tbuckley/cabot-search huggingface dataset:
Prolonged efficacy of sunitinib in a cohort of patients with metastatic renal cancer: A retrospective analysis from the Hellenic Cooperative Oncology Group.
Authors: Vasilios Karavasilis, Aristotelis Bamias, Evangelia Razis, Georgia Gourgioti, Konstantinos N. Syrigos, Gerasimos Aravantinos, Christos Christodoulou, George Fountzilas, Christos Papandreou
Journal: Journal of Clinical Oncology (2014)

e15597 Background: Long-term disease control is a relatively rare phenomenon in metastatic renal cancer. We aimed to identify metastatic renal cell cancer (mRCC) patients on first-line treatment with sunitinib for a prolonged period and characterize their course of disease. Methods: Data from first-line mRCC patients treated with sunitinib within collaborating centers were reviewed in our electronic database. Patient’s data that had been on treatment for a minimum of 18 months were retrieved for analysis to form this cohort. Clinical and pathological data describing the course of the disease are presented below. Results: From a total of 175 mRCC patients, 40 patients (29M/11F) fulfilled the study criteria. Median age at diagnosis was 58 years and median PS was 0. Nephrectomy was performed in 2 patients with histology being predominantly clear cell. All patients were at favorable or intermediate risk according to the MSKCC risk stratification. Sites of metastatic disease were distributed between lung (50%), bones (25%), lymph nodes (23%), renal bed (23%) and liver (10%). In 37 (93%) of the patients, the number of metastatic sites were ≤2. Treatment with sunitinib was administered for a median of 27 months (range 18–60 months). Two patients had a complete response, while all others were progression-free for a median of 37 months. Most common toxicities were anemia (73%), fatigue (67%), hand-foot syndrome (37%), diarrhea (35%), abnormal liver function (32%), hypertension (32%) and hyperthyroidism (20%). Grade 3 toxicities consisted of diarrhea (3 patients), hand-foot syndrome (3), hypertension (3) and fatigue (2), while one patient developed a thromboembolic event. All grade 3 toxicities resolved after a short cessation of the treatment. Dose reductions or temporary treatment discontinuations were necessary in 17 (43%) of the patients. Conclusions: The present mRCC patient cohort stayed on treatment with sunitinib for a remarkable period of time, achieving sustained clinical benefit with acceptable toxicities. It would certainly be important to look into specific molecular mechanisms for factors that might be prognostic for favorable outcomes in such patients.
Comprehensive genomic sequencing of prostate sarcomatoid carcinoma tumors identifies differences in genomic alterations compared to prostate adenocarcinoma tumors.
Authors: Sherri Z. Millis, Philip J. Stephens, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, Jue Wang
Journal: Journal of Clinical Oncology (2017)

226 Background: Sarcomatoid carcinoma of the prostate is a rare variant of prostatic cancer and has a significantly worse prognosis. The genomic features underpinning this rare subtype of malignancy are not well understood, and at present, there are no effective therapies. Methods: Tissue from 1417 prostate cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified different patterns in GAs between prostate adenocarcinoma (1409) and prostate sarcomatoid carcinoma (8) (table), most notably in the commonly identified alterations in prostate cancers: TP53, RB1, and TMPRSS2-ERG. Additionally, the PI3K/mTOR pathway was altered in 50% of the sarcomatoid carcinoma cohort. None of the sarcomatoid carcinoma patients had a high TMB, while 4% of the prostate adenocarcinomas had TMB greater than 19 mutations/Mb. The sarcomatoid carcinoma cohort also had on average 8 GAs, while the prostate adenocarcinoma cohort had an average of 13 GAs. Conclusions: Genomic profiles of tumors from patients with prostate cancers reveal that those with sarcomatoid carcinoma features are more likely to have genomic alterations in TP53, RB1, and TMPRSS2 but fewer overall GA’s. Based on rearrangements and the sarcoma profile, utilization of a broad CGP panel that includes analysis of a larger panel of rearrangements identifies more commonly rearranged genes that would not be identified in non-comprehensive panels that do not evaluate these rearrangements. These findings may contribute to a better understanding of the oncogenesis of sarcomatoid prostate carcinoma and for defining novel systemic treatment options. [Table: see text]
Fusion proteins composed of mouse IgG2a Fc and mouse beta-2-glycoprotein 1 bind to endothelial cells with exposed phosphatidylserine
Authors: Troy Luster, Philip Thorpe
Journal: Cancer Research (2007)

