tbuckley/cabot-search huggingface dataset:
Neutrophil/lymphocyte ratio (NLR) may predict prognostic factor with gemcitabine/cisplatin/S-1 (GCS) for patients with advanced biliary tract cancer (MITSUBA /KHBO1401-1B).
Authors: Toru Otsuru, Tatsuya Ioka, Hiroaki Nagano, Etsuro Hatano, Hidetoshi Eguchi, Masashi Kanai, Shogo Kobayashi, Satoru Seo, Hideo Baba, Akinobu Taketomi, Kenichi Yoshimura
Journal: Journal of Clinical Oncology (2019)

e15656 Background: There is little information available about prognostic markers of gemcitabine, cisplatin, and S-1 (GCS) in patients with advanced biliary tract cancer (aBTC). Neutrophil/lymphocyte ratio (NLR) in several cancers including aBTC was reported to be a prognostic and/or predictive factor associated with clinical outcomes. There are no data about relation between NLR and clinical outcome in patient with aBTC who underwent GCS. Methods: Baseline demographics and NLR at enrollment were retrospectively evaluated in 119 patients who received GCS treatment in MITSUBA / KHBO1401 randomized phase III trial, which showed significant superiority of GCS to GC. The clinical utility of the NLR was evaluated by receiver operating characteristic (ROC) curves, and the cutoff values for NLR were 3.7. We divided these patients based on estimated NLR, and evaluated the clinicopathological factors and survival in the two groups (NLR ≧ 3.7 or &lt; 3.7). Results: 32 patients were in NLR ≧ 3.7group and 87 patients were in NLR &lt; 3.7 group. The progression-free survival between two groups was not significantly different (p = 0.45). Although, the median overall survival (OS) of NLR ≧ 3.7 group was 10.4 months, while OS of NLR &lt; 3.7 group was 18.5 months (HR 0.55, 95% confidential interval [CI] 0.36-0.87; p = 0.01).The ratio that was able to continue chemotherapy from initial administration six months later was 83.4%of NLR &lt; 3.7 group, and 65.6% of NLR ≧ 3.7 group (p = 0.04). Conclusions: Our study confirmed that high NLR is associated with worse OS, and suggested it may be a predictive marker for GCS chemotherapy in patients with aBTC.
Treatment sequence in elderly metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in a prospective cohort study.
Authors: Maria Jose Mendez-Vidal, Rebeca Lozano, Elena Castro, Nuria Romero-Laorden, Alejo Rodriguez-Vida, Nuria Lainez, Amaia Hernandez, Rosa Villatoro, Francisco Zambrana, Jose Carlos Villa Guzman, Rocío García Domínguez, Saray Galvan Ruiz, Ricardo Escribano, Enrique Gallardo Díaz, Rosa Querol, Raquel Luque, Aránzazu Gonzalez del Alba, Javier Puente, David Olmos, David Lorente
Journal: Journal of Clinical Oncology (2019)

5053 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. SIOG guidelines (Droz, Eur Urol 2017) recommend that fit elderly pts should receive the same treatment as younger patients. Evidence of the optimal treatment sequence in this patient subpopulation is lacking. Methods: We evaluated the outcome of elderly (≥ 75 years [yrs]) pts treated in the prospective PROREPAIR-B cohort study (NCT03075735). We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS) and progression-free survival (PFS) to 1L-therapy following PCWG2criteria. Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included local therapy, Gleason Score, stage IV at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (Hb; ≤LNL), albumin (≤LNL) and ECOG PS. Results: 419 pts were included in the study. Of these, 137 (32,7%) had age ≥ 75 yrs. 48 (35%) received docetaxel and 88 (64.2%) had Abi/Enza as first-line therapy. Of the 121 pts that progressed on 1L-therapy, 30 (24.8%) did not receive 2L therapy. Choice of 2L-therapy was: Doc in 37 (30,6%), Abi/Enza in 38 (31.4%), Cabazitaxel in 9 (7.4%) and Radium-223 in 7 (5.8%) pts. Pts treated with 1L-Doc had higher rates of visceral metastases (22.9% vs 5.7%; p=0.003), high ALP (68.8% vs 43.2%; p=0.004) and low Hb (12.5% vs 3.4%). PFS to 1L-therapy was longer for Abi/Enza than for Doc treated pts (9.6 vs 8.3m; HR: 0.52; p=0.001). The pattern of disease progression (PSA, radiographic, clinical) was similar in Doce and Abi/Enza treated pts. No difference between pts treated with initial Abi/Enza vs Doc was observed in OS (28.2 vs 24.8m; HR:1.18; p=0.474). No significant OS differences were observed in the MV model. Conclusions: No differences in OS were observed between treatment sequences starting with Doc vs Abi/Enza in pts ≥ 75 yrs. Pts treated with 1L-Doc had worse baseline prognostic features. Age should not be considered as a factor for treatment choice in elderly mCRPC pts based on treatment outcome.
Use of machine learning to identify relevant research publications in clinical oncology.
Authors: Fernando Jose Suarez Saiz, Corey Sanders, Rick J Stevens, Robert Nielsen, Michael W Britt, Anita Preininger, Gretchen Jackson
Journal: Journal of Clinical Oncology (2019)

