tbuckley/cabot-search huggingface dataset:
Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy.
Authors: Yoshifumi Kadono, Takahiro Nohara, Kouji Izumi, Yasuhide Kitagawa, Konaka Hiroyuki, Atsushi Mizokami, Mikio Namiki, Mizuki Onozawa, Shiro Hinotsu, Hideyuki Akaza
Journal: Journal of Clinical Oncology (2017)

e604 Background: The current tumor–node–metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. Methods: A total of 5,618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan–Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox’s proportional hazard regression model. Results: Regarding age, patients with M1b tumors were significantly older than were those in the other groups. Prostate-specific antigen (PSA) levels tended to increase as the stage progressed. The Gleason score (GS) was significantly higher in the M1a group compared with the other groups. The 5-year OS was 76.0 % in the N1M0, 57.5 % in M1a, 54.0 % in M1b, and 40.0 % in M1c cases. The 5-year CSS was 83.2 % in the N1M0, 69.0 % in M1a, 63.1 % in M1b, and 51.5 % in M1c cases. The 5-year PFS was 38.8 % in the N1M0, 23.0 % in M1a, 23.0 % in M1b, and 16.6 % in M1c cases. OS, CSS, and PFS declined as the stage progressed; however, there were no statistically significant differences between M1a and M1b cases. Among the patients in the M1b group, the 2,445 cases of N0M1b and the 1,607 cases of N1M1b were compared. OS, CSS and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a GS ≥ 8, and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a PSA &gt; 100 ng/ml only in M1b. Conclusions: Patient prognosis worsened with stage progression. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics. CAB is recommended as the primary treatment for mPC.
Single-institution retrospective review of newly diagnosed glioblastoma (GBM) patients (pts) treated on bevacizumab (BEV) in clinical practice.
Authors: Henry S. Friedman, James Emmett Herndon, Frances McSherry, Arliene Ravelo, Eric S Lipp, Patrick Healy, Katherine B. Peters, Tulika Ranjan, Gordana Vlahovic, Jason Watts, John Howard Sampson, Allan H. Friedman, Annick Desjardins
Journal: Journal of Clinical Oncology (2014)

2082 Background: Following the FDA approval of BEV for recurrent GBM pts, two multicenter phase III trials, RTOG0825 and AVAglio, evaluated the addition of BEV to radiation and temozolomide in newly diagnosed GBM. These trials failed to show statistically significant increased survival [median overall survival (OS) of 15.7 and 16.8 months for the BEV groups, respectively]. We performed a retrospective chart review of newly diagnosed GBM pts treated with BEV at Duke, with the goal to identify subgroups of pts who might benefit from BEV in the community. Methods: Newly diagnosed adult GBM pts treated at Duke were identified through our “Primary and Recurrent Glioblastoma Registry”. We conducted a retrospective chart review of pts who initiated BEV off clinical trial between January 1, 2009 and May 14, 2012. Pts who participated in a clinical trial prior to receiving BEV were excluded from analysis. Pts alive on May 15, 2012 consented to the prospective collection of their data. Demographic, clinical, and outcome data were analyzed. Results: Thus far, a total of 181 pts have been identified. Median age at start of BEV was 57 years (range 20-80) and 66% were male. Gross total resection was obtained in 46%, biopsy in 20%, and subtotal resection in 34% of pts. At a median follow-up of 31.2 months, median OS from the time of GBM diagnosis was 26.2 months (95% Confidence Interval [CI], 23.3-32 months) and median progression-free survival (PFS) was 17.8 months (95%CI, 14.9-19.8 months). Grade 3 or higher proteinuria occurred in 6% of pts; grade 3 or higher thromboembolic events occurred in 9% of pts. Two grade 2 intracranial hemorrhages were observed. Conclusions: This retrospective review suggests a median OS of 26.2 months and median PFS of 17.8 months in newly diagnosed GBM pts treated on BEV in clinical practice. One possible explanation for the long-term survival could be our practice of continuing BEV at progression. Further prospective and retrospective analyses to identify subgroups of pts who can benefit from the addition of BEV to the standard of care will be performed.
Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study
Authors: Xavier Sáez-Llorens, Vianney Tricou, Delia Yu, Luis Rivera, Suely Tuboi, Pedro Garbes, Astrid Borkowski, Derek Wallace
Journal: The Lancet Infectious Diseases (2017)
Experience with the Routine Use of Erythromycin for Chlamydial Infections in Pregnancy
Authors: Julius Schachter, Richard L. Sweet, Moses Grossman, Daniel Landers, Marilyn Robbie, Ellen Bishop
Journal: New England Journal of Medicine (1986)

