median age was 62 years (range 30–74) and all had ECOG PS 0 or 1, with a median of 4 prior lines of therapy (range 1–9). Treatment-emergent adverse events (TEAEs) occurred in 16/17 pts (94.1%), of which 11 (64.7%) were treatment-related. The most frequent related TEAEs (≥ 10%) were infusion-related reactions (5, 29.4%), stomatitis (4, 23.5%), maculopapular rash (4, 23.5%), decreased white blood cell count (3, 17.6%), pyrexia (2, 11.8%), headache (2, 11.8%), and anemia (2, 11.8%). Two pts had grade 3 TEAEs (not related). No pt experienced a DLT. Two pts had confirmed partial responses (1 melanoma, 1 esophageal), and 5 had stable disease for > 3 months. To date, 12 pts (70.6%) have discontinued treatment: 10 (58.8%) for progression, 1 (5.9%) for death, and 1 (5.9%) for other reason. Five pts (29.4%) remain on treatment. All 17 pts were evaluable for PK analysis. Half-life was 88.6, 121.8, and 114.0 h for dose levels 3, 10, and 20 mg/kg, respectively. The parameters Cmax and AUC were approximately proportional with dose, showed low variability, and were similar to those previously obtained in Caucasian pts. Conclusions: Avelumab can be safely administered to Japanese pts in doses up to 20 mg/kg Q2W. Additional phase II/III studies to evaluate the clinical activity of avelumab at 10 mg/kg Q2W in select tumor types are currently being planned. *Proposed INN. Clinical trial information: NCT01943461.
Efficacy of Sr-89 to painful bone metastases for Japanese breast cancer patients.
Authors: Kimito Yamada, Hiroshi Kaise, Fuyou Kimura, Mari Hosonaga, Kana Miyahara, Yuko Kawai, Ai Ueda, Saeko Teraoka, Mana Yoshimura, Takashi Ishikawa
Journal: Journal of Clinical Oncology (2015)

e12063 Background: Bone modifying agents, zoledronic acid or Denosumab are first choice for bone metastases as standard therapy. However some patients are still painful. The purpose of this study was to examine the safety and efficacy of the concurrent use of the radiopharmaceutical strontium-89 (Sr-89) chloride with zoledronic acid in standard anticancer therapy for breast cancer patients with painful multifocal bone metastases. Methods: The subjects were 42 breast cancer Japanese women with painful bone metastases detected by bone scintigraphy, computed tomography or magnetic resonance imaging, in whom Sr-89 was added to zoledronic acid continuous therapy, or was added after an initial administration of zoledronic acid at the Department of Radiology in our hospital, between October 2007 and December 2014. Results: The median age of the subjects was 56 y-o (39–77 y-o).The average period of using zoledronic acid before Sr-89 administration is 15.8 months (0-64months). In this study, the median survival period after Sr-89 administration was 15.1 months. When evaluating the efficacy of this combination with respect to changes in the doses of analgesic agents, 30 (71%) of the 42 patients responded to this therapy. In this study, we also reviewed chemotherapeutic regimens combined before and after Sr-89 administration. Chemotherapy with vinorelbine, gemcitabine, capecitabine, and nab-paclitaxel, which may cause bone marrow suppression, was performed before and/or after Sr-89 administration. Adverse events were tolerable. Conclusions: Our results suggest that simultaneous combination therapy with chemotherapy before or after Sr-89 administration, or combination therapy early after Sr-89 administration is possible in patients with bone metastasis from breast cancer.
Primary outcomes of the placebo-controlled phase 2 study PERSEUS (NCT01360840) investigating two dose regimens of abituzumab (DI17E6, EMD 525797) in the treatment of chemotherapy-naive patients (pts) with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maha Hussain, Kurt Miller, Ilona Rybicka, Rolf Bruns
Journal: Journal of Clinical Oncology (2014)