6558 Background: Finding high-quality science to support decisions for individual patients is challenging. Common approaches to assess clinical literature quality and relevance rely on bibliometrics or expert knowledge. We describe a method to automatically identify clinically relevant, high-quality scientific citations using abstract content. Methods: We used machine learning trained on text from PubMed papers cited in 3 expert resources: NCCN, NCI-PDQ, and Hemonc.org. Balanced training data included text cited in at least two sources to form an “on topic” set (i.e., relevant and high quality), and an “off-topic” set, not cited in any of the above 3 sources. The off-topic set was published in lower ranked journals, using a citation-based score. Articles were part of an Oncology Clinical Trial corpus generated using a standard PubMed query. We used a gradient boosted-tree approach with a binary logistic supervised learning classification. Briefly, 988 texts were processed to produce a term frequency-inverse document frequency (tf-idf) n-gram representation of both the training and the test set (70/30 split). Ideal parameters were determined using 1000-fold cross validation. Results: Our model classified papers in the test set with 0.93 accuracy (95% CI (0.09:0.96) p ≤ 0.0001), with sensitivity 0.95 and specificity 0.91. Some false positives contained language considered clinically relevant that may have been missed or not yet included in expert resources. False negatives revealed a potential bias towards chemotherapy-focused research over radiation therapy or surgical approaches. Conclusions: Machine learning can be used to automatically identify relevant clinical publications from biographic databases, without relying on expert curation or bibliometric methods. The use of machine learning to identify relevant publications may reduce the time clinicians spend finding pertinent evidence for a patient. This approach is generalizable to cases where a corpus of high-quality publications that can serve as a training set exists or cases where document metadata is unreliable, as is the case of “grey” literature within oncology and beyond to other diseases. Future work will extend this approach and may integrate it into oncology clinical decision-support tools.
Reply to Takeshi Takahashi's Letter to the Editor re: Bimal Bhindi, Christine M. Lohse, Phillip J. Schulte, et al. Predicting functional outcomes after partial and radical nephrectomy. Eur Urol 2019;75:766–72. Partial Nephrectomy: “Geocentrism” of the 21st century in the Church of Urology?
Authors: Bimal Bhindi, Christine M. Lohse, Phillip J. Schulte, Ross J. Mason, John C. Cheville, Stephen A. Boorjian, Bradley C. Leibovich, R. Houston Thompson
Journal: European Urology (2019)
Supramolecular Nanomachines as Stimuli-Responsive Gatekeepers on Mesoporous Silica Nanoparticles for Antibiotic and Cancer Drug Delivery
Authors: Chi-An Cheng, Tian Deng, Fang-Chu Lin, Yao Cai, Jeffrey I Zink
Journal: Theranostics (2019)

