tbuckley/cabot-search huggingface dataset:
Proteomic profiling of HPV-positive head and neck cancer to identify new candidates for targeted therapy.
Authors: Lauren Averett Byers, Lixia Diao, Patrick Kwok Shing Ng, Claudia Heymach, You Hong Fan, Adel K. El-Naggar, Jing Wang, Gordon B. Mills, Faye M. Johnson
Journal: Journal of Clinical Oncology (2014)

6030 Background: The incidence of oropharyngeal cancer (OPC) has increased 5% per year over the past decade due to a rise in human papilloma virus (HPV)-driven OPC. HPV+ OPC is clinically and molecularly distinct from HPV- head and neck squamous cell carcinomas (HNSCC). However, there are currently no validated therapeutic targets for HPV+ HNSCC. Methods: Reverse phase protein array (RPPA) was performed on HNSCC tumors from The Cancer Genome Atlas to measure cancer-associated pathways and targets. Differences in individual markers and proteomic pathway scores between HPV+ and HPV– tumors were assessed by t-test in the overall group and for the subset of OPC. Results: Significant proteomic differences were observed in 14 HPV+ and 186 HPV- HNSCC. Of 160 proteins, the top marker overexpressed in HPV+ HNSCC was p16, an established clinical biomarker of HPV status (p<0.0001). Other cell cycle proteins significantly dysregulated were p27; cyclins B1, E1 and E2; and E2F1 (higher in HPV+) and pRb (lower in HPV+) (p<0.03). In the OPC subset, several E2F1 targets were overexpressed in HPV+ cancers, including those involved in apoptosis (Bcl2, BIM) and DNA repair (PCNA, Chk2) (p<0.05). Despite frequent PIK3CA mutations, no significant PI3K pathway activation was observed in PIK3CA-mutated HPV+ tumors. Interestingly, total and pEGFR were expressed at lower levels in HPV+ tumors while pSTAT3, paxillin, and FAK were elevated (p=0.04). Finally, consistent with previous gene signature analyses showing less EMT in HPV+ HNSCC, they expressed higher levels of E-cadherin (p=0.04). Conclusions: Proteomic profiling of HPV-positive HNSCC identified potential therapeutic targets including DNA repair proteins and Src. These results are consistent with the known role of HPV E6/E7 oncoproteins in activating DNA damage response and of paxillin/FAK activation contributing to anoikis-resistance. The activation of Src substrates (STAT3/paxillin/FAK) despite inactive EGFR suggests an alternate mechanism of Src/STAT pathway activation that may have implications for response to EGFR inhibitors. Inhibitors of CDK2, Chk2, Bcl2, and Src are in clinical development suggesting that rapid translation to clinical practice could be achieved.
Quality of life and psychosocial distress in young women with advanced breast cancer.
Authors: Davinia Shien Seah, Shari Gelber, Kathryn Jean Ruddy, Rulla M. Tamimi, Lidia Schapira, Steven E. Come, Meghan E Meyer, Bryce G. Larsen, Eric P. Winer, Ann Partridge
Journal: Journal of Clinical Oncology (2013)