5030 Background: The humanized monoclonal IgG2 antibody abituzumab inhibits αv integrins expressed on CRPC cells, tumor vessels, and osteoclasts involved in bone (B) metastasis. It showed antitumor effects in in vivo CRPC models and was well tolerated in a phase 1 study in mCRPC pts previously treated with docetaxel. Methods: PERSEUS is an exploratory double-blind trial with 180 pts randomized 1:1:1 to placebo, abituzumab 750, or 1,500 mg i.v. given every 3 weeks in addition to standard of care. Eligible pts had radiologic disease progression (rPD) of B lesions <28 days prior to randomization. Pts were treated until rPD in either B or soft tissue (ST) lesions, skeletal event, death, or unacceptable toxicity. Primary endpoint was progression-free survival (PFS). In addition, overall response (OR, RECIST 1.0) and safety were assessed. Results: Baseline characteristics were balanced across arms. In pts treated with placebo, abituzumab 750, and 1500 mg, median PFS (ITT) was 3.3 (95% CI: 2.8, 4.8), 3.4 (95% CI: 2.8, 5.6; HR = 0.89 [95% CI: 0.57, 1.39]), and 4.3 months (95% CI: 2.8, 6.6; HR = 0.81 [95% CI: 0.52, 1.26]), respectively. Progression occurred in 72, 68, and 65% of pts, respectively, incl. B lesion progression observed in 42% of pts in the control arm and in 23% of pts in each abituzumab arm. Of 74 OR-evaluable pts with confirmed ST lesions at baseline, 2 achieved partial responses (placebo: 1/28 pts; abituzumab 1500 mg: 1/24 pts). Treatment-emergent adverse events (TEAEs) occurred in 92, 85, and 88% of pts in the placebo, abituzumab 750, and 1500 mg arms, respectively, incl. serious TEAEs in 27, 22, and 23% and TEAEs with fatal outcomes in 3, 3, and 5% (treatment-related AE: 1 pt in the placebo arm). Conclusions: Median PFS with abituzumab 1500 mg was above the duration observed with 750 mg or placebo. Compared with placebo, pts receiving abituzumab experienced B progression less frequently. Considering these favorable trends, further investigation of abituzumab efficacy is needed. Its previously observed safety profile was confirmed. Clinical trial information: NCT01360840.
Phase II trial evaluating imatinib (I) in patients (pts) with anaplastic thyroid carcinoma (ATC)
Authors: H. T. Ha, J. S. Lee, S. Urba, R. J. Koenig, J. Sisson, T. Giordano, F. P. Worden
Journal: Journal of Clinical Oncology (2009)

6057 Background: There is no standard treatment for ATC. Response to doxorubicin ranges between 5–22%; median survival ranges between 3–6 months. Affymetrix gene chip showed PDGFR overexpression in ATC. In p53 mutated/deficient ATC cell lines, c-Abl is overexpressed, and selective inhibition of c-Abl resulted in cytostatic effect. (I) inhibits tyrosine kinase activity of Bcr-Abl and PDGF. We hypothesize that ATC that overexpress PDGFR or Abl will respond to (I). Methods: Pts ≥ 18 years old with histologically confirmed ATC, overexpressing PDGFR or c-Abl by immunohistochemistry who had measurable disease were eligible. Pts must have Zubrod performance status ≤ 1, and adequate hepatic and renal function. Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration. (I) was administered at 400mg orally twice daily without drug holiday. Response to treatment was assessed after every 8 weeks. Pts with complete response (CR)/partial responses (PR)/stable disease (SD) were treated until disease progression. The study was terminated early due to poor accrual. Results: From February 2004 to May 2007, eleven pts from our institution were enrolled and were started on (I) (6 men; 5 women) with a median age of 63 years (ranges 53–80). At baseline, 4/11 pts (36%) had locoregional disease, 5/11 pts (45%) had distant metastases, and 2/11 pts (18%) had both. Nine pts had prior chemoradiation, and 7 pts had thyroidectomy. Out of 11 pts, 8 were evaluable for response; 3 were excluded for lack of follow up radiological evaluation. The overall responses at 8 weeks were CR 0/8; PR 2/8 (25%); SD 4/8 (50%); and PD 2/8 (25%). The median time to follow up was 26 months (ranges 23–30 months). The estimate of 6-month progression free survival was 27% (95% CI, 7–54%). The estimate of 6-month overall survival was 46% (95% CI, 17–71%). The most common G3 toxicity was lymphopenia in 45%; other G3 toxicities included edema (27%), anemia (18%), and hyponatremia (18%). There was no G4 or higher or treatment related death. Conclusions: (I) appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing pts with a rare malignancy at a single institution, investigation of (I) in ATC may be warranted in a multi-institution setting. No significant financial relationships to disclose.
GFR Evaluation in Living Kidney Donor Candidates
Authors: Andrew S. Levey, Lesley A. Inker
Journal: Journal of the American Society of Nephrology (2017)