Major objectives in nanomedicine and nanotherapy include the ability to trap therapeutic molecules inside of nano-carriers, carry therapeutics to the site of the disease with no leakage, release high local concentrations of drug, release only on demand - either autonomous or external, and kill the cancer cells or an infectious organism. This review will focus on mesoporous silica nanoparticle carriers (MSN) with a large internal pore volume suitable for carrying anticancer and antibiotic drugs, and supramolecular components that function as caps that can both trap and release the drugs on-command. Caps that are especially relevant to this review are rotaxanes and pseudorotaxanes that consist of a long chain-like molecule threaded through a cyclic molecule. Under certain conditions discussed throughout this review, the cyclic molecule can be attracted to one end of the rotaxane and in the presence of a stimulus can slide to the other end. When the thread is attached near the pore opening on MSNs, the sliding cyclic molecule can block the pore when it is near the particle or open it when it slides away. The design, synthesis and operation of supramolecular systems that act as stimuli-responsive pore capping devices that trap and release molecules for therapeutic or imaging applications are discussed. Uncapping can either be irreversible because the cap comes off, or reversible when the cyclic molecule is prevented from sliding off by a steric barrier. In the latter case the amount of cargo released (the dose) can be controlled. These nanomachines act as valves. Examples of supramolecular systems stimulated by chemical signals (pH, redox, enzymes, antibodies) or by external physical signals (light, heat, magnetism, ultrasound) are presented. Many of the systems have been studied in vitro proving that they are taken up by cancer cells and release drugs and kill the cells when stimulated. Some have been studied in mouse models; after IV injection they shrink tumors or kill intracellular pathogens after stimulation. Supramolecular constructs offer fascinating, highly controllable and biologically compatible platforms for drug delivery.
Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results
Authors: Matthew J. Wieduwilt, Nela Pawlowska, Scott Thomas, Rebecca Olin, Aaron C. Logan, Lloyd E. Damon, Thomas Martin, McNancy Kang, Peter H. Sayre, Wanda Boyer, Karin M.L. Gaensler, Kirsten Anderson, Pamela N. Munster, Charalambos Andreadis
Journal: Clinical Cancer Research (2019)

The histone deacetylase (HDAC) inhibitor panobinostat potentiates anthracycline and cytarabine cytotoxicity in acute myeloid leukemia (AML) cells. We hypothesized that panobinostat prior to and during induction chemotherapy would be tolerable and augment response in patients showing increased histone acetylation.Patients received panobinostat 20-60 mg oral daily on days 1, 3, 5, and 8 with daunorubicin 60 mg/m2/day intravenously on days 3 to 5 and cytarabine 100 mg/m2/day intravenously by continuous infusion on days 3 to 9 ("7+3"). Peripheral blood mononuclear cells (PBMCs) were isolated for HDAC expression and histone acetylation changes.Twenty-five patients ages 60-85 years (median age, 69) were treated. Fifteen patients had de novo AML, six AML with myelodysplasia-related changes, two AML with prior myeloproliferative neoplasm, one therapy-related myeloid neoplasm, and one myelodysplastic syndrome with excess blasts-2. No dose-limiting toxicities occurred in dose escalation cohorts. In dose expansion, six patients received panobinostat at 60 mg and nine patients at 50 mg due to recurrent grade 1 bradycardia at the 60-mg dose. The complete response (CR)/incomplete count recovery (Cri) rate was 32%. Median overall survival was 10 months: 23 months with CR/CRi versus 7.8 months without CR/CRi (log-rank P = 0.02). Median relapse-free survival was 8.2 months. Increased histone acetylation 4 and 24 hours after panobinostat was significantly associated with CR/CRi.Panobinostat with "7+3" for older patients with AML was well tolerated. Panobinostat 50 mg on days 1, 3, 5, and 8 starting 2 days prior to "7+3" is recommended for future studies. Panobinostat-induced increases in histone acetylation in PBMCs predicted CR/CRi.
A non-interventional, multicenter study to assess prevalence of BRCA1 and BRCA2 mutation among ovarian, primary peritoneal, and fallopian tube cancer patients in India.
Authors: Rohit Kodagali, Sudeep Gupta, Senthill J Rajappa, Suresh Hariram Advani, Amit Agarwal, Shyam Aggarwal, Chanchal Goswami, Palanki Satya Dattatreya, Devavrat Arya, Shekhar Patil
Journal: Journal of Clinical Oncology (2019)