e20508 Background: Little is known about the quality of life (QOL), prevalence and predictors of psychosocial distress in young women with advanced breast cancer (ABC). Methods: As part of an ongoing longitudinal multi-center study of women aged &lt; 40 with newly diagnosed breast cancer, we identified women with ABC. Using baseline survey and medical chart data, we assessed QOL (measured by the Medical Outcomes Study Short Form-36 [SF-36], with norm based means [NBM] &lt;47 indicating a clinically meaningful worsening QOL compared to the general population), and evaluated relationships between demographic and clinical variables and psychosocial distress (measured by the Hospital Anxiety and Depression Scale [HADS], with higher scores indicating more distress). Demographic and clinical factors were tested in univariate models. Factors with a p &lt; 0.2 were evaluated in multivariate models to determine factors associated with anxiety or depression (HADS subscale scores &gt;11). Results: Of the 725 women who completed a baseline survey, 40 had ABC. Median age of ABC diagnosis was 37 (range 23-40). Median time between diagnosis and survey completion was 143 days. Other than general health (NBM 56.8) and role limitations due to emotional problems (NBM 53.8), SF-36 subscale scores of young women with ABC were lower compared to the general population, especially, bodily pain (NBM 27.4), social functioning (NBM 33.5) and mental health (NBM 44.3) scores. Physical and mental component summary NBM scores were 44.3 and 45.8 respectively. 30% (12/40) were anxious and 10% (4/40) were depressed according to HADS. The 4 depressed women also met criteria for anxiety. Women who were more financially comfortable were less anxious (OR 0.07, p=0.04). Logistic regression identified no other factors associated with anxiety, and no factors were associated with depression. Conclusion: QOL is impaired in young women with recently diagnosed ABC, particularly from bodily pain and disruption to social functioning. Many young ABC patients are anxious, while few are depressed. This study will be expanded to include young women who progressed to ABC. Further research is warranted to evaluate interventions to improve QOL and psychosocial distress in this population.
A phase Ib, open-label, dose-finding study of ruxolitinib in patients (pts) with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF) and baseline platelets (PLTs) 50 to &lt;100 x 10<sup>9</sup>/l.
Authors: Heinz Gisslinger, Mary Frances McMullin, Nadja Jaekel, Carole Brennan Miller, Srdan Verstovsek, Claire N Harrison, Giovanni Barosi, Jean-Jacques Kiladjian, Haifa-Kathrin Al-Ali, Denis Weber, Jing Hu, L. Andres Sirulnik, Alessandro M. Vannucchi
Journal: Journal of Clinical Oncology (2012)

TPS6642^ Background: Ruxolitinib, a potent and selective oral JAK1/2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies in pts with PMF, PPV-MF, or PET-MF. There is considerable experience in pts who develop thrombocytopenia on study, and ruxolitinib is well-tolerated with dose adjustment. However, there is limited experience in pts with baseline thrombocytopenia as those with low PLTs (&lt; 100 x 10 9 /L) were excluded from the phase 3 protocols. EXPAND (Evaluating RuXolitinib in Patients with Low Baseline PlAtelet CouNts Diagnosed With Myelofibrosis) will evaluate the safety of ruxolitinib and establish the maximum safe starting dose (MSSD) in thrombocytopenic pts with MF. Methods: This is a phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLT 50-100 x 10 9 /L. A Bayesian logistic regression model with escalation with overdose control will be used to guide dose-escalation decisions. The study consists of 2 phases: dose-escalation and safety-expansion. The starting dose is ruxolitinib 5 mg twice daily (BID) with a maximum of 15 mg BID. In the dose-escalation phase, cohorts will be: 5 mg BID, 5 mg am/10 mg pm, 10 mg BID, 10 mg am/15 mg pm, and 15 mg BID; only pts with PLT 75-100 x 10 9 /L (1st stratum) will initially be enrolled. Once safety is established at the first 2 dose levels (5 mg BID; 5 mg am/10 mg pm), pts with PLT 50-75 x 10 9 /L will be included (2nd stratum). Each dose level in the 2nd stratum will be open only if both that dose and the following one are deemed safe in the 1st stratum. In the safety-expansion phase, 20 pts (10 from each stratum) additional to those treated at the MSSD during dose escalation will be treated at the respective MSSD for their stratum. In cohort 1 (n = 4), 3 pts were evaluable as they completed &gt; 28 days of treatment; 1/4 pts discontinued after 6 doses due to disease progression. No dose-limiting toxicities were observed. The second cohort (5 mg am/10 mg pm) has completed enrollment (n = 3) and is ongoing.
Prediction of pathological complete response (pCR) by Homologous Recombination Deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC: Results from GeparSixto.
Authors: Gunter Von Minckwitz, Kirsten Timms, Michael Untch, Eric P. Elkin, Peter A. Fasching, Andreas Schneeweiss, Christoph Salat, Mahdi Rezai, Jens Uwe Blohmer, Dirk Michael Zahm, Christian Jackisch, Bernd Gerber, Peter Klare, Sherko Kümmel, Holger Eidtmann, Stefan Paepke, Julia E. Reid, Valentina Nekljudova, Anne-Renee Hartman, Sibylle Loibl
Journal: Journal of Clinical Oncology (2015)