Evaluation of GFR, required in the evaluation of living kidney donor candidates, is now receiving increasing emphasis because recent data demonstrate increased risk of kidney disease after donation, including a small increase in the risk of kidney failure. The international guideline development group, Kidney Disease Improving Global Outcomes, recently published a comprehensive set of recommendations for living donor evaluation, with three recommendations regarding GFR. ( 1 ) Donor candidacy is evaluated in light of long-term risk, in which GFR is one of many factors. ESRD is considered a central outcome, and a method for estimating long-term risk of ESRD in donor candidates is described. ( 2 ) Two GFR thresholds are used for decision-making: a high threshold (≥90 ml/min per 1.73 m 2 ) to accept and a low threshold (&lt;60 ml/min per 1.73 m 2 ) to decline, with 60–89 ml/min per 1.73 m 2 as an intermediate range in which the decision to accept or decline is made on the basis of factors in addition to GFR. ( 3 ) GFR is evaluated using several methods available at the transplant center, including estimating equations and clearance measurements. We review the rationale for the guideline recommendations, principles of GFR measurement and estimation, and our suggestions for implementation.
Impact of response to induction chemotherapy (CT) and prior paclitaxel (TXL)-based CT on the outcome of salvage high-dose chemotherapy (HDCT) for relapsed germ-cell tumors (GCT) in the modern era: An EBMT Solid Tumors Working Party study.
Authors: Andrea Necchi, Rosalba Miceli, Marco Bregni, Karin Oechsle, Edward Kanfer, Christophe Massard, Aude Flechon, Daniele Laszlo, Fikret Arpaci, Patrick Wuchter, Martina Margrit Crysandt, Ali Unal, Arnon Nagler, Anders Wahlin, Mariagrazia Michieli, Karl-Heinz Pflueger, Mark Ringhoffer, Manuela Badoglio, Paolo Pedrazzoli, Francesco Lanza
Journal: Journal of Clinical Oncology (2015)

4535 Background: The prognostic impact of response to induction CT preceding salvage HDCT courses, and prior TXL-therapy for advanced GCT is unknown. This knowledge can inform trial design, stratification and eligibility criteria to HDCT. Methods: 23 European centers contributed data. Eligibility included adult male patients (pts) with GCT, and treatment with salvage HDCT between the years 2002 and 2012. Both TXL used in prior CT lines of therapy and in induction-mobilization regimens pre-HDCT were considered. Multivariable Cox analyses (MVA) evaluated the association of prespecified factors (prior TXL therapy, line of HDCT, primary site, prognostic category, response to induction CT and chemosensitivity), with progression-free (PFS) and overall survival (OS). Results: Since 10/2013, 324 of 442 registered pts were suitable for present analysis. 165 pts (51%) received HDCT in second-line, 102 (31%) in third and 57 (18%) beyond the third-line. 76 (23%) HDCT regimens were taxane-containing. 192 pts (59.3%) have received prior TXL-regimens. 61 pts (19%) had a progression (PD) to induction CT, 234 (72%) a response (29 [9%] missing or GCSF only). Median follow up was 36 months (IQR: 19-70). PD to induction CT and prior TXL were significantly associated with shorter OS in the univariable model (p < 0.001 and p = 0.032). However, on MVA while PD to induction CT was significantly prognostic for PFS and OS (HR: 1.92, 95%CI, 1.24-2.98, p = 0.003, and HR: 2.09, 95%CI, 1.27-3.42, p = 0.003), prior TXL-therapy was not: HR: 1.10 (95%CI, 0.70-1.73, p = 0.674) and HR: 1.09 (95%CI, 0.64-1.86, p = 0.739). Also, line of HDCT was not significant (p = 0.338 and p = 0.340 for PFS and OS). A separate model evaluated the interaction between prior TXL-therapy and taxane-containing HDCT: no significant interaction was found (p = 0.221 and p = 0.077 for PFS and OS). Conclusions: While PD to induction CT was independently prognostic for PFS and OS, prior TXL-regimens did not affect the outcome of HDCT. Stratification of trials for the latter factor did not appear to be required when accounting for the other clinical predictors.
Late effects among young thyroid cancer survivors.
Authors: Brenna Blackburn, Patricia A. Ganz, Kerry G. Rowe, Yuan Wan, Vikrant Deshmukh, Michael Newman, Alison M Fraser, Ken R Smith, Jaewhan Kim, Anne C. Kirchhoff, Christina Poruznik, Heidi Hanson, Marcus Monroe, Mia Hashibe
Journal: Journal of Clinical Oncology (2017)