In an effort to prevent perinatal acquisition of Chlamydia trachomatis, we offered treatment with erythromycin ethylsuccinate (400 mg four times a day for seven days, given at 36 weeks' gestation) to 184 pregnant women with cervical chlamydial infections. Thirty-two women refused treatment; 24 of their infants were followed and served as the controls. Therapy was discontinued by 5 of 10 women who had gastrointestinal disturbances. Forty-seven women who completed therapy refused infant follow-up; in four (9 percent) of these women, therapy had failed to eradicate the infection. Sixty women and 59 infants completed the entire protocol; 55 (92 percent) of the women had negative cultures for chlamydia at follow-up. Chlamydial infection developed in 4 (7 percent) of the 59 infants of treated mothers, as compared with 12 (50 percent) of the 24 infants of untreated mothers; this difference was significant (P<0.001). With a success rate of 92 percent (98 of 107 patients) in treating maternal infection and with a relatively low intolerance rate (3 percent; 5 of 152), this regimen appears to be an effective, although not ideal, therapy for chlamydial infection in pregnant women. We conclude that in settings in which the prevalence of chlamydia infection is high, a routine program of screening pregnant women for cervical C. trachomatis, followed by treatment of those infected, would be cost effective and would reduce infant morbidity. (N Engl J Med 1986; 314:276–9.)
Effect of XPO1 inhibition in cancer cells on the 3D nuclear organization of telomeres: Quantitative analysis of short-term effects.
Authors: Daniel Lichtensztejn, Mary Cheang, Erkan Baloglu, William Senapedis, Sharon Shacham, Michael Kauffman, Sabine Mai
Journal: Journal of Clinical Oncology (2015)

e22148 Background: The three-dimensional (3D) organization of the nucleus, especially the nuclear pore complex (NPC), is key to its normal function. Cancer cells have a disrupted nuclear organization that can be quantified by using 3D nuclear telomere imaging. Perturbation of NPCs can alter cell proliferation and signal transduction pathways and can lead to cancer cell death. We hypothesize that the 3D nuclear architecture of cancer cells is affected when NPCs are compromised through XPO1 inhibition by Selective Inhibitors of Nuclear Export (SINE). Methods: We used three SINE compounds; KPT-330, KPT-185, and KPT- 8602. They were individually administered at 1 μM concentration for 4 hours to proliferating cancer cell lines. The cancer cells investigated included lymphoid (Raji and Jurkat) and breast cancer cell lines (T47D and HCC1937). After four hours of incubation, the cells were 3D fixed, processed for 3D telomere hybridizations, and 3D imaged. The 3D nuclear telomere organization was measured and quantified. Results: All SINE compounds affected the 3D nuclear architecture significantly. The overall disruption of the telomere organization in the four cancer cell lines was significant (p < 0.0001). Measured alterations included the distribution of telomere signals and of telomeric aggregates, the average signal intensity, the total intensity, the nuclear volumes, and the distribution of signals per nuclear volume. Conclusions: We conclude that XPO1 inhibition in cancer cells disrupts 3D telomere organization and therefore the structure of the genome. The disruption measured does not appear to be compatible with cancer cell survival.
Preoperative risk factors predicting postoperative complications in radical cystectomy for bladder cancer.
Authors: Derek Jensen, Stefan Graw, Sida Niu, Vassili Glazyrine, Devin Koestler, Eugene K. Lee
Journal: Journal of Clinical Oncology (2017)