1004 Background: We previously showed that adding carboplatin to paclitaxel/liposomal doxorubicin (PM) can improve pCR rates in patients with TNBC at the cost of added toxicity (von Minckwitz, Lancet Oncology 2014). In this study we examine whether HRD, together with BRCA mutation in the primary tumor (tmBRCA), can predict pCR (ypT0/is ypN0). Methods: In GeparSixto, patients were randomized to receive PM or PM plus carboplatin stratified by subtype (TNBC, HER2+/HR-, HER2+/HR+) and Ki67 level. FFPE tumor samples with sufficient DNA were available in 193 (61.3%) out of 315 participants of GeparSixto with TNBC. TmBRCA and HRD scores (defined as the unweighted sum of LOH (Abkevich, 2012), TAI (Birkbak, 2012), and LST (Popova, 2012) scores) were determined. HR deficiency was defined as either a high HRD score (predefined with ≥ 42) or tmBRCA (HRD Positive). Results: Patients included in this analysis did not differ clinically from all study patients with TNBC in GeparSixto, except for Ki67 levels which were higher for patients included in the current analysis. HR deficiency was found in 136 (70.5%) tumors; 82 (60.3%) of them showed high HRD score without tmBRCA. HR deficient tumors were more likely to respond with a pCR (55.9%) than HR non-deficient tumors (29.8%; p = 0.001). Adding carboplatin to PM increased the pCR rate from 45.2% to 64.9% in HR deficient tumors (p = 0.025). The response rate in HR non-deficient patients was 20% and 40.7% in the PM vs PM plus carboplatin respectively and was not significant (p = 0.146). In patients with non-tmBRCA a high HRD score was associated with a higher pCR rate (49.4%) than a low HRD score (30.9%; p = 0.050) irrespective of the use of carboplatin. Conclusions: HR deficiency in TNBC as well as HRD score in non-tmBRCA TNBC are predictors of response to neoadjuvant anthracycline and taxane containing chemotherapy irrespective of the use of carboplatin with the highest response rate being in the HR-deficient group treated with carboplatin (pCR rate of 64.9%). HR deficiency may be used to identify patients likely to have a high response to DNA-damaging agents. Clinical trial information: NCT01426880.
The association of treatment-emergent proteinuria (TEP) with baseline/treatment variables in patients (pts) treated with antiangiogenic tyrosine kinase inhibitors (AA-TKIs): A pooled analysis of NCIC Clinical Trial Group (NCIC CTG) trials.
Authors: Maria Bonomi, Hao Xu, Scott Andrew Laurie, Elizabeth A. Eisenhauer, Dongsheng Tu, Joseph L. Pater, Lesley Seymour, Penelope Ann Bradbury
Journal: Journal of Clinical Oncology (2014)

11126 Background: TEP is an expected effect of AA-TKIs. This pooled analysis of NCIC CTG trials aimed to assess its incidence, risk factors and clinical impact. Methods: 423 pts with baseline (BL) and ≥ 1 on treatment urinalysis were included in 2 cohorts: 1) AA-TKI (VEGFR2/PDGFR/KIT; VEGFR2/MET) ± other targeted agent; 2) AA-TKI (panVEGFR/KIT) + chemotherapy (CT; platinum based regimens capecitabine). Cohort 1 (138 pts) included ovary, cervix, mesothelioma, lymphoma, breast, non small cell lung cancer (NSCLC); cohort 2 (285 pts) colorectal and NSCLC. BL uncontrolled HTN and abnormal renal function were always excluded; BL > G1 proteinuria only in cohort 2 (all but 1 trial). Dose modifications and algorithms for treatment emergent (TE) HTN or TEP were provided. TEP was defined as any value > BL and ≥ G2. BL/treatment variables considered were age, PS, sex, proteinuria, HTN, diabetes, obesity, nephrotoxic and nephroprotective drugs, TE HTN, increased creatinine, hypoalbuminemia. Results: Incidence of TEP in cohort 1 and 2 was 10.1% and 18.2% (p .03 Fisher’s exact test). Median onset of TEP was 12.4 vs 6.4 weeks (wks) in cohort 1 and 2 (p 0.005 log rank). Only TE HTN and increased creatinine were significantly associated with TEP in a stratified logistic regression (table). Median time on AA-TKIs in pts with (TEP +) and without TEP (TEP-) was 19.3 vs 16.0 wks (cohort 1), and 23.5 vs 20.6 wks (cohort 2). Neither renal nor cardiovascular nor thromboembolic complications were more common in TEP + vs TEP – pts. G3 TEP caused treatment discontinuation in 2 pts (cohort 1). Conclusions: In this population, TEP was more common and began earlier if CT was added to AA-TKIs . TEP was associated with other AA-related effects but was not predicted by BL variables evaluated. It rarely caused treatment discontinuation, did not affect time on treatment, and had little clinical impact. TE hypertension ↑ Creatinine OR (CL) p OR (CL) p Univariate 3.32 (1.90 - 5.80) <0.0001 1.92 (1.06 - 3.48) 0.03 Multivariate 4.00 (2.18 - 7.35) <0.0001 2.41 (1.23 – 4.72) 0.01 Abbreviations: OR, odds ratio; CL, 95% confidence limits.
A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.
Authors: Elizabeth Robins Gerstner, Mike Levine, Xiaobu Ye, Tom Mikkelsen, Louis B. Nabors, Jeffrey J. Olson, Thomas Joseph Kaley, Patrick Y. Wen, Tracy Batchelor, Stuart A. Grossman
Journal: Journal of Clinical Oncology (2013)

