tbuckley/cabot-search huggingface dataset:
Phase I study of sequential sapacitabine and seliciclib in patients with advanced solid tumors.
Authors: Geoffrey Shapiro, Eunice Lee Kwak, James M. Cleary, Sara Tolaney, Leena Gandhi, Jeffrey W. Clark, Andrew Wolanski, Sheelagh Frame, Scott J. Rodig, Judy H. Chiao
Journal: Journal of Clinical Oncology (2012)

3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 27 patients were treated. The MTD and RP2D is sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Two confirmed PRs occurred in patients with pancreatic and breast cancer, both BRCA mutation carriers. SD as best response &gt;/= 12 weeks was observed in 6 additional patients, including one BRCA mutation carrier with ovarian cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types.
Treatment outcome of advanced gastric cancer with doubole or multiple primary cancer.
Authors: Shigeo Yamaguchi, Tatsu Shimoyama, Kaori Toneyama, Makoto Saitou, Yusuke Kanemasa, Eisaku Sasaki, Yasushi Omuro, Yoshiharu Maeda, Tsuneo Sasaki
Journal: Journal of Clinical Oncology (2014)

e15015 Background: Double or multiple primary cancers ( DMPC ) including gastric cancer is difficult for clinicians to set a therapeutic target. For the poor prognosis, the chemotherapy regimens targeting gastric cancer have been chosen ignoring other primary cancer. We conducted a chart review to explore the effective therapeutic strategy. Methods: The clinical data of advanced gastric cancer patients treated by chemotherapy at Komagome Hospital between 2003 July and 2012 July were retrospectively reviewed. Results: Of the 454 patients, 42 patients had DMPC. All 42 patients were treated by fluorouracil agent and cisplatin combination therapy. Among these 42 patients, 20 had synchronous primary cancers. Of the 20 synchronous primay cancer patients, 11 patients received treatments for second primary cancers except gastric cancer, such as operation, radiation therapy, and chemotherapy in addition to fluorouracil agent and cisplatin combination chemotherapy for gastric cancer. Six of the 20 patients had kinds of DMPC which were applied for fluorouracil agent and cisplatin combination therapy, and other 14 patients had kinds of DPMC that were not adaptive this combination therapy. With a median follow-up of 13 months, no difference in OS was observed between DMPC patients and simple gastric cancer patients (p=0.42). Likewise, there was no difference in OS between patients treated only gastric cancer and treated both cancers (p=0.64). Moreover, no difference in OS was observed between fluorouracil agent and cisplatin combination therapy sensitive DMPC patients and non-sensitive DMPC patients (p=0.83). All except one of DMPC patients were dead of progression of gastric cancer. One patient was dead of treatment related event. Conclusions: Advanced gastric cancer patients with DMPC could be treated by fluorouracil agent and cisplatin combination therapy regarding gastric cancer as a first therauptic target.
Margaret McCartney: Why is it so hard to do what we know works?
Authors: Margaret McCartney
Journal: BMJ (2017)

It’s hiding in plain sight. Poor people live less long than those who are rich,1 and people with a learning disability are more likely to die sooner than people without.2 GPs have been urged to respond to this in the way the contract knows best: by offering health checks and a checklist of items to be ticked.

In Scotland the Keep Well programme, aimed at people in deprived areas, has demonstrated only minimal or marginal benefits but is still used in some areas.3

Health checks for people with learning disabilities often detect symptomatic conditions. This is itself …
Association of PET index quantifying skeletal uptake in NaF PET/CT images with overall survival in prostate cancer patients.
Authors: Sarah Lindgren Belal, May Sadik, Reza Kaboteh, Nezar Hasani, Olof Enqvist, Linus Svärm, Fredrik Kahl, Jane Simonsen, Mads Hvid Poulsen, Mattias Ohlsson, Poul Flemming Høilund-Carlsen, Lars Edenbrandt, Elin Tragardh
Journal: Journal of Clinical Oncology (2017)