395 Background: Radical cystectomy is an extensive operation with complications reported in up to 30.5% of patients. High complication rates contribute to increased costs, patient morbidity and mortality. Accurate prospective predictions of patients’ risk for post−surgical complications have the potential to identify at risk patients. Risk estimators have been developed but often involve an extensive number of factors or produce expansive results that are not clinically useful. Methods: 330 patients who underwent radical cystectomy for bladder cancer from January 2008 to July 2014 were included in this study. Potential preoperative risk predictors were collected from medical history, TURBT pathology, preoperative labs, proposed procedure type, and prior treatments. Postoperative complications were graded using the Clavien−Dindo scale. Multivariate logistic regression models were used to predict post−operative complications. Accuracy of prediction models was assessed using the area under the receiver operating characteristic curve. Results: Of the potential preoperative risk factors, 5, 10 and 16 unique predictors along with two way interactions were determined to have strong association with 90 day postoperative complications, yielding an AUC of 0.69, 0.79 and 0.91 respectively. Conclusions: Our findings suggest routinely collected preoperative patient−level clinical variables may be useful for determining patient risk for short−term postoperative complications. The flexibility in our prediction model for the number of predictor inputs allow users to tailor the degree of risk assessment based on a patient’s baseline heath status. A simple and accessible prediction model with selective predictors may help identify at risk patients for patient education, counseling and development of risk reduction strategies.
CUSTOM (Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies trial): A radical redesign of clinical trial structure—Use of mass customization and product postponement.
Authors: Ariel Lopez-Chavez, Anish Thomas, Arun Rajan, Seth M. Steinberg, David M. Dilts, Austin Doyle, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2013)

6524 Background: Traditionally, the structure of clinical trials has relied upon histology as the top eligibility criterion for enrollment. While more modern trial designs (i.e. BATTLE and I-SPY2) have implemented molecular selection for treatment assignment, histology has remained at the top of the clinical trial structure (1. Histology 2. Molecular selection 3. Treatment assignment). CUSTOM is the first completed prospective clinical trial designed by implementing the ideas of mass customization and product postponement into its structure. This report discusses CUSTOM’s innovative clinical trial design strategy. Methods: In CUSTOM, the task of differentiating a particular treatment’s efficacy by statistical analysis based on histology was postponed until the latest possible point in the trial’s structure (1. Molecular selection 2. Treatment assignment 3. Histology). An optimal two-stage phase II design was used to identify compounds with high clinical activity defined by a response rate of more than 40%. Patients were eligible for enrollment regardless of performance status, previous number of therapies or organ function. Results: CUSTOM was able to enroll 668 patients in only 18 months at 2 academic institutions and conduct a parallel and simultaneous evaluation of multiple targeted therapies (5) in molecularly selected patients in 3 cancer histological types. Its design allowed for the inclusion of rare cancers resulting in the largest prospective molecularly based clinical trial in patients with thymic malignancies and small cell lung cancer. Overall, its design resulted in a more rapid, cost-effective and efficient strategy for pharmaceutical development compared to traditional approaches. Conclusions: The traditional methodology used to design and execute clinical trials (i.e., histology-driven, single treatment vs. SOC) is dated, inefficient and expensive. The CUSTOM’s clinical trial design is one approach to increase the efficiency, reduce the cost, and increase the speed of the early phase pharmaceutical development process. Clinical trial information: NCT01306045.
Effect of pan-PI3K and HER2 blockade on antitumor activity in preclinical models of breast cancer resistance to trastuzumab therapy.
Authors: Pradip De, Yuliang Sun, Lori Friedman, Nandini Dey, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2013)

