tbuckley/cabot-search huggingface dataset:
Sorafenib in hepatocellular carcinoma (HCC) patients after liver transplantation
Authors: L. G. Feun, D. Levi, J. Moon, S. Nishida, E. Island, G. Selvaggi, P. Martin, N. Savaraj, F. Mendes, A. Tzakis
Journal: Journal of Clinical Oncology (2009)

e15579 Background: Sorafenib has been approved for the treatment of advanced HCC. However, there is no data on its use for HCC patients (pts) after liver transplantation (OLT). Pts at high risk for tumor recurrence (native liver showing vascular invasion, multiple tumors &gt;3 in number, size &gt;6 cm, or lymph node involved) after OLT or who develop recurrence after OLT have worse prognosis. These pts may potentially benefit from sorafenib. Methods: We reviewed our experience with HCC pts after OLT treated with sorafenib. 15 pts had a starting dose of 400 mg po bid and 3 had a starting dose of 200 po bid. Sorafenib was started 3 months (mo) after OLT as adjuvant therapy (7 pts) or at the time of tumor recurrence after OLT (11 pts). CT or MRI scans of the chest/abdomen and physical exams were performed every 2–3 mo. Lab tests including serum AFP were performed monthly. Results: Median age was 60 (range 53–75). Median performance status was 90%(range 80–100). In terms of toxicity, 4 of the 15(27%) pts on the initial dose of 400 mg bid stopped sorafenib due to unacceptable toxicity and 5 (33%) had dose reduction due to toxicity. Grade 3/4 toxicity included skin rash, fatigue and anorexia, hyperbilirubinemia, chest/abdominal pain. Only 40% could continue at the full recommended starting dose of sorafenib.For the 11 pts with recurrent disease after OLT treated with sorafenib, the sites of evaluable disease include liver (5 pts), lung (3), others (3). One pt (9%) had a partial response in lung metastases for 10 mo. and the median time to tumor progression (TTP) was 4 mo. (range 2–10 mo). For pts on adjuvant sorafenib after OLT, no pt has relapsed so far with a median followup of 6+ mo. (range 2+ to 15+ mo). Conclusions: The response rate and TTP for pts treated with sorafenib for recurrent HCC after OLT is similar to HCC pts without OLT (Llovet, NEJM 2008). Since the majority of HCC pts after OLT treated with sorafenib required either dose reduction or stoppage due to toxicity which is higher than previously reported, a lower starting dose with dose escalation may be preferred. Contributing factors for toxicity may include the anti-rejection drugs (tacrolimus, mycophenolate, steroids) used for OLT which might affect pharmacokinetics(PK) of sorafenib. Further PK studies with sorafenib in HCC pts after OLT for future clinical trials are indicated. No significant financial relationships to disclose.
Activity of PU-H71, a novel HSP90 inhibitor, and bortezomib in Ewing sarcoma preclinical models.
Authors: Srikanth R. Ambati, Eloisi Caldas Lopes, Kohji Kosugi, Ullas Mony, Ahmet Zehir, Andre L. Moreira, Paul A. Meyers, Gabriela Chiosis, Malcolm A.S. Moore
Journal: Journal of Clinical Oncology (2013)

3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezomib and in combination. Results: In vitro, PU-H71 and bortezomib treatment resulted in caspase mediated cell death in a dose-dependent and time-dependent manner. Using PU-H71 beads we showed that some of the critical proteins, including IGF1R, hTERT and EWS-FLI1, are stabilized by HSP90. Exposure to PU-H71 resulted in depletion of AKT, ERK, MYC, C-kit, IGF1R and EWS-FLI1. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. We noted increased expression of cleaved PARP and cleaved caspase 3 when Ewing cell lines were exposed to a combination of PU-H71 and bortezomib. Based on PK studies we treated mice (4 groups) using vehicle, PU-H71 75mg/kg i.p three times/wk, bortezomib 0.8mg/kg i.v twice/wk or a combination of PU-H71 and bortezomib for 4 wk. Ewing xenografts were significantly inhibited when treated with combination of PU-H71 and bortezomib compared to vehicle or either drug alone. Conclusions: Both PU-H71 and bortezomib have single agent activity against Ewing sarcoma. However they exhibit synergism when combined in in vitro and in vivo models providing a strong rationale for clinical evaluation in Ewing sarcoma.
Whole-exome sequencing in radically resected gastric cancer (GC): Analysis of patients (pts) with poor prognostic factors from the Italian Trial of Adjuvant Chemotherapy Adenocarcinoma (ITACA-S) trial.
Authors: Maria Di Bartolomeo, Devecchi Andrea, Silvana Canevari, Alessandro Pellegrinelli, Filippo Pietrantonio, Antonia Martinetti, Alessandro Paoli, Donata Penso, Giorgio Valle, Vittoria Disciglio, Loris Bertoldi, Erika Feltrin, Gerardo Rosati, Fernando De Vita, Francesca Dominoni, Filippo G. De Braud, Rosa Berenato, Monica Niger, Rosalba Miceli, Loris De Cecco
Journal: Journal of Clinical Oncology (2017)