178 Background: Bone Scan Index (BSI) derived from 2D whole-body bone scans is considered an imaging biomarker of bone metastases burden carrying prognostic information. Sodium fluoride (NaF) PET/CT is more sensitive than bone scan in detecting bone changes due to metastases. We aimed to develop a semi-quantitative PET index similar to the BSI for NaF PET/CT imaging and to study its relationship to BSI and overall survival in patients with prostate cancer. Methods: NaF PET/CT and bone scans were analyzed in 48 patients (aged 53-92 years) with prostate cancer. Thoracic and lumbar spines, sacrum, pelvis, ribs, scapulae, clavicles, and sternum were automatically segmented from the CT images, representing approximately 1/3 of the total skeletal volume. Hotspots in the PET images, within the segmented parts in the CT images, were visually classified and hotspots interpreted as metastases were included in the analysis. The PET index was defined as the quotient obtained as the hotspot volume from the PET images divided by the segmented bone tissue volume from the CT images. BSI was automatically calculated using EXINIbone BSI . Results: The correlation between the PET index and BSI was r 2 = 0.54. The median BSI was 0.39 (IQR 0.08-2.05). The patients with a BSI ≥ 0.39 had a significantly shorter median survival time than patients with a BSI &lt; 0.39 (2.3 years vs. not reached after 5 years). BSI was significantly associated with overall survival (HR 1.13, 95% CI 1.13 to 1.41; p &lt; 0.001), and the C-index was 0.68. The median PET index was 0.53 (IQR 0.02-2.62). The patients with a PET index ≥ 0.53 had a significantly shorter median survival time than patients with a PET index &lt; 0.53 (2.5 years vs. not reached after 5 years). The PET index was significantly associated with overall survival (HR 1.18, 95% CI 1.01 to 1.30; p &lt; 0.001) and C-index was 0.68. Conclusions: PET index based on NaF PET/CT images was correlated to BSI and significantly associated with overall survival in patients with prostate cancer. Further studies are needed to evaluate the clinical value of this novel 3D PET index as a possible future imaging biomarker.
Association of outcome with genes involved in tumor dormancy in patients with resected colorectal liver metastases.
Authors: Dongyun Yang, Stefan Stremitzer, Wu Zhang, Yan Ning, Sebastian Stintzing, Ana Sebio, Yu Sunakawa, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Judith Stift, Friedrich Wrba, Thomas Gruenberger, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

e14512 Background: Recurrence after liver resection in patients with colorectal liver metastases (CLM) is frequent, despite the chance of cure and long-term survival. The mechanisms of recurrence are not well understood. Tumor dormancy has been described as a state of hibernation until eventual outgrowth playing a critical role in tumor recurrence. In this study we investigated genetic variations within genes that are associated with tumor dormancy and their association with recurrence and outcome in patients with CLM. Methods: Genomic DNA was extracted from resected bevacizumab-pretreated CLM (FFPE) from 149 patients (median age 62 years, 58.4% male, median follow-up 3.9 years). Single nucleotide polymorphisms (SNP) in 13 genes associated with dormancy (TCF7L2, AXIN2, CD44, LGR5, ALDH1A1, uPA, uPAR, ITGA5, ITGB1, EGF, EGFR, Dll4, NOTCH3) were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS) and overall survival (OS). Results: In univariate analysis, rs1044009 (NOTCH3) and rs7903146 (TCF7L2) showed a significant difference in 3-year OS rate [(T/T 73%, T/C or C/C 55%; HR 2.17, P=0.010) and (C/C 71%, C/T 60%, T/T 100%; HR 1.83 and 0.26, P=0.024), respectively]. In multivariate analysis, rs1044009 remained significant (HR 2.54, P=0.005). With respect to radiological response, rs1044009 and rs1043994 (NOTCH3) showed a significant difference [(T/T 85%, T/C 85%, C/C 25%, P=0.024) and (C/C 85%, C/T 81%, T/T 0%, P=0.029), respectively]. With respect to histological response, rs2227983 (EGFR) showed significant different rates between the groups [C/C 33% major histological response (MjHR), 27% partial histological response (PHR), 40% no histological response (NHR); C/T 40% MjHR, 30% PHR, 30% NHR; T/T 75% MjHR, 25% PHR, 0% NHR, P=0.031]. Recursive partitioning analyses revealed that rs12441495 (Dll4) and rs1044009 (NOTCH3) were the dominant SNPs predicting histological response and OS, respectively. Conclusions: Our data suggest that gene variations of genes involved in tumor dormancy are associated with response and outcome in patients with resected CLM. These data might lead to improved treatment strategies targeting tumor dormancy.
Lung adenocarcinoma microRNA-31 expression levels to predict lymph node metastasis and patient survival.
Authors: Tim Lautenschlaeger, Wei Meng, Zhenqing Ye, Ri Cui, James Perry, Alexander Huebner, Vaia Dedousi-Huebner, Volinia Stefano, Nakanishi Hiroshi, Taewan Kim, Sung-Suk Suh, Leona W. Ayers, Patrick Ross, Carlo M Croce, Victor Jin, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2013)