e13570 Background: PI3K-AKT-mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2-enriched breast cancer and generally herald a poor response and resistance to trastuzumab (T). Targeting the PI3K-AKT-mTOR pathway is an attractive strategy in HER2+ breast cancer that is refractory to trastuzumab. The hypothesis is that the suppression of this pathway by pan-PI3K inhibitor, GDC-0941 may lead to overcome trastuzumab-resistance. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of GDC-0941 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with GDC-0941 and T (alone and in combination). Results: (1) GDC-0941 exhibited in vitro cell killing activity in MTT assay with IC50’s ranging from 0.35 µM to 1 µm and potency was augmented by the addition of T, (2) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following GDC-0941 treatment, and the combination of GDC-0941 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) GDC-0941 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of GDC-0941 and T has strongly enhanced anti-tumor effect in both sensitive (82%) and resistant models (79%), something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, and 2) targeting both the HER2 and the PI3K signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.
Urinary Exosomes Detect Amyloidogenic Light Chain in Patients Who Have Renal Progression Despite a Hematologic Complete Response
Authors: Nelson Leung, David R Barnidge, Angela Dispenzieri, Marin-Argany Marta, Dick J Christopher, Cooper A Shawna, Nasr H Samih, Ward J Christopher, Ramirez-Alvarado Marina
Journal: Blood (2016)
Effect of treatment with hedgehog inhibitor, PF-04449913, on leukemia-initiation potential in acute myeloid leukemia cells.
Authors: Yosuke Minami, Nobuaki Fukushima, Tomoki Naoe
Journal: Journal of Clinical Oncology (2013)

e13520 Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell population in several experimental systems. PF-04449913 (PF) is a novel oral small molecule inhibitor that targets Smoothened (SMO) in the Hh pathway. Treatment with PF has shown promising results regarding safety, tolerability, and early signs of efficacy in a phase 1 study of hematologic malignancies including acute myeloid leukemia (AML) (Jamieson C, et al. ASH, 2011). Methods: We used AML cell lines and primary AML cells in order to elucidate mechanisms and biomarkers in PF treatment. We also used a co-culturing system with HS-5 stromal cells, and an immunodeficient NOD/SCID/IL2rγ null (NOG) mouse model serially xenotransplanted with primary AML cells to evaluate effects of PF on AML propagation. Results: In vivo-treatment with PF attenuated leukemia-initiation potential in acute myeloid leukemia cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Ex vivo-treatment with PF inhibited proliferation and minimally induced cell death in leukemia cell lines and primary AML cells increased expression of the myeloid differentiation marker, CD11b. In addition, PF treatment down-regulated mRNAs encoding downstream effector GLIs in the canonical Hh pathway using RQ-PCR assays and decreased nuclear expression of GLI-2 using immunofluorescence assays. Moreover, combined treatment with PF abrogated resistance to Ara-C in MOLM-14 cells co-cultured with HS-5 stromal cells. We are also investigating biomarkers in these models including CD markers (such as CD44) as well as the toxicity for normal cord blood cells with PF treatment. Conclusions: These results imply that PF treatment can attenuate leukemia-initiation potential in acute myeloid leukemia cells and improve AML therapy through overcoming the resistance to chemotherapy in the bone marrow microenvironment.
Use of tumor size to predict long-term survival in colon cancer patients: Analysis of National Cancer Data Base (NCDB).
Authors: Sukamal Saha, Mohammed Shaik, Supriya Kumar Saha, Alpesh K. Korant, Gregory Johnston, Vikrom K. Dhar, David Wiese, Trevor Singh, Madan L. Arora, Andrew Stewart
Journal: Journal of Clinical Oncology (2013)