64 Background: At present, the clinical management of resected GC is only based on risk stratification according to the AJCC staging. This project evaluates molecular factors on formalin-fixed, paraffin-embedded (FFEP) specimens of the primary tumor radically resected in an omogeneous group patients considered at poor prognosis according by nodal involvement (pN3a/b AJCC 7 th edition) and included in the ITACA-S trial. Methods: Matched pairs of tumor-normal GC FFPE specimens collected from 15 patients were subjected to whole-exome sequencing using TruSeq Exome technology and NextSeq500 (Illumina). Somatic mutations (single-nucleotide variants) were identified, filtered and then searched for recurrently mutated genes and pathways. Patients with recurrence (cases) were compared to an equally-sized sample of patients without recurrence (controls) with the same follow up time (60 months). Results: Clinical characteristics of 15 pts: median age 61 (41-71) yrs. Nodal involvement: pN3a( 5); pN3b (10). Histotype: Intestinal (4); diffuse (8); mixed (3). Primary site: gastroesophageal junction (1); gastric (14). Patients with GC relapse (8) and without relapse (7). Whole exome sequencing revealed the presence of an average of 553 somatic mutations (range: 197 - 1318) following removal of not exonic/silent variants and of variants with an alternative allele depth &lt; 5. Among a list of 48 genes, reported as mutated in some GC studies, we found that CDH1, GNAS and DCC were mutated in 57% of patients, whereas CTNNB1, LRP1B, LRRK2, NOTCH1, and TRRAP were mutated in 42%. Furthermore RHOA, KRAS, FGFR2, PDGFRA and PRKDC showed mutation in 28% of cases. We are currently evaluating the presence of mutual exclusive relationships mechanisms, functions and molecular pathways in “cases” versus “controls”. Conclusions: Our findings confirm a relevant role of disregulation of cell adhesion pathway involving CDH1 and DCC in GC. However, a validation analysis with an independent and bigger cohort of GC patients is ongoing, in order to find outcome-related mutational patterns that could be relevant for the selection of treatment in GC.
The effect of sorafenib (S) starting dose and dose intensity on survival in patients with advanced hepatocellular carcinoma (HCC).
Authors: Mohammed Abdullah Alghamdi, Richard Lee-Ying, Mina Swiha, Kelvin K. Chan, Winson Y. Cheung, Maria Ho, Vincent C. Tam
Journal: Journal of Clinical Oncology (2017)