4089  A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane under normal conditions. We have previously shown that PS becomes exposed on the surface of viable endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, a murine monoclonal antibody (3G4) was developed. 3G4 specifically localizes to the vasculature of solid tumors and inhibits growth of murine and human tumor xenografts. A chimeric version of 3G4 (bavituximab) is currently in clinical trials for treatment of solid tumor malignancies.  Recently we determined that 3G4 recognizes PS through the formation of a complex with plasma protein beta-2-glycoprotein 1 (β2GP1). β2GP1 is a 50 kDa glycoprotein composed of five domains, including the positively charged domain V that binds anionic phospholipids. However, the interaction of β2GP1 with anionic phospholipids is weak under physiological conditions. Importantly, we demonstrated that 3G4 enhances the avidity of β2GP1 for membrane surfaces with exposed PS through the formation of multivalent 3G4/β2GP1/PS complexes. This increased avidity of β2GP1 for PS is likely responsible for targeting of 3G4 to tumor EC with exposed PS.  We report here the construction of recombinant fusion proteins composed of mouse IgG2a Fc and mouse β2GP1. The Fc region is fused to the N-terminus of full-length β2GP1 or domain V only. This orientation was chosen to avoid interference with the lipid binding region in domain V of β2GP1, which is located at the extreme C-terminus of the protein. These compounds are generated as dimers, linked via disulfide bonds in the hinge region of the Fc tags. The dimeric construction provides the increased avidity necessary for these compounds to bind EC with exposed PS; thus, they behave in vitro much like the 3G4/β2GP1 complexes described previously. These Fc-β2GP1 compounds have potential as tumor therapeutic or imaging agents.
A phase II, single-armed, multicenter trial of neoadjuvant vismodegib in patients with large and/or recurrent basal cell carcinoma: NICCI.
Authors: Ulrike Leiter, Uwe Hillen, Ralf Gutzmer, Holger Haenssle, Hans-Martin Haefner, Peter Mohr, Claus Garbe
Journal: Journal of Clinical Oncology (2014)

TPS9116^ Background: Vismodegib is useful to treat locally advanced or metastatic basal cell carcinoma (BCC) but has not been evaluated for use in a neoadjuvant setting to shrink BCCs before surgery. This multicenter, non-randomized, single-armed phase II clinical study is performed to evaluate the efficacy of neoadjuvant vismodegib in patients with large or large recurrent basal cell carcinoma (BCC). Methods: The primary endpoint is to evaluate the efficacy of vismodegib as measured by the percentage of basal cell carcinomas that reach complete remission (CR, as determined by histopathology), partial remission (PR), or stable disease (SD) versus progressive disease (PD) after 12 weeks of treatment. Secondary endpoints include the assessment of i) size-reduction of BCC in cm² as intended for excision (baseline vs. 12 weeks of treatment by planimetrics), ii) treatment-induced changes assessed by non-invasive imaging techniques (optional: in vivo confocal laserscan-microscopy, optical coherence tomography, high resolution ultrasonography) in correlation with histopathology, and iii) toxicity and tolerability including health-related quality of life questionnaire (Skindex-16) Study design: 75 patients with a BCC or recurrent BCC (≥ 2 cm in diameter in head/neck region, ≥ 5 cm for trunk/extremities plus at increased risk for cosmetic disfigurement or functional defects) will be enrolled. After 12 weeks of treatment with vismodegib 150mg/d all patients will receive micrographic excision of the remaining tumor area. Patients will be observed for one year. Documentation of the two-dimensional tumor size (in cm2) as intended for excision will be performed by planimetrics at the time of study inclusion, at week 13 before surgery and at the end of study. Clinical trial information: 2013-004767-31.
Prolonged survival of small cell ovarian cancer-hypercalcemic type (SCCOHT): Should radiotherapy play a larger role?
Authors: Donato Callegaro Filho, Alpa Manchandia Nick, Mark F. Munsell, Pedro T Ramirez, David Marc Gershenson, Andrea S. Dickens, Dina Patel, Patricia J. Eifel, Elizabeth D. Euscher, Kathleen M. Schmeler
Journal: Journal of Clinical Oncology (2015)