3583 Background: Tumor size (TS) is a known prognostic factor in breast, renal, and lung cancers, however, not in colon cancer (CCa). Tumor (T) depth, nodal status (N), and metastasis (M) are used in the TNM staging. Hence, we studied if TS is an independent risk factor for death in CCa. Methods: Data included TS, grade, T-stage, N, and M-status from the NCDB for 298,021 CCa pts (1998-2010). We divided pts into 4 groups by TS (&lt;2cm;2-4cm;4-6cm;&gt;6cm). Data was analyzed using Spearman’s rho correlation (r) and Kaplan-Meier for overall 5-yr survival (5yrOS). Hazard ratios (HR) were calculated using a Cox model adjusting for age, sex, grade, T, N-status and TNM stage. Results: Proportion of pts with TS 0-2, 2-4, 4-6 and &gt;6cm were 13.25%, 38.95%, 29.54%, and 18.26% respectively. Median TS was 4cm. TS was positively correlated with grade, T, N-status and TNM stage (p=0.0001) and negatively correlated with 5yrOS (65.5%, 52.4%, 45.5%, and 41.2% for four sizes respectively) (Table). Cox modeling demonstrated TS of 4-6cm and &gt;6cm had HRs of 1.23 (95%CI 1.14-1.34) and 1.7 (95%CI 1.5-1.8) respectively. Conclusions: A primary TS of 4-6cm and &gt;6cm is associated with a 23% and 70% increased risk of death, respectively, over 5-yrs in CCa. Prospective studies are needed to evaluate the role of primary TS in CCa prognosis. [Table: see text]
Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology
Authors: Lenka Hovorkova, Marketa Zaliova, Nicola C. Venn, Kirsten Bleckmann, Marie Trkova, Eliska Potuckova, Martina Vaskova, Jana Linhartova, Katerina Machova Polakova, Eva Fronkova, Walter Muskovic, Jodie E. Giles, Peter J. Shaw, Gunnar Cario, Rosemary Sutton, Jan Stary, Jan Trka, Jan Zuna
Journal: Blood (2017)
Cardiovascular diseases after Hodgkin lymphoma treatment: 35-year disease risk and sequence of events.
Authors: Frederika A. van Nimwegen, Michael Schaapveld, Cecile P.M. Janus, Augustinus D.G. Krol, John M.M. Raemaekers, Eefke J. Clevers-Petersen, Berthe M.P. Aleman, Flora E. van Leeuwen
Journal: Journal of Clinical Oncology (2014)

9505 Background: Hodgkin lymphoma (HL) survivors are known to be at increased risk of cardiovascular disease (CVD), causing excess morbidity and mortality. It is unclear, however, whether the increased risk persists after 35 years and whether there are specific patterns in the sequence of multiple CVDs in individual patients. Methods: A cohort study was performed including 2,528 5-year HL survivors, diagnosed before age 51 and treated between 1965-1995. We assessed CVD endpoints (ischemic heart disease [IHD], congestive heart failure and cardiomyopathy [HF] and valvular heart disease [VHD]) up to October 2013 through questionnaires to GPs and cardiologists. Cumulative incidence of CVDs was estimated accounting for death as a competing risk. Risk factors were evaluated using Cox regression. Standardized Incidence Ratios (SIRs) were estimated to compare CVD risk with the general population. Results: We identified 1,419 CVDs in 752 patients, after a median follow-up of 21 years. Following mediastinal radiation (medRT), 35-year cumulative incidence of CVD was 46.3% (95%CI: 43.5%-49.1%), compared to 18.6% in patients not treated with medRT (14.3%-23.4%). The most frequently diagnosed first cardiac event was IHD (49%), followed by VHD (40%). 49% of CVD patients developed multiple CVDs; 92% of these patients received medRT; among patients with one CVD and patients without any CVDs, this was 90% and 77%, respectively (p<0.001). HF was mostly diagnosed as last CVD (67% of HF). Both medRT (Hazard Ratio (HR): 3.6, 95%CI: 2.8-4.7) and anthracycline-containing chemotherapy (HR: 1.6, 95%CI: 1.3-1.9) increased the risk of any CVD independently. More than 35 years after HL diagnosis, our patients had a 2.1–fold increased SIR of primary IHD or HF (95%CI: 1.1-3.7), compared to the general population, corresponding to 126 excess cases per 10,000 person years. 9.4% of patients who died, died from CVDs. Median survival time after a first CVD was 5.1 years. Conclusions: The risk of CVD is strongly increased for at least 35 years following HL treatment, especially after medRT. Multiple CVDs are frequently observed. Physicians should be aware of the persistently increased risk of CVDs and the increased risk of developing subsequent CVDs.