2054 Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.
Erratum: "Tungiasis: 'The greatest curse that has ever afflicted Africa'" in the July issue of JAMA Dermatology (2014;150[7]:708. doi:10.1001/jamadermatol.2014.176)
Authors: Fabrizio Vaira, Gianluca Nazzaro, Stephano Veraldi
Journal: JAMA Dermatology (2014)
Rectal bleeding and bowel habit are predictive of disease in younger patients
Authors: Jacqui Wise
Journal: BMJ (2017)

Rectal bleeding and a change in bowel habit are both strongly predictive of colorectal cancer and inflammatory bowel disease when combined with abnormal haematology in patients under 50, a study has found.1

Researchers said in the British Journal of General Practice that the findings should help GPs prioritise patients for colonoscopy where the diagnosis is not immediately apparent.

Lower gastrointestinal tract symptoms in younger patients are difficult …
Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group
Authors: Hernán Trimarchi, Jonathan Barratt, Daniel C. Cattran, H. Terence Cook, Rosanna Coppo, Mark Haas, Zhi-Hong Liu, Ian S.D. Roberts, Yukio Yuzawa, Hong Zhang, John Feehally, Charles E. Alpers, Ana María Asunis, Sean Barbour, Jan U. Becker, Jie Ding, Gabriella Espino, Franco Ferrario, Agnes Fogo, Michelle Hladunewich, Kensuke Joh, Ritsuko Katafuchi, Jicheng Lv, Keiichi Matsuzaki, Koichi Nakanishi, Antonello Pani, Ran Perera, Agnieszka Perkowska-Ptasinska, Heather Reich, Yuko Shima, Maria Fernanda Soares, Yusuke Suzuki, Katsuo Takahashi, Stéphan Troyanov, Jacobien C. Verhave, Suxia Wang, Jan Weening, Robert Wyatt, Nori Yoshikawa, Caihong Zeng
Journal: Kidney International (2017)
Sorafenib treatment in recurrent hepatocellular carcinoma post liver transplantation.
Authors: Nazanin Fallah-Rad, Yanshuo Cao, Jennifer J. Knox, Raymond Woo-Jun Jang, Neesha C. Dhani, Gonzalo Sapisochin, David Grant, Paul D Greig, Leslie Lilly, Eric Chen
Journal: Journal of Clinical Oncology (2017)