7573 Background: In this study we performed genome-wide microRNA-seqencing (miRNA-seq) in lung adenocacinoma (ADC) patient samples and used bioinformatic analyses to identify novel and annotated microRNAs that are differentially expressed between patients with and patients without lymph node metastasis, as well as examining their potential prognostic value. Methods: Sixty four frozen tissue specimens from lung ADC patients collected between 2003 and 2012 were obtained through the OSUCCC Tissue Procurement Shared Resource, approved by internal review board (IRB). Total RNA samples were processed and loaded on the Applied Biosystems SOLiD 4 sequencing system for data acquisition. 249 patients from the TCGA lung ADC cohort were used for results validation. Human lung ADC cell lines H23 and H1573 were used for in vitro functional assays. Results: We identified several microRNAs that were associated with the presence of lymph node metastasis in primary lung adenocarcinoma tissues using genome-wide miRNA-seq. We confirmed miR-31 to be up-regulated in lung ADC tissues from patients with lymph node metastasis in a separate patient cohort (p=0.009, t-test), and to be expressed higher in ADC tissues than in matched normal adjacent lung tissues (p&lt;0.0001, paired t-test). MiR-31 was then validated as a marker for lymphnode metastasis in an external validation cohort of 233 lung ADC cases of the TCGA that did not have distant metastasis (p=0.031, t-test). In vitro functional assays showed that miR-31 upregulation increases cell migration, invasion, and proliferation. In addition, overexpression of mir-31 increased the expression of markers of epithelial-mesenchymal transition (EMT) and associated with activated ERK1/2 signaling. MiR-31 was a significant predictor of survival in a multivariate Cox regression model even when controlling for tumor stage. In silico analysis showed that low expression of miR-31 was associated with excellent survival for T2N0 patients. Conclusions: In summary, we applied microRNA-seq to study microRNomes in lung ADC tissue samples for the first time and identified a microRNA that could predict the presence of lymph node metastasis and survival outcomes in lung ADC patients.
Predictive value of baseline serum MIP-1α and CRP on symptom burden and tumor response to induction therapy in patients with multiple myeloma.
Authors: Charles S. Cleeland, Xin Shelley Wang, Sheeba K. Thomas, Ping Liu, Mary H Sailors, Tito R. Mendoza, James M. Reuben, Evan N. Cohen, Katherine R. Gilmore, Venus M Ilagan, Loretta A. Williams, Valen E. Johnson
Journal: Journal of Clinical Oncology (2012)