400 Background: The SHARP trial showed that S improves survival in advanced HCC. In clinical practice full dose (FD) of S at 400mg bid can be difficult to tolerate and so a reduced dose (RD) is often required. The purpose of this study was to determine whether starting dose or dose intensity of S affects survival in patients with HCC. Methods: All patients treated with S for HCC in Alberta, Canada from January 2008 to July 2016 were included in this study. Patient demographics, clinical, tumor characteristics, S starting dose and dose intensity were collected and analyzed. Patients were dichotomized into starting FD or RD of S. A mean dose intensity of &gt; 75% and &lt; / = 75% were considered normal and reduced, respectively. Survival outcomes were assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox-proportional hazard model was constructed with starting dose, dose intensity and relevant clinical and pathologic factors to assess their impact on survival. Results: A total of 156 patients were included. Median age was 63, 78% were men, 34% were East Asian, 77% were Childs-Pugh A, and the most common causes of liver disease were hepatitis B (30%) and C (30%). Most patients had EGOG performance status of 0 and 1 prior to starting S (29% and 62%, respectively). S was started at FD in 58% of patients and 50% had a dose intensity &gt; 75%. The median survival for both starting FD and RD was 10.3 months, and not significantly different (p = 0.14).The median survival for a dose intensity &gt; 75% vs &lt; / = 75% was 10.7 vs 9.5 months, respectively (p = 0.76). In multivariable models that adjusted for demographic, stage, performance status and liver function, starting dose (HR 0.8 95%CI 0.5-1.2) and dose intensity (HR0.9 95% CI 0.6-1.4) were not associated with survival. Conclusions: Starting S with a RD may be a reasonable strategy for HCC, since it does not appear to impact survival. Also, dose intensity did not impact survival, suggesting that additional dose modifications may not compromise effectiveness. Though limited by small numbers, we are planning to confirm these findings in a larger, pan-Canadian dataset.
Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.
Authors: Thomas E. Hutson, Dmitry Nosov, Mihai Harza, Brooke Esteves, Andrew Louis Strahs, Anna Berkenblit, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

4564 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Superior progression-free survival (PFS) and overall response rate (ORR) with tivozanib versus sorafenib were demonstrated in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (PFS: 11.9 vs 9.1 months in ITT population, 12.7 vs 9.1 months in patients who received no prior systemic treatment for mRCC; ORR: 33% vs 23% in ITT population). Hypertension was more common with tivozanib, while lower rates of certain off-target adverse events (AEs) relative to sorafenib were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present detailed dose adjustment data. Methods: In total, 517 patients were enrolled and randomized 1:1 to tivozanib 1.5 mg/d (once daily 3 weeks on, 1 week off) or sorafenib 400 mg/d (twice daily, continuously). Treatment duration and AEs leading to discontinuation and dose adjustment were assessed in these patients. Results: Median duration of treatment with tivozanib was 12.7 months vs 9.5 months with sorafenib; fewer patients in the tivozanib arm experienced drug reduction or dose interruption due to AEs (see Table). Treatment-related AEs, as defined by the investigator, led to drug discontinuation in 3.9% of tivozanib patients and 5.4% sorafenib patients. Conclusions: Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib. Clinical trial information: NCT01030783. [Table: see text]
Quantum dot-aptamer conjugates for synchronous cancer imaging and therapy based on bi-fluorescence resonance energy transfer
Authors: Liangfang Zhang, Vaishali Bagalkot, Etgar Levy-Nissenbaum, Sangyong Jon, Robert Langer, Omid Farokhzad
Journal: Clinical Cancer Research (2007)

A19  We report a novel quantum dot (QD)-aptamer(Apt)-doxorubicin (Dox) conjugate [QD-Apt(Dox)] as a targeted cancer imaging, therapy and sensing system. By functionalizing the surface of fluorescent QD with the A10 RNA aptamer which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), we developed a targeted QD imaging system (QD-Apt) that is capable of differential uptake and imaging of prostate cancer cells which express the PSMA protein. The intercalation of Dox, a widely used anti-neoplastic anthracycline drug with fluorescent properties, in the double stranded stem of the A10 aptamer results in a targeted QD-Apt(Dox) conjugate with reversible self-quenching properties based on a Bi-FRET mechanism. A donor-acceptor model FRET between QD and Dox, and a donor-quencher model FRET between Dox and aptamer result when Dox intercalated within the A10 aptamer. This simple multifunctional nanoparticle system can deliver Dox to the targeted prostate cancer cells and sense the delivery of Dox by activating the fluorescence of QD which concurrently images the cancer cells. We demonstrate the specificity and sensitivity of this nanoparticle conjugate as a cancer imaging, therapy and sensing system in vitro.
Survival and care advantage in patients with AJCC T1 stage hepatocellular carcinoma in transplant centers: UNOS and SEER population studies.
Authors: Minzhi Xing, Hyun Sik Kim
Journal: Journal of Clinical Oncology (2015)