e16542 Background: SCCOHT is a rare and aggressive disease. Regardless of tumor stage, most patients relapse and die of disease within two years of diagnosis. However, a small proportion of patients survive beyond two years. The aim of this study was to describe the treatment approaches in these patients with extended survival. Methods: We performed a retrospective study of 47 patients with SCCOHT evaluated at a tertiary cancer center between January 1990 and August 2014. Twelve patients (26%) were alive more than two years after diagnosis and included in this study. Medical records were reviewed for demographic information, pathologic findings, treatment regimens and outcomes. Results: Median age at diagnosis was 30 years (range, 14-43). Eight patients (67%) had stage I disease, two (16.5%) had stage II disease, and two (16.5%) had stage III disease. All patients underwent surgery. Seven (58%) received adjuvant treatment with chemotherapy alone, four (33%) received chemotherapy followed by radiotherapy and one (8%) patient received no adjuvant therapy. Five patients (42%) developed recurrent disease a median of 24 months (range, 8-125) from diagnosis. Treatment for recurrence included surgery (n = 5, 100%), chemotherapy (n = 3, 60%), and/or radiotherapy (3, 60%). Radiotherapy was used in six (50%) of the 12 patients with survival > 2 years as adjuvant primary therapy or treatment for recurrent disease, compared with three (9%) of the 35 patients with survival < 2 years (p = 0.005). With a median follow up of 53 months (range, 25-211), eight patients (67%) were alive without disease, two (17%) alive with disease and two (17%) have died of the disease 25 and 35 months from diagnosis. Conclusions: Our findings suggest that prolonged survival can be achieved in patients with SCCOHT, even with advanced stage disease. Radiotherapy may play an important role in the management of this disease. Molecular characterization of the tumors from these patients with prolonged survival is under development.
Ligand expression of the EGFR ligands amphiregulin, epiregulin, and amplification of the EGFR gene to predict for treatment efficacy in KRAS wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: Analysis of the randomized AIO CRC-0104 trial.
Authors: Sebastian Stintzing, Andreas Jung, Christine Kapaun, Jana Reiche, Dominik Paul Modest, Clemens Albrecht Giessen, Ursula Vehling-Kaiser, Martina Stauch, Holger Hass, Ludwig Fischer von Weikersthal, Thomas Kirchner, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

3519^ Background: We investigated the expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) as well as the amplification of the EGFR-gene in tumor specimens of mCRC patients (pts) treated first-line with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI. Expression levels were correlated with overall response rate (ORR), progression free survival (PFS) and overall survival (OS) to determine their relationship with effectiveness in this setting. Methods: A total of 185 mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by 250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine 800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of both agents for pts older than 65 years) or plus CAPOX (oxaliplatin 130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every three weeks). The primary study endpoint was ORR. KRAS mutational status did not correlate with treatment outcome. The cut-offs for EGFR-amplification using FISH, AREG and EREG levels determined by RT-qPCR were calculated using ROC analysis for ORR. Results: Within the subgroup of KRAS wildtype tumors, analysis of EREG- and AREG-expression was possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels correlated significantly with higher ORR (83% vs 46%, p=0.006, OR 0.31), longer PFS (9.6mo vs 4.9, p&lt;0.001, HR 0.35) and longer OS (39.9mo vs 17.2mo, p&lt;0.001, HR 0.36). Higher EREG levels showed a significant correlation with ORR (74% vs 47%, p=0.036, OR 0.54), longer PFS (7.9mo vs 4.9mo, p=0.026, HR 0.57) and OS (33.0mo vs 20.2mo, p=0.041, HR 0.57). EGFR-amplification correlated significantly with higher ORR (71% vs 33%, p=0.004, OR 0.49), longer PFS (8.4mo vs 4.6mo, p=0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p=0.001, HR 0.44). Conclusions: In the treatment setting of cetuximab combined with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors, EGFR-FISH and AREG expression have the strongest relationship with treatment efficacy.
An international multi-center study to assess the clinical accuracy of the molecular subclassification of leukemia by gene expression profiling
Authors: T. Haferlach, K. Mills, W. Kern, W. Hofmann, T. Te Kronnie, J. Hernandez Rivas, J. Downing, J. De Vos, T. Kipps, R. Foa
Journal: Journal of Clinical Oncology (2006)

