tbuckley/cabot-search huggingface dataset:
Prognostic and predictive impact of primary tumor sidedness in first-line trials for advanced colorectal cancer: An analysis of 7,828 patients in the ARCAD database.
Authors: Jun Yin, Romain Cohen, Zhaohui Jin, Heshan Liu, Levi Pederson, Richard Adams, Tim Maughan, Alan P. Venook, Eric Van Cutsem, Chiara Cremolini, Niall Tebbut, Matt Seymour, Carsten Bokemeyer, Eduardo Diaz-Rubio, Harpreet Singh Wasan, Volker Heinemann, Aimery De Gramont, Qian Shi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

188 Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the prognostic and predictive impact of PTS on outcomes. Methods: PTS data of 7,828 mCRC patients (pts) from 10 first-line randomized trials in the ARCAD database were pooled. PTS was defined as right-sided (RS) or left-sided (LS) if tumor arose from the cecum to the hepatic flexure or from the splenic flexure to the rectum, respectively; transverse colon cancers were not included. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status (PS), prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (anti-EGFR plus chemotherapy vs. chemotherapy alone). Results: Compared to RS pts (2407, 31%), LS pts (5421, 69%) had better OS (median: 21.6 v 16.8 mos; HR adj : 0.73, 95% CI 0.69-0.78, P &lt; .001) and PFS (median 8.4 v 7.2 mos; HR adj : 0.81, 95% CI 0.76-0.86, P &lt; .001). Results were consistent among subgroups defined by age, sex, PS, metastatic sites and chemo backbone (irinotecan- and oxaliplatin-based). Interaction between PTS and KRAS mutation was significant (P interaction &lt; .001): LS is associated with better prognosis only among KRAS wild-type (wt) (HR adj : OS 0.62, 95% CI, 0.55-0.70; PFS 0.71, 95% CI 0.63-0.80), but not among KRAS mutated pts. Among KRAS wt pts, survival benefit from anti-EGFR was observed for LS, but not for RS (table). Conclusions: The prognostic value of PTS is restricted to the KRAS wt population. PTS is predictive of anti-EGFR efficacy, with a significant improvement of survival for LS mCRC pts. These results suggest treatment stratification in mCRC studies by both PTS and KRAS status. [Table: see text]
Projected time to elimination of cervical cancer in the USA: a comparative modelling study
Authors: Emily A Burger, Megan A Smith, James Killen, Stephen Sy, Kate T Simms, Karen Canfell, Jane J Kim
Journal: The Lancet Public Health (2020)

In May, 2018, the Director-General of WHO issued a global call to eliminate cervical cancer as a public health problem, which will involve ambitious screening and vaccination coverage targets. We aimed to assess the potential for, and timing of, cervical cancer elimination in the USA and whether this could be expedited by adopting ambitious coverage targets, using two cervical cancer simulation models.In this modelling study, we used two independently-developed cervical cancer microsimulation models-Harvard and Policy1-Cervix-to estimate changes in the incidence of human papillomavirus (HPV)-induced cervical cancer over time in the USA, including herd effects from vaccination. We compared nine alternative scenarios for prophylactic HPV vaccination and cervical screening scale-up with a status quo scenario that involved no additional interventions in the context of a threshold for cervical cancer elimination of four or fewer cases per 100 000 women-years. We also estimated the number of cervical cancer cases that could be averted between 2019 and 2100 associated with the adoption of ambitious goals for cervical cancer screening and vaccination coverage, and other potential strategies.Under status quo assumptions, the Havard and Policy1-Cervix models projected that cervical cancer incidence would decrease to less than four or fewer new cases per 100 000 women-years by the 2038 and 2046, respectively. Scaling up screening coverage to 90% in 2020, was the most effective intervention to expedite time to elimination (10-13-year reduction), averting a mean of 1400-2088 additional cases annually between 2019 and 2100. Increasing HPV vaccination coverage to 90% or vaccinating adults aged 26-45 years had relatively little effect on cervical cancer incidence. Sensitivity analysis using different population structures resulted in differences in time to elimination (range -10 years to +27 years) compared with status quo predictions.The USA is on track to eliminate cervical cancer as a public health problem in the next two to three decades. Time to elimination could be expedited by 10-13 years by achieving higher screening coverage. Targeting of underscreened and under-vaccinated women remains key to achieving cervical cancer elimination for all women.US National Cancer Institute.
Population study of thymidylate synthase, dihydropyrimidine dehydrogenase and orotate phosphoribosyltransferase in patients with solid tumors
Authors: Masakazu Fukushima, Yousuke Fukui, Yoshikazu Sugimoto, Toshinori Oka, Sekio Nagayama
Journal: Cancer Research (2006)