e15113 Background: To compare overall survival (OS) of hepatocellular carcinoma (HCC) Stage T1 patients listed for orthotopic liver transplant (OLT) with or without bridging locoregional therapy (LRT), patients who did not receive OLT within transplant centers, and patients who received best supportive care in a national population study. Methods: The United Network for Organ Sharing (UNOS) database was queried for patients with T1 HCC who were listed for OLT between 2004-2010. Patients within Milan Criteria for whom an HCC Model for End-Stage Liver Disease (MELD) exception was approved were included. Similar T1 HCC patients were selected from the national SEER database. Kaplan-Meier estimation and log-rank test were used for survival analysis. Results: Of 5352 patients with T1 HCC who were listed for OLT in the UNOS database, 4120 received OLT, mean age 55.2 years, 73.8% male; 1042 (25.3%) received bridging LRT. 1415 similar T1 HCC patients identified on the SEER database. Comparison groups were similar for age, waitlist duration, sex and race. Significantly prolonged OS from listing was observed in patients who received OLT with bridging LRT (103.7mo), compared with OLT without bridging LRT (89.6 mo), no OLT or LRT (12.4mo) and best supportive care (3.0mo), p < .001. Conclusions: In a large-scale population study of T1 HCC, survival was significantly prolonged in patients who received care within transplant centers, as compared to best supportive care. Bridging LRT with OLT resulted in the best survival outcomes.
The S-Index and the National Institute of Mental Health Data Archive
Authors: Svetlana Novikova, Dan Hall, Gregory K. Farber
Journal: JAMA Psychiatry (2017)

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Estimated number of breast cancer deaths in the Brazilian Public Health System due to lack of access to adjuvant trastuzumab between 2005 and 2012.
Authors: Marcio Debiasi, Carlos H. Barrios
Journal: Journal of Clinical Oncology (2015)

e17601 Background: Breast cancer (BC) is the most frequent tumor and the leading cause of cancer-death in Brazilian women. Even though Trastuzumab (T) has been proven effective in the adjuvant setting for HER2+ BC since 2005, it became available for patients (pts) in the Brazilian public system (which covers 73.7% of the population) only in 2013. This analysis aims to estimate the number of lives lost to HER2+ BC due to lack of access to T during that period. Methods: We considered the annual number of BC pts according to the Brazilian NCI published information. We estimated the proportion of HER2+ pts with potential indication for adjuvant T according to available epidemiological data. The overall survival (OS) benefit of adjuvant T was estimated based on the recently published results from NSABP B-31 and NCCTG N9831. Results: We assumed a constant number of new BC cases/year overtime and based our estimations on the numbers for 2014 according to the Brazilian NCI (57,120 new cases/year). Based on available epidemiological data we considered that 94% of the pts presented with stage I, II or III disease (53,693 pts). Considering that 73.7% of these pts do not have private health insurance, the Brazilian Public Health System has 39,571 pts/year who are candidates for (neo)adjuvant therapy. Approximately 7,914 of these pts (20%) do have HER2+ tumors and are candidates to receive T each year. Assuming a constant incidence over time, we estimate that approximately 59,355 pts should have been treated with adjuvant T between July 2005 and December 2012. Considering an absolute benefit of 8.8% in OS according to the joint analysis, we estimate that 5.223 women are fated to die in Brazil due to lack of access to T from July 2005 to December 2012. Conclusions: Even though with clear limitations, this analysis points out that a significant number of lives are lost due to lack of or delayed access to high-cost medications. As cancer will have an increasing impact in the developing world in the near future, these numbers will likely grow. An urgent, focused and honest discussion of all involved (advocacy groups, medical societies, Pharma and government) is essential to change this unacceptable situation.
Phase II trial of gemcitabine and cisplatin plus ipilimumab as first-line treatment for metastatic urothelial carcinoma.
Authors: Benjamin Adam Gartrell, Noah M. Hahn, Thomas E. Hutson, Guru Sonpavde, Ralph J. Hauke, Alexander Starodub, Alexander C. Small, Che-Kai Tsao, Matt D. Galsky
Journal: Journal of Clinical Oncology (2012)