e13073 Background: BRCA1 and BRCA2 are tumour suppressor genes. 1,2 Functional BRCA proteins regulate cell growth and prevent abnormal cell division that might lead to tumour development. Approximately 17% (Range 3 – 27 %) of ovarian cancer patients worldwide have a BRCA mutation. 3 This study aimed to estimate the prevalence of germline BRCA mutations among previously and newly diagnosed ovarian, primary peritoneal or fallopian tube cancer patients in India. Methods: This is a non-interventional, cross-sectional, multicenter, prospective, observational study conducted at 15 sites from different geographical regions across India. The study targets to enroll 240 patients over 6 months. The calculated sample size for this study is 228, assuming 5 % precision and a dropout rate of 10 %. The study enrolled females with new or previous diagnosis of ovarian, primary peritoneal, or fallopian tube cancer. No study medication was administered as a part of study procedure. Results: In the interim analysis performed on the first 100 enrolled patients, 22% of Ovarian, primary peritoneal or fallopian tube cancer patients were found to be BRCA1/BRCA2 mutation positive (CI 0.1433-0.3139). 52% of these enrolled patients were found to have serous histopathology, 23.1% of which were found to be BRCA1/2 positive. The percentage of BRCA1/2 mutation status in patients who had a family history of ovarian or breast cancer was found to be 66.7% and 62.5% respectively. Conclusions: In this study, the prevalence of BRCA1 and BRCA2 mutations among patients with ovarian, primary peritoneal and fallopian tube cancer patients in the first 100 patients enrolled was found to be 22%. References: 1. Vos S, et al. Crit Rev Oncol Hematol. 2018 Jul;127:29-41; 2. Solodskikh SA et al. Mutat Res. 2019 Jan;813:51-57; 3. Alsop K, et al. J Clin Oncol. 2012;30(21):2655-2663.
Asymptomatic versus symptomatic metastatic breast cancer: Potential effects on prognosis and treatment strategies.
Authors: Sayaka Kuba, Kosho Yamanouchi, Shigeto Maeda, Hiroshi Yano, Shigeki Minami, Hiroki Moriuchi, Megumi Matsumoto, Ryota Otsubo, Michi Morita, Chika Sakimura, Eiko Inamasu, Junzo Yamaguchi, Kengo Kanetaka, Mitsuhisa Takatsuki, Takeshi Nagayasu, Susumu Eguchi
Journal: Journal of Clinical Oncology (2019)

e12568 Background: Early breast cancer (BC) patients in Japan can receive a follow-up CT scan, which can diagnose asymptomatic metastatic (M)BC. How symptomatic and asymptomatic MBC differ regarding prognosis and whether treatment strategies should differ is unclear. Methods: A retrospective, multicenter, cohort study was performed. We reviewed records of MBC women treated at four institutions between 2008 and 2018. Follow-up CTs were not routinely performed. Patients were divided into three BC subtypes: Luminal (ER+, PgR+, or both, but HER2-), HER2 (HER2+), and triple negative (TN) (ER-, PgR-, HER2-). Results: Of 205 MBC patients, 120 were luminal, 51 HER2, and 34 TN. Ninety were diagnosed with symptomatic and 115 with asymptomatic MBC. Symptomatic MBC patients had the following symptoms: locoregional metastasis (43%), bone pain (25%), cough or dyspnea (16%), and brain-related symptoms (10%). Diagnosis of asymptomatic MBC was based on follow-up imaging (71%) and elevated tumor markers (27%). The proportion of the patients with symptomatic MBC were different in each subtype: 38% luminal, 45% HER2, and 65% TN (p = 0.02). Among luminal patients, median overall survival (OS) after metastasis was longer for those with asymptomatic versus symptomatic MBC (62 vs 41 M, respectively; p = 0.04), although disease-free interval (48 vs 54 M, respectively; p = 0.40) and OS after breast surgery (119 vs 126 M, respectively; p = 0.93) did not differ significantly. Conversely, among TN patients, those with asymptomatic MBC had significantly longer median OS after metastasis and after breast surgery. Although the median period of cumulative endocrine therapy after metastasis did not differ between groups, luminal BC patients with asymptomatic MBC received chemotherapy longer than those with symptomatic MBC (20 vs 12 M, respectively; p = 0.02). Most patients switched to chemotherapy because of endocrine resistance without life threatening disease. To diagnose asymptomatic MBC might lead to longer use chemotherapy. Conclusions: Physicians should take symptomatic versus asymptomatic MBC into consideration in predicting prognosis to optimize treatment strategies.
O-GlcNAc modification of Sox2 regulates self-renewal in pancreatic cancer by promoting its stability
Authors: Nikita S Sharma, Vineet K Gupta, Patricia Dauer, Kousik Kesh, Roey Hadad, Bhuwan Giri, Anjali Chandra, Vikas Dudeja, Chad Slawson, Santanu Banerjee, Selwyn M Vickers, Ashok Saluja, Sulagna Banerjee
Journal: Theranostics (2019)