3639   Purpose: Thymidylate synthase(TS), dihydropyrimidine dehydrogenase(DPD) and orotate phosphoribosyltransferase(OPRT) has been suggested to be predictive factors of 5-fluorouracil(5FU) therapy in cancer patients. To determine the differences in expression levels of these enzymes in solid tumors, we carried out a large-scale population study of the mRNA expression, enzyme content and enzyme activity of TS, DPD and OPRT. Methods: Surgical specimens were obtained from collaborating universities and hospitals in Japan. A total of 29957 clinical dissected specimens, consisting 4871 for mRNA, 13433 for enzyme amount, 11653 for enzyme activity, were collected between July 1998 and June 2005. The expression of TS, DPD and OPRT mRNA were assayed by Danenberg tumor profile (DTP). Enzyme amount of TS, DPD and OPRT were measured by enzyme linked immunosorbent assay (ELISA). TS activity and DPD activity of collected specimens were analyzed by [ 3 H]-FdUMP binding assay and radio-enzymatic assay used [ 14 C]-5-FU, respectively. Results: TS expression in the gastric cancer was significantly higher than matched non-cancerous tissue in mRNA, amount and activity. DPD expressions in the gastric, breast and lung cancer were significantly higher than matched non-cancerous tissues in amount and activity. We classified each type of carcinoma into four categories by using the median TS and DPD levels of all tumors as cut off value. About 60% of the population of gastric cancer had high DPD in the expression of mRNA, enzyme amount and activity, and about 65% of colorectal cancer had low DPD population. About 50% to 70% of the lung and pancreas cancer patients were distributed in low TS/high DPD group. There was no correlation between TS and DPD expression, so TS and DPD in tumors seemed to be independent factor. However, the TS expression of mRNA was correlated with OPRT expression (Spearman’s correlation coefficient = 0.42, p
Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption
Authors: Julie L. Mitchell, Hiroshi Takata, Roshell Muir, Donn J. Colby, Eugène Kroon, Trevor A. Crowell, Carlo Sacdalan, Suteeraporn Pinyakorn, Suwanna Puttamaswin, Khunthalee Benjapornpong, Rapee Trichavaroj, Randall L. Tressler, Lawrence Fox, Victoria R. Polonis, Diane L. Bolton, Frank Maldarelli, Sharon R. Lewin, Elias K. Haddad, Praphan Phanuphak, Merlin L. Robb, Nelson L. Michael, Mark de Souza, Nittaya Phanuphak, Jintanat Ananworanich, Lydie Trautmann
Journal: Journal of Clinical Investigation (2020)

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.
Local immune response in colon cancer: Indicative of good or poor prognosis?
Authors: Peter G Alexander, Jitwadee AF In, Antonia K. Roseweir, Arfon GMT Powell, Joanne Edwards, Campbell SD Roxburgh, Paul G. Horgan, Donald C. McMillan, James Hugh Park
Journal: Journal of Clinical Oncology (2020)

213 Background: The tumour microenvironment is an important determinant of survival in patients with colon cancer. Although the generalised inflammatory infiltrate as assessed by Klintrup-Mäkinen (KM) grade is a stage-independent prognostic marker, immunohistochemical staining for specific immune cell populations, such as T-cells, may have greater prognostic value. The present study examines the clinical utility of combined assessment of KM grade in addition to cytotoxic (CD8) and regulatory (FoxP3) T-cells. Methods: KM, CD8 and FoxP3 were assessed retrospectively in a cohort of 520 patients with stage I-III colon cancers. The relationship between KM grade, T-cell density and cancer-specific survival was examined. Results: KM was high in 33% of patients, of which: 16% had high FoxP3, 12% high CD8 and 56% both FoxP3 and CD8, while the remaining 15% were high KM alone. Conversely, 67% had low KM and of these: 47% had high CD8 alone or with FoxP3; 27% were high for FoxP3 alone and 25% had no inflammatory infiltrate. KM in the presence of other T-cells resulted in good outcome (Table), whereas CD8 with low KM with or without FoxP3 resulted in intermediate outcome. FoxP3 alone with low KM resulted in poor outcome. Similarly, KM alone without T-cells resulted in poor outcome. When no inflammatory cells were present, outcomes were comparable to KM or FoxP3 alone. Conclusions: A co-ordinated immune response results in good outcome and this can be assessed using a combination of a simple H&amp;E based method (KM) in addition to T-cell markers. Where KM is low, despite the presence of cytotoxic T-cells, survival outcome is worse. Conversely, high KM in the absence of T-cells, or FoxP3 alone, are associated with poor outcome, comparable to no inflammatory response. [Table: see text]
MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2–Positive and/or Hormone Receptor–Negative Breast Cancers in the I-SPY 2 Trial
Authors: A. Jo Chien, Debasish Tripathy, Kathy S. Albain, W. Fraser Symmans, Hope S. Rugo, Michelle E. Melisko, Anne M. Wallace, Richard Schwab, Teresa Helsten, Andres Forero-Torres, Erica Stringer-Reasor, Erin D. Ellis, Henry G. Kaplan, Rita Nanda, Nora Jaskowiak, Rashmi Murthy, Constantine Godellas, Judy C. Boughey, Anthony D. Elias, Barbara B. Haley, Kathleen Kemmer, Claudine Isaacs, Amy S. Clark, Julie E. Lang, Janice Lu, Larissa Korde, Kirsten K. Edmiston, Donald W. Northfelt, Rebecca K. Viscusi, Douglas Yee, Jane Perlmutter, Nola M. Hylton, Laura J. van’t Veer, Angela DeMichele, Amy Wilson, Garry Peterson, Meredith B. Buxton, Melissa Paoloni, Julia Clennell, Scott Berry, Jeffrey B. Matthews, Katherine Steeg, Ruby Singhrao, Gillian L. Hirst, Ashish Sanil, Christina Yau, Smita M. Asare, Donald A. Berry, Laura J. Esserman
Journal: Journal of Clinical Oncology (2020)