479 Background: Liver transplantation (LT) is a potentially curative treatment for patients (pts) with selective hepatocellular carcinoma (HCC). HCC recurrence post LT is estimated to be 15-20%. Data on systemic therapy post-recurrence is scarce and limited case series suggest that sorafenib (SOR) may have benefit in this population. We reviewed a single center experience with SOR in recurrent HCC post LT. Methods: A retrospective review was conducted on patients with recurrent HCC post LT at University Health Network (UHN) who were treated with SOR. Pt characteristics were collected including age, gender, comorbidities, background liver disease, type of LT, and time to recurrence after LT. Treatment information collected included: initial SOR dose and subsequent adjustments, adverse events (AEs), duration of treatment and survival. Results: Between 2006 and 2016, 24 patients were identified. The average age was 60 years (range: 18-72), most patients were male (20/4), living/cadaveric transplant: 11/13. HCC etiology included hepatitis B (10), alcohol (4), NASH (3), hepatitis C (2), hemochromatosis (2), Budd-Chiari (2) and unknown (1). The average time to recurrence of HCC was 16.08 (range: 1.5-60) months post LT. There was a bimodal time to recurrence with a median of 6 months. SOR starting doses were 200 mg BID in 18 pts, 300 mg BID in 1 and 400 mg BID in 4. 14 pts required dose adjustment due to AEs, mainly relating to fatigue and palmar-plantar syndrome. The median time on treatment was 2.5 (range: 0.25-37) months, 4/24 patients were on treatment &gt; 6 months. The average time to progression on SOR and/or discontinuation due to AEs was 4.30 (+/- 7.2) months. Conclusions: SOR is reasonably tolerated in patients with recurrent HCC post LT, with expected AE profiles. In this small case series, the median time on sorafenib was short and estimated time to progression was shorter than that in non-transplant HCC population. Overall, sorafenib has limited activity in this population, but selected patients may derive extended benefit. Better understanding of responders and investigations of other therapies are needed for this population.
Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL.
Authors: Steven E. Coutre, Richard R. Furman, Jeff Porter Sharman, Bruce D. Cheson, John M. Pagel, Peter Hillmen, Jacqueline Claudia Barrientos, Andrew David Zelenetz, Thomas J. Kipps, Ian Flinn, Paolo Ghia, Herbert Aaron Eradat, Thomas J. Ervin, Nicole Lamanna, Bertrand Coiffier, Andrew Pettitt, Yeonhee Kim, Thomas Michael Jahn, Susan Mary O'Brien, Michael J. Hallek
Journal: Journal of Clinical Oncology (2014)

7012 Background: Idelalisib (IDELA), an oral inhibitor of PI3Kδ, is highly active in heavily pretreated patients with CLL as single agent or combined with rituximab (R) as demonstrated in Phase 1 trials. Methods: A Phase 3 study evaluated IDELA+R vs placebo (PBO)+R in pts with CLL requiring therapy after progression <24 mos since completion of last therapy and considered unfit to receive cytotoxic therapy. Primary endpoint PFS was assessed by IRC and standard criteria (Hallek 2008/2012, Cheson 2012). After progression, pts could enroll into a blinded extension study to receive IDELA at 150 mg BID (prior PBO+R) or 300 mg BID (prior IDELA+R). The first interim analysis (Furman et al, 2014) led to a decision of early stop for overwhelming efficacy. Results: 220 pts (110/group) with median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12) were randomized. 44% of pts had del17p/TP53 mutation, 84% had unmutated IGHV. Table 1 summarizes efficacy and safety. Conclusions: Similar to the first interim analysis, IDELA+R demonstrated significant improvement in PFS, ORR, and LNR compared to control, with acceptable safety. OS of pts on IDELA+R remains superior, including pts that crossed over into the extension study. Clinical trial information: NCT01539512. Efficacy Group Stats IDELA+R PBO+R PFS, all Median NR 5.5 mos HR=0.18 95% CI: 0.10-0.32 p<0.0001 At 24 wks 90% 50% - Overall response rate, all 75% 15% OR=17.3 p<0.0001 Lymph node response rate, all 92% 6% OR=165.5 p<0.0001 Overall survival (incl. extension study) Median NR NR HR=0.28 95% CI: 0.11-0.69 p=0.003 At 24 wks 96% 86% - Safety Group (any Grade/Grade ≥3, %) Category Term IDELA+R PBO+R AEs in ≥20% of pts Any AE 96/64 98/52 Pyrexia 35/3 17/1 Fatigue 26/5 28/3 Nausea 26/0 21/0 Chills 21/2 16/0 Infusion-related reaction 19/0 30/4 Cough 17/1 28/2 Select AEs Diarrhea* 19/4 15/0 Bleeding** 14/1 19/1 Pneumonia 10/8 13/9 Rash 10/1 5/0 Pneumonitis 6/4 1/1 Colitis* 5/3 1/0 Select labs ALT elevation 35/8 10/1 Creatinine increased 13/0 9/1 Neutropenia 60/37 51/27 Anemia 29/7 32/17 Thrombocytopenia 19/11 32/18 *3/5 pts w/colitis on IDELA+R also reported diarrhea; **Includes 16 preferred terms.