8091 Background: Macrophage inflammatory protein-1α(MIP-1α) is a growth factor for human multiple myeloma (MM) cells. As an osteoclastic factor, its presence provides pathophysiological evidence of the development of lytic bone lesions in MM. C-reactive protein (CRP) indicates systemic inflammation. The relationship between disease-driven inflammatory markers and both patient-experienced symptoms and tumor response to induction therapy is unknown. Methods: MM patients (N=39) who were either newly diagnosed or had received fewer than 2 cycles of chemotherapy, and who also were to receive induction therapy, were enrolled. To test concentrations of MIP-1α and CRP, serum samples were collected before and after induction and assayed by Luminex. Multiple symptoms were measured twice a week via the M. D. Anderson Symptom Inventory MM module (MDASI-MM) from -8 to +112 days of induction. The MM-specific items of the MDASI-MM are bone aches, constipation, muscle weakness, diarrhea, sore mouth or throat, rash, and difficulty paying attention. Correlation between symptom severity and inflammatory markers at baseline was examined by linear regression modeling. Kruskal-Wallis significance test and Wilcoxon test were used to examine association between MIP-1α and tumor response. Results: Patients received either bortezomib-based (89%) or lenalidomide-based induction therapy. Baseline MIP-1α and CRP were significantly inversely related to the mean severity component score of the 5 most-severe symptoms (fatigue, pain, bone aches, poor sleep, drowsiness) (p=.03; p=.02), and significantly inversely related to the severity of a component score of the module-specific symptoms (p=0.04; p=.002). Change over time in MIP-1α differed significantly by tumor response category (p=.04), with the partial response group having a higher median score than the complete response group (1.483 vs. 0.016, p=.01). Conclusions: Our data suggest that higher baseline levels of serum MIP-1α and CRP predict effective chemotherapy-induced reduction of disease-related symptoms in MM patients. Higher serum MIP-1α expression after induction therapy was related to less-ideal tumor response.
Racial disparities in initiation of endocrine therapy for early-stage breast cancer.
Authors: Katherine Elizabeth Reeder-Hayes, Anne-Marie Meyer, Stacie Dusetzina, Huan Liu, Stephanie B. Wheeler
Journal: Journal of Clinical Oncology (2013)

6572 Background: Oral endocrine therapy (ET) is the cornerstone of adjuvant therapy for hormone receptor-positive (HR+) breast cancer, greatly reducing the risk of recurrence and death when taken for at least 5 years. Failure to initiate ET is a known problem that adversely affects recurrence and survival. The survival gap between black and white women with breast cancer is most pronounced in HR+ subtypes, and could be related to differences in ET use. The relationship between race and failure to initiate ET is not well defined. We investigated patterns of ET initiation by race in a diverse cohort of women covered by commercial health insurance. Methods: We identified 2753 women with incident HR+ breast cancer in the North Carolina Central Cancer Registry whose records linked to insurance claims using the statewide Integrated Cancer Information and Surveillance System (ICISS) database maintained by the University of North Carolina. The sample included privately insured women age &lt;65 years who were diagnosed with stage I-III HR+ breast cancer between 2004 and 2009 and received primary therapy including breast surgery within 12 months of diagnosis. We used multivariate Poisson regression with robust variance to examine the effect of race on likelihood of initiating ET (tamoxifen, anastrozole, letrozole or exemestane). Results: 14% of eligible women did not initiate any form of ET within 12 months of diagnosis. Black women initiated ET at a significantly lower rate (IRR 0.83, 95% CI 0.73-0.93) after adjustment for age, disease characteristics, other treatments, and socioeconomic variables. Women receiving breast conserving surgery (BCS) without radiation (RT) were less likely to initiate compared to those receiving BCS + RT or mastectomy, and women whose treatment included chemotherapy were less likely to initiate ET. Conclusions: Black women in our sample were significantly less likely to initiate ET in a timely fashion than their white counterparts. This underutilization may contribute to the pronounced survival gap among black women with HR+ breast cancer, and represents an opportunity for intervention to reduce breast cancer disparities. Further investigation is needed to understand the reasons why black women do not initiate ET.
Late-breaking abstract: The impact of extended cervical mediastinoscopy in staging of left lung carcinoma
Authors: Adnan Sayar, Necati Çitak, Songül Büyükkale, Muzaffer Metin, Abdulaziz Kök, Sibel Yurt, Alper Çelikten, Atilla Gürses
Journal: European Respiratory Journal (2011)