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
心血管臨床試験のための標準化された出血定義 BARC(Bleeding Academic Research Consortium)からのコンセンサス報告 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Mehran Roxana, V Rao Sunil, L Bhatt Deepak, Gibson C. Michael, Caixeta Adriano, Eikelboom John, Kaul Sanjay, D Wiviott Stephen, Menon Venu, Nikolsky Eugenia, Serebruany Victor, Valgimigli Marco, Vranckx Pascal, Taggart David, F Sabik Joseph, E Cutlip Donald, W Krucoff Mitchell, Ohman E. Magnus, Steg Philippe Gabriel, White Harvey
Journal: Circulation (2011)
Do Serum Urate–Associated Genetic Variants Differentially Contribute to Gout Risk According to Body Mass Index? Analysis of the UK Biobank
Authors: Vicky Tai, Ravi K. Narang, Greg Gamble, Murray Cadzow, Lisa K. Stamp, Tony R. Merriman, Nicola Dalbeth
Journal: Arthritis & Rheumatology (2020)

To examine whether urate-associated genetic variants differ in their influence on gout risk according to body mass index (BMI).This research was conducted using the UK Biobank Resource (n = 358,728). Participants were divided into 3 groups: BMI <25 kg/m2 (low/normal), BMI ≥25 kg/m2 -<30 kg/m2 (overweight), and BMI ≥30 kg/m2 (obese). Gene-BMI interactions for gout association were tested by logistic regression using a urate genetic risk score (GRS).Compared to participants with a GRS less than the mean, the prevalence of gout was higher in those with a GRS greater than or equal to the mean in the low/normal BMI group (0.27% versus 0.77%), in the overweight BMI group (1.02% versus 3.02%), and in the obese BMI group (2.49% versus 6.23%). A GRS greater than or equal to the mean was positively associated with gout compared to a GRS less than the mean in the low/normal BMI group (odds ratio [OR] 2.89 [95% confidence interval (95% CI) 2.42-3.47]), in the overweight BMI group (OR 3.09 [95% CI 2.84-3.36]), and in the obese BMI group (OR 2.65 [95% CI 2.46-2.86]). There was a mildly attenuated effect of the GRS on gout risk in the obese BMI group compared to the overweight BMI group, but no difference in the effect of the GRS between the low/normal BMI and overweight BMI groups, nor between the low/normal BMI and obese BMI groups.The association of a urate GRS with gout is mildly attenuated in obese individuals compared to overweight individuals. However, genetic variants have a strong effect on gout risk in those with overweight and obese BMIs, with an effect similar to that observed in low/normal BMI.
Long-term oncologic safety of self-expandable metal stent as a bridge to surgery for malignant colorectal obstruction: Our experience.
Authors: Se Hyun Jang, Bora Keum, Sanghyun Kim, Kang Won Lee, Han Jo Jeon, Sang Hoon Kim, Seong Ji Choi, Jae Min Lee, Hyuk Soon Choi, Eun Sun Kim, Yoon Tae Jeen, Hong Sik Lee, Hoon Jai Chun, Chang Duck Kim
Journal: Journal of Clinical Oncology (2020)