111 Background: Thyroid cancer is the most rapidly increasing cancer with over 600,000 thyroid cancer survivors in the U.S. Thyroid cancer affects a young population and the 5-year survival rate is over 98%. There have been few studies on the late effects of thyroid cancer, especially in younger populations. The aim of this study was to examine if thyroid cancer survivors diagnosed &lt; 40 years experience greater risks of late effects than older age groups for diseases associated with aging. Methods: Up to 5 cancer free individuals were matched to each thyroid cancer survivor based on birth year, sex, birth state, and follow up time from case diagnosis date, within the Utah Population Database. Electronic medical records, statewide ambulatory surgery and inpatient discharge data were used to identify late effects stratified over three time periods: 1-5, 5-10, and &gt; 10 years after cancer diagnosis. Cox proportional hazards models were used to estimate hazard ratios (HR) with adjustment on matching factors, race, BMI at diagnosis, and Charlson Comorbidity Index at diagnosis. Results: There were 4,060 thyroid cancer survivors and 18,557 matched cancer free individuals (1,407 cases diagnosed ages &lt; 40 years, 2,076 cases diagnosed ages 40-65 years). The risk for hypertension was significantly increased in both younger (HR = 1.54, 95%CI = 1.18, 2.01) and older patients (HR = 1.30, 95%CI = 1.11, 1.53) &gt; 10 years after cancer diagnosis. For heart disease, increased risks persisted for the young patients &gt; 10 years after cancer diagnosis for heart valve disorders (HR = 2.43, 95%CI = 1.36, 4.33) and for peri-, endo- or myocarditis (HR = 5.12, 95%CI = 1.04, 25.14), while corresponding HRs for the older age group did not suggest increased risks. For osteoporosis, the younger patients had a higher risk (HR = 8.77, 95%CI = 3.18, 24.18) than the older population (HR = 2.55, 95%CI = 2.07, 3.13) 1-5 years after cancer diagnosis. Conclusions: Thyroid cancer survivors diagnosed at &lt; 40 years had increased risks for diseases associated with aging such as hypertension, heart disease, and osteoporosis. As thyroid cancer affects a young population, understanding what late effects may result from the treatment can lead to better surveillance and disease management.
Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction
Authors: Samer Tohme, Hamza O. Yazdani, Yao Liu, Patricia Loughran, Dirk J. van der Windt, Hai Huang, Richard L. Simmons, Sruti Shiva, Sheng Tai, Allan Tsung
Journal: Hepatology (2017)

The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PGC‐1α) and up‐regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC‐1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC‐1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine‐induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll‐like receptor‐9. This binding leads to activation of p38 and subsequent phosphorylation of PGC‐1α, with resultant up‐regulation of mitochondrial biogenesis. Conclusion : Taken together, our findings suggest that during hypoxia HMGB1 up‐regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (H epatology 2017;66:182–197).