6522 Background: Microarray analysis can identify differentially expressed genes of pediatric and adult leukemias. Recently, the MILE (Microarray Innovations in Leukemia) study has started in 11 centers (European Leukemia Network: 7, USA: 3, Singapore: 1). MILE compares the accuracy of gene expression profiles of 16 acute and chronic leukemia subclasses, MDS, and non-leukemia as control group to routine diagnostic workup. Methods: In a pre-phase each center was trained on the identical microarray protocol (HG-U133 Plus 2.0 microarrays). 2 cell lines (MCF-7, HEPG2) and cell lysates of three leukemia patients (AML t(8;21), CML, CLL) were tested. After proficiency testing, centers started to analyze 2000 leukemia samples. Results: The pre-phase demonstrated a very high intra- and inter-laboratory comparability among centers. Using principal component analysis each sample type was clustered with no observable sub-grouping of the different centers. Replicates of leukemia samples demonstrated squared correlation coefficients between 0.930–0.997 for CML, 0.936–0.998 for CLL, and 0.940–0.999 for AML t(8;21).Here we present classification results of the first series of 607 pts. that were included prospectively in a training data set (total n=1,049) to form linear classifiers for all 153 class pairs. The average cross-validation accuracy is 89.4%. In first independent cohort (HG-U133 Plus 2.0, n=105) 89.5% classification accuracy were achieved. In a second independent cohort (n=1,094), analyzed previously in two centers on HG-U133A/B microarrays, 83.5% classification accuracy were achieved. In detail, 136 out of 139 (97.8%) chronic leukemia samples (CML or CLL) were classified fully in agreement with standard diagnostic procedures. For acute leukemia subtypes 767 out of 904 (84.8%) were classified correctly. Interestingly, an AML-like signature can be found in MDS samples with IPSS &gt;1.5. Conclusions: This international multi-center study demonstrates a very high inter- and intralaboratory reproducibility of microarray analyses. Data will be used to design a new custom format microarray dedicated to further develop the application of gene expression profiling for diagnosis and subclassification of leukemia. No significant financial relationships to disclose.
Risk of axillary node metastasis in Paget disease with invasive ductal carcinoma.
Authors: Stephanie M. Wong, Rachel A. Freedman, Emily Stamell, Yasuaki Sagara, Jane E. Brock, Stephen DeSantis, Mehra Golshan
Journal: Journal of Clinical Oncology (2015)

1054 Background: Paget disease of the nipple is a rare manifestation of breast cancer that is associated with underlying invasive ductal carcinoma in approximately 60% of cases. The underlying pathology of patients with Paget disease and IDC is typically aggressive, with a tendency towards larger, high grade, hormone receptor-negative and HER2-positive tumors. Using population-based data, we sought to examine whether the presence of Paget disease was associated with increased risk of axillary node metastases in patients with underlying IDC. Methods: We identified women diagnosed with Paget disease and IDC (PD-IDC) or IDC alone and managed surgically from 2000 to 2011 using the Surveillance, Epidemiology and End Results database. We compared baseline patient demographic and tumor characteristics between the PD-IDC and IDC alone groups. We used multivariate logistic regression to examine the potential association of PD-IDC and axillary lymph node metastasis. Results: The study cohort consisted of 1,102 patients with PD-IDC, and 302,242 controls with IDC alone. The groups were similar with respect to patient demographics such as age (mean age 58.9 years PD-IDC vs. 58.6 years IDC, p = 0.46) and race distribution (p = 0.12). On analysis comparing characteristics of PD-IDC to IDC alone, tumors were more likely to be centrally located (26.9 vs. 5.5%, p < 0.001), high grade (63.5 vs. 40.3%, p < 0.001), larger than 2 cm (47.1 vs. 35.7%, p < 0.001), and estrogen/progesterone receptor-negative (45.2 vs. 22.1%, p < 0.001). In adjusted analysis controlling for patient age, tumor size, location, histologic grade, and hormone receptor status, PD-IDC had higher odds of axillary node metastasis (OR 1.83, p < 0.001) than IDC alone patients. Conclusions: In the context of invasive ductal carcinoma, the presence of Paget disease is independently associated with an increased risk of axillary lymph node metastasis compared with IDC alone.
Industry links with patient organisations
Authors: Jeremy Taylor, Simon Denegri
Journal: BMJ (2017)