153 Background: About 10-25% patients of colorectal cancer suffer from acute colonic obstruction. Traditional management of acute malignant bowel obstruction has focused on emergency resection but showed high mortality and morbidity rates. Recently, placement of a self-expanding metal stent(SEMS) was widely used and SEMS seems to be as a safe and effective “bridge to surgery” and to offer good palliation. But there is concern about long-term survival after the use of SEMS. Theoretically, tumor cell seeding can occur due to mechanical force during the stent insertion. To identify this theoretical validity, we surveyed long-term survival of malignant colonic obstruction using SEMS placement. Methods: This retrospective study included 303 patients who presented in Korea University Anam Hospital between 2006 and 2014 with obstructing CRC, and underwent surgical resection. Patients were devided into two group: the “SEMS” group included 148 patients who underwent endoscopic stent as a bridge to surgery, and the surgery group included 155 patients who underwent emergency or elective surgery without stenting. In addition, candidates for curative resection were identified (98 patients in “SEMS” group vs 101 patients in “surgery” group). The clinicopathologic characteristics, overall survival(OS), and recurrence-free survival (RFS) were compared between the two groups. Results: There was no significant difference in demographics, tumor stage between the two group. The median follow-up times were 48.5 months (IQR, 19.1-73.1 months) for the SEMS group and 39.4 months (IQR, 15.1-39.4 months) for the surgery group. There was no significant difference in 5-year OS rate between two groups (59.6% vs 56.8%; p = 0.3). The 5-year RFS rate did not significantly differ between two groups (71.0% vs. 61.3%; p = 0.221). The long-term oncologic safety did not significantly differ between two groups in either the 5-year OS rate (79.5% vs 74.5%; P= 0.6). or the 5-year RFS rate (95.8% vs 95.8%; P = 0.3). Conclusions: SEMS as bridge to surgery in obstructive CRC did not worsen the long-term oncologic outcomes compared to those of the primary surgery.
Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.
Authors: Thomas J. George, David L. DeRemer, Hiral D. Parekh, Ji-Hyun Lee, Merry Jennifer Markham, Karen Colleen Daily, Frederic J. Kaye, Stephen Staal, Dennie V. Jones, Bruce K. Stechmiller, Carmen Joseph Allegra, Robert A. Hromas
Journal: Journal of Clinical Oncology (2020)

TPS591 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks on treatment. Enrollment continues to a maximum of 47 evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]
Comparison of treatment plans feasible through AI enabled multidisciplinary online tumor board solution versus NCCN-based clinical decision support system (CDSS).
Authors: Bhawna Sirohi, Sushil Beriwal, C. S. Pramesh, Supriya Chopra, Mahesh Goel, Aju Mathew, Vikas S. Ostwal, Durgatosh Pandey, Malolan Sri Rajagopalan, Anant Ramaswamy, Bj Sunil, Rajendra A. Badwe
Journal: Journal of Clinical Oncology (2020)

816 Background: Multidisciplinary tumor boards at Academic Medical Centers (AMC) maximize cancer outcomes. Guidelines based CDSS are alternatives to determine care pathways. Since 2015, 300 AMC cancer experts in USA and India use an AI enabled online tumor board solution, “NAVYA,” to scale low cost access to multidisciplinary expertise, on 1-2 minutes of expert time per decision (ASCO 2017). Methods: GI patients who used NAVYA between 5/1/15-8/31/19 were analyzed. Actionable treatment plans generated by NAVYA were compared to NCCN. Actionable treatment plans include chemotherapy protocols (doses, frequencies), radiation protocols (sites, fractions), etc. Inactionable specialty level decisions (CT-RT vs. surgery) lack specificity. Results: 1302 patients (4638 treatment decisions) were analyzed: 61% (794) male, 80% between age 45 to 75, mostly with Colon, Pancreas, Gallbladder, Rectum, or Stomach cancer; 49.7% non-metastatic. Cohort was comparable to GLOBOCAN estimates. In 82.2% (3812/4638) decisions, NAVYA added value beyond NCCN. First, in 4.5% (212/4638), NAVYA recommended a patient-specific treatment plan that was not part of NCCN. Second, in 3.2% (148/4638), NAVYA recommended treatments plan for clinical scenarios not covered by NCCN, (for eg. 3rd line therapies). Third, in 74.5% (3452/4638), NAVYA used patient specific criteria including resource constraints and patient preference to choose a treatment plan amongst the multiple pathways provided by NCCN and added actionable treatment details. Conclusions: Guideline based CDSS are insufficient to make the vast majority of actionable treatment decisions. Scaling rapid access to multidisciplinary experts is critical. Leapfrogging existing guidelines based CDSS, NAVYA online tumor board makes actionable expert treatment plans possible at a large scale.