Pancreatic adenocarcinoma (PDAC) claims more than 90% of the patients diagnosed with the disease owing to its aggressive biology that is manifested by high rate of tumor recurrence.Aberrant upregulation in the transcriptional activity of proteins involved in self-renewal like Sox2, Oct4 and Nanog is instrumental in these recurrence phenomena.In cancer, Sox2 is aberrantly "turned-on" leading to activation of downstream genes those results in relapse of the tumor.Molecular mechanisms that regulate the activity of Sox2 in PDAC are not known.In the current study, we have studied the how glycosylation of Sox2 by O-GlcNAc transferase (OGT) can affect its transcriptional activity and thus regulate self-renewal in cancer.Methods: RNA-Seq analysis of CRISPR-OGTi PDAC cells indicated a deregulation of differentiation and self-renewal pathways in PDAC.Pancreatic tumor burden following inhibition of OGT in vivo was done by using small molecule inhibitor, OSMI, on subcutaneous implantation of PDAC cells.Sox2 activity assay was performed by Dual Luciferase Reporter Assay kit.Results: Our study shows for the first time that in PDAC, glycosylation of Sox2 by OGT stabilizes it in the nucleus.Site directed mutagenesis of this site (S246A) prevents this modification.We further show that inhibition of OGT delayed initiation of pancreatic tumors by inhibition of Sox2.We also show that targeting OGT in vivo with a small molecule-inhibitor OSMI, results in decreased tumor burden in PDAC.Conclusion: Understanding this mechanism of SOX2 regulation by its glycosylation is expected to pave the way for development of novel therapy that has the potential to eradicate the cells responsible for tumor-recurrence.
Phase I-II open label multicenter study of PD0332991 in <i>BRAF<sup>V600mut</sup></i> metastatic melanoma patients harboring <i>CDKN2A</i> loss and RB1 expression and treated with vemurafenib.
Authors: Baptiste Louveau, Matthieu Resche-Rigon, Thierry Lesimple, Marc Pracht, Barouyr Baroudjian, Julie Delyon, Fanelie Jouenne, Mona Amini-Adle, Caroline Dutriaux, Laetitia Da Meda, Zineb Ghrieb, Didier Bouton, Annick Tibi, Samuel Huguet, Keyvan Rezai, Maxime Battistella, Samia Mourah, Celeste Lebbe
Journal: Journal of Clinical Oncology (2019)

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAF V600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.
Variations in patient-reported outcome (PRO) collection and reporting in novel FDA approved anticancer therapies.
Authors: Surbhi Singhal, Evan Thomas Hall, Brooke Peterson Gabster, James Dickerson, Lidia Schapira
Journal: Journal of Clinical Oncology (2019)

e18202 Background: Patient-reported outcomes (PROs) are increasingly valued as a key tool in patient-focused treatment decisions. However, a lack of standardization leads to significant variability in PRO collection and reporting in ground-breaking clinical trials of novel agents. We sought to characterize the mechanisms of assessment and variability by which PROs are reported for newly approved anti-cancer therapies. Methods: We reviewed the U.S. Food and Drug Administration (FDA) approvals between 2011 and 2017 for anti-cancer new molecular entities (NMEs) and new biologic approvals (BLAs). For each therapy, the pivotal clinical trial leading to FDA approval was identified using the national clinical trial (NCT) number and assessed for inclusion of PROs. A separate PubMed search was conducted to evaluate for PRO publication distinct from the original trial based on national clinical trial registry number. Results: From 2011 to 2017, the FDA approved 66 NMEs/BLAs based on 74 clinical trials for cancer treatment. Of the 74 clinical trial publications, 21 (28%) of the trials published PRO data in their original clinical publication, 18 (24%) published a separate PRO analysis, and 35 (47%) did not publish PRO data in either format. Among the 32 clinical trials (43%) that listed PROs as pre-specified outcomes, 72% published PROs (23/32). The separate PRO analyses (N = 18) were published considerably later following FDA approval (mean 605 days) than the original clinical trials (mean 20 days, N = 74, P &lt; 0.001). Conclusions: As cancer treatment options expand, therapy decisions become increasingly nuanced. PROs assist decision-making by providing detailed information on important aspects of quality of life and tolerability. Our research has identified a significant lag in the publication of companion studies of PRO data associated with pivotal clinical trials, representing a meaningful gap in information critical to patients and oncologists in the process of making informed decisions.