TPS4676 Background: While metastatic urothelial carcinoma is a chemosensitive neoplasm, current therapeutic approaches are inadequate. Preclinical and clinical data suggests that bladder cancer is immunogenic. For example, CD8+ tumor infiltrating lymphocytes correlate with survival in patients with muscle-invasive disease (Sharma, PNAS, 2007). However, immunotherapeutic approaches have been rarely investigated for advanced urothelial cancer. CTLA4 blockade with ipilimumab is a novel approach to immunotherapy that interrupts T-cell pathways responsible for immune down-regulation or tolerance. In a proof of concept study, ipilimumab was administered to 12 patients with muscle-invasive disease preoperatively (Carthon, Clin Can Res, 2010). Treatment resulted in perivascular infiltration of cells positive for CD3, CD8, CD4, and granzyme and intriguing evidence of antitumor activity. In the current trial, we will explore a “phased” schedule of chemotherapy and ipilimumab with the goal of “autovaccinating” patients to tumor antigen with chemotherapy prior to introduction of immune checkpoint blockade. Methods: We have initiated a phase II clinical trial of gemcitabine (G), cisplatin (C), plus ipilimumab in chemonaive patients with unresectable and/or metastatic urothelial cancer within the Hoosier Oncology Group network. During cycles 1 and 2, G (1000 mg/m 2 D day 1 + 8) and C (70 mg/m 2 D 1) will be administered every 21 days without ipilimumab. During cycles 3-6, GC plus ipilimumab (10 mg/kg day 1) will be administered every 21 days. Patients without evidence of disease progression after completion cycle 6 will continue single-agent ipilimumab “maintenance” every 3 months. The primary objective is to determine the 1-year overall survival. The trial will enroll 36 patients and is powered to detect an improvement in 1-year survival from 60% to 80%. Secondary objectives include progression-free survival, disease control rate, safety, and immunologic outcomes. Correlative studies will include serial measurements of the global composition of immune cells in the blood by polychromatic flow cytometry, whole blood transcriptional profiling, and tumor-antigen specific CD8+ T cells assays.
An exploration of Pap smear history and behavior of patients with newly diagnosed cervical cancer in Taiwan
Authors: H. Cheng, A. Chao, H. Huang, H. Chou, T. Chang, M. Liao, C. Lai
Journal: Journal of Clinical Oncology (2009)

e20582 Background: The national health insurance policy has provided a yearly Pap smear for women &gt;= 30 years old since 1994 in Taiwan, yet the coverage rate is still unsatisfactory. The purpose of this study is (1) to investigate the Pap smear screening history of women newly diagnosed with cervical cancer and (2) to examine factors that influence participation in Pap smear screening program in these women. Methods: Patients primarily treated for cervical cancer at Chang Gung Memorial Hospital between November 2006 and June 2007 were enrolled into this prospective study. Questionnaires included (1) socio-demographic data, and (2) knowledge on Pap smear and cervical cancer. Results: Two hundred sixty-nine patients were eligible for analysis. The median age was 51 years old (range, 25–83). Of the 269 patients, 147 (54.6%) had never had a Pap smear before diagnosis, and 35 (13.0%) did not know about Pap smear. Socio-demographic factors that significantly influenced number of previous Pap smear screening (0 vs &gt;=1) were education level, income less than 600 U.S. dollars per month, menopaused, multiple sexual partners, and increase number of sexual partners of the male consort. Of the 147 never received Pap women, the most common reasons were thought that Pap smear screening was not necessary (46.3%), embarrassment (42.0%), busy (43.5%), and worry about the screening findings (20.4%). Of the 122 patients who have received Pap smear, 56.6% patients thought that Pap smear screening was necessary, 35.2% patients worried about the disease, 24.6% were alert on their check-ups, and 20.5% did the screening for the convenience to nearby clinics. Conclusions: Public health organizations in Taiwan should put more efforts to provide women in low education level, low income and multiple sexual partners with information on Pap smear. No significant financial relationships to disclose.
Erratum: Inviting patients to read their doctors' notes: A quasi-experimental study and a look ahead (Annals of Internal Medicine (2012) 157 (461-470) DOI: 10.7326/0003-4819-157-7-201210020-00002)
Authors: T. Delbanco, J. Walker, S. K. Bell, J. D. Darer, J. G. Elmore, N. Farag
Journal: Annals of Internal Medicine (2015)