Background:  Extended cervical mediastinoscopy (ECM) is a method used for staging non-small cell lung cancer (NSCLC).   Methods:  Between 1998 and 2011, 159 patients underwent ECM who had left NSCLC, were retrospectively analyzed. If the cN2 was limited to the paratracheal or subcarinal spaces without infiltrating the paraortic or subaortic spaces, these cases excluded from the study (negative cases of ECM and positive cases of SCM). Patients who had been reported as cN0 by mediastinoscopy underwent thoracotomy for tumor resection.   Results:  Localization of the tumor was upper lobe in 81 patients (50.9%), central in 56 patients (35.3%), lower lobe in 22 patients (13.8%). ECM was successful at harvesting one or more aortopulmonary (APW) lymph nodes in 153 patients (96.2%) (#5 and #6 sampling in 82 patients, #5 or #6 sampling in 71 patients). Mediastinal lymph node metastasis was observed in 36 patients (22.6%) via mediastinoscopy. APW lymph node metastases were shown in 26 of these patients (true-positive of ECM), remaining 10 patients who had mediastinal lymph nodes metastasis that could be accessed only via SCM were exclueded. 123 patients who identified as cN0 by mediastinoscopy were operated; 64 lobectomies, 43 pneumonectomies, 16 exploratory thoracotomies. The pathological examination of the mediastinal lymphadenectomies revealed APW lymph node metastases in 11 patients (false-negative of ECM). Sensitivity, NPV and accuracy of ECM were calculated as 0.70, 0.91, and 0.92, respectively.   Conclusions:  ECM has an adequate NPV and accuracy in determining metastases to the APW lymph nodes in patients with left NSCLC
High level of suppressor-of-fused (SuFu) expression and tumor cells dissemination in human glioblastoma.
Authors: Noemi Garcia-Romero, Maria Peris-Celda, Josefa Carrion-Navarro, Cristina Zahonero, Carmen Escobedo, Pilar Sanhez, Cristina Gonzalez Perez, Esther Holgado, Ricardo Prat, Cristobal Belda-Iniesta, Angel Ayuso-Sacido
Journal: Journal of Clinical Oncology (2014)

e22118 Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults accounting for -75% of astrocytic tumors. It corresponds to WHO grade IV glioma. Hedgehog (Hh)-Gli pathway is activated in primary glioblastoma-initiating cells, where inhibition of the pathway reduces growth either in vitro or in vivo. However, inhibition of the Hh-Gli pathway has render not significant results in clinical trials. The aim of the present study is to analyze the expression of Hh-Gli intermediates in a series of human GBM and glioblastoma-initiating cells, and correlate the results with clinical parameters. We found that high level of suppressor-of-fused (SuFu) expression increases tumour cells dissemination in human glioblastoma. We observed that SuFu over-expression alter cell-cell and cell-matrix interaction. Altogether, SuFu seems to play an important role as regulator of migration/growth dichotomy. Methods: Primers targeting Hh-Gli pathway intermediates were designed, validated and used to evaluate the Hh-Gli pathway intermediate expression within a exploratory cohort (n=55). SuFu was up-regulated and down-regulated in a primary GBM-initiating cell culture. These cells were used to conduct migration and proliferation studies either in vitro or in vivo. mRNA microarrays was carried out to find the relation between SuFu and downstream targets. Finally, the results were tested in a confirmatory cohort (n=62). Results: We found that high level of suppressor-of-fused (SuFu) mRNA expression increases tumour cells dissemination in human glioblastoma (P= 0,01). The up-regulation of SuFu in GBM-initiating cells increases dissemination in vivo. This effect is mediated by altering the level of the actin/vinculin cytoskeletal proteins, and membrane proteins like integrin alpha 2,3, v, 5 and 6. Conclusions: The level of suppressor-of-fused (SuFu) mRNA expression is a key regulator of the migration/growth dichotomy in Glioblastoma. While down-regulation induces tumor cell growth, the over-expression increases tumor dissemination. Therefore, the duality of its function regarding tumor biology is key factor that will influence any therapy directed to SuFu-dependent pathways.