Are patient organisations overly influenced by industry funding?Two recent articles give fresh currency to a perennial debate.The first is a survey of a sample of leaders of patient advocacy organisations (439 surveyed, representing 5.6% of 7865 identified US patient advocacy organisations).The authors found that although most of the 289 organisations that responded reported modest industry funding, a minority had substantial support, raising concerns about their independence.Survey respondents acknowledged a need to improve conflict of interest policies. 1A second study of 104 patient advocacy organisations found similar funding patterns and that only 12 had published policies for managing institutional conflicts of interest. 2Nobody disputes that funders of all types-regardless of whether they are from the public or private sector-can bias those in receipt of funding.There are well understood and researched risks for health professionals, researchers, and patient organisations alike.But to suggest on the basis of such surveys that patient groups are not sufficiently representing the interests of patients and citizens, as a linked opinion piece by Moynihan and Bero argues, 3 is overdone.Nor is their proposal that patient groups should "ultimately disentangle" themselves from industry realistic in a health sector increasingly characterised by collaboration between public, private, and non-profit organisations.
Exploratory analyses of efficacy and safety of pemetrexed (Pem) plus bevacizumab (Bev) and bev alone as maintenance therapy (MT) in patients (Pts) with stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC).
Authors: Jyoti D. Patel, Edward B. Garon, Ramaswamy Govindan, Craig H. Reynolds, David R. Spigel, Mark R. Olsen, Robert C. Hermann, Jingyi Liu, Susan C. Guba, Eduardo J. Pennella, Coleman K. Obasaju, Philip D. Bonomi, Mark A. Socinski
Journal: Journal of Clinical Oncology (2013)

8012 Background: In a phase III superiority study, Pem+carboplatin (Cb)+Bev followed by Pem+Bev improved PFS compared with paclitaxel (Pac)+Cb+Bev followed by Bev in NS-NSCLC pts. Superior OS (primary endpoint) was not met. These analyses assessed the efficacy and safety in pts who received MT. Methods: Prespecified exploratory analyses were performed in the maintenance population (MP) and timed from the start of induction. Pts ≥18 years with stage IIIB/IV NS-NSCLC (ECOG status 0–1) from the multicenter, randomized, open-label, phase III superiority study were included in the MP if they received at least one dose of MT. For MT, pts received intravenous Pem 500 mg/m 2 +Bev 15 mg/kg (n=292) or Bev 15 mg/kg (n=298). OS, PFS, and safety were evaluated. Comparison is made to the intent-to-treat (ITT; Pem=472, Pac=467) or safety population (SP; Pem=442, Pac=443; received at least one dose of one drug). Results: Baseline pt and disease characteristics for the ITT and MP were similar between arms. In the ITT/MP population, the median number of cycles was 7/10 (range, 1-41/4–41) in the Pem arm and 6/9 (range, 1-39/5–39) in the Pac arm. In the ITT/MP, OS was 12.6/17.7 months (mos; Pem) and 13.4/15.7 mos (Pac). Survival rates (%) at 12 and 24 mos with Pem (ITT/MP) were 52.7/71.7 and 24.4/34.5; Pac, 54.1/66.5 and 21.2/26.5%. In pts not receiving MT, OS was 4.7 mos (Pem) and 6.1 mos (Pac). PFS (mos) in the ITT/MT was 6.0/8.6 (Pem) and 5.6/6.9 (Pac). In pts not receiving MT, PFS was 2.3 mos and 2.5 mos with Pem and Pac, respectively. From induction, both SP/MP had significantly more grade 3/4 thrombocytopenia, anemia, and fatigue with Pem and neutropenia and sensory neuropathy with Pac (p≤0.001). During MT only, the difference in grade 3/4 neutropenia rates between arms was no longer significant. Conclusions: Improved efficacy outcomes were consistent with previous Pem maintenance and Bev studies and no new toxicities were observed. Clinical trial information: NCT00762034.