tbuckley/cabot-search huggingface dataset:
Specific clonal expansion at disease progression (PD) in solid cancers pinpointed by cell free DNA analysis.
Authors: Elisa Frullanti, Maria Palmieri, Margherita Baldassarri, Francesca Fava, Alessandra Fabbiani, Elisa Gelli, Rossella Tita, Pamela Torre, Roberto Petrioli, Theodora Hadijstilianou, Daniela Galimberti, Elisa Cinotti, Maria Antonietta Mencarelli, Anna Maria Pinto, Edoardo Francini, Stafania Marsili, Guido Francini, Alessandra Renieri
Journal: Journal of Clinical Oncology (2019)

e13144 Background: More than 50% of solid cancers sooner or later escape control of standard treatments. Detection and analysis of cell free circulating DNA (cfDNA) now offer the possibility to detect key mutations of cancer driver genes which may play a major role in the therapy escaping mechanism. We sought to identify clones of solid tumors escaping standard treatments in order to assess personalized treatment at PD. Methods: A cohort of patients with 10 different solid tumors progressing after standard therapy were selected. CfDNA analysis was performed using PAXgene blood ccfDNA tubes (QIAGEN), MagMAX cell-free total nucleic acid isolation kit, and ION PROTON platform (ThermoFisher Scientific). Results: Next generation sequencing analysis of 52 cancer-driver genes of cfDNA samples of 39 patients allowed for picking up clones plausibly involved in the PD mechanism in 60% of cases. A mean of 1.3 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and CNV in FGFR3 were the most commonly observed, with a rate of 41%, 16%, and 13%, respectively. Increased copy number variations of FGF receptors were identified in patients with non-small cell lung, pancreatic, and gastric cancer, and cholangiocarcinoma. Other clones had mutations in ESR1 (breast), CTNNB1 (uterus), KRAS and CCND2 (pancreas), EGFR and BRAF (lung). Interestingly, retinoblastomas resistant to Melphalan showed expanding mutated clones in PTEN or SMAD4. Increased levels of cfDNA were observed in the plasma of all patients. Conclusions: The results presented here show that irrespective of the primary tumor mutational burden and subsequent complex clonal evolution, a simplified mutational load is present at PD. One or few “sniper” clones drive progression and the molecular profile has a weak correlation with the primary tumor. Single driver mutations in TP53 remain the main target of a not yet developed specific therapy in most tumors such as breast, ovarian, uterine, lung, gastric cancers and glioblastoma. Among the actionable mutations, PIK3CA were found, not only in breast cancers, but also in uterine carcinoma, Sezary syndrome and glioblastoma, pinpointing the needs of specific trials in these tumors.
Survivorship care: Improving delivery of care plans for hematology patients at the Washington Cancer Institute (WCI).
Authors: Hira Latif, Maya Beplat, Prabhjyot Singh, Asma Ali Dilawari
Journal: Journal of Clinical Oncology (2019)

6605 Background: Cancer and long-term sequalae of its treatment impact the future health and psychosocial wellness of these survivors. ASCO guidelines recommend providing survivorship care to cancer patients who have completed treatment with curative intent. The Commission on Cancer (COC) recommends that survivorship care including treatment summaries be delivered to 50% of eligible patients. In our ASCO Quality Training Program project, we aimed to achieve this COC goal of 50% for the year 2018. Methods: Baseline data collected from Jan 1, 2016 to June 30, 2018 indicated that 33% of hematologic malignancy survivors at WCI received treatment summaries and survivorship care. For the year 2018, there were 11 survivors of hematologic malignancy, and 4 of them (36%) had received survivorship care prior to initiation of the project. We surveyed 12 providers to obtain data for perceived challenges to deliver survivorship care. Large volume of patients, lack of resources, no standardized process and high no-show rates were identified as the most important barriers. A bi-monthly survivorship clinic run by hematology/oncology fellows was initiated in September 2018 to address some of these barriers. Patient referral forms were mounted in the clinic work rooms to assist providers with identifying patients that qualify for survivorship; a pathway for referrals to the survivorship clinic was created and providers were informed about the clinic. Information flyers regarding survivorship care and the clinic were placed in the waiting room to increase awareness amongst patients. Results: By November 30, 2018, 63% of hematological cancer survivors received survivorship care and treatment summaries. Compared to the average from the preceding two years, survivorship care delivery increased by 30%. Conclusions: Our institution was able to meet the COC requirement by delivering survivorship care to 63% of survivors of hematological malignancies through the intervention from this quality improvement study. We intend to extend this process to other tumor types to increase the delivery of consolidated survivorship care at the WCI.
Characterization of temporal relationships of comorbidities developed following cancer diagnoses in veterans.
Authors: Julian C. Hong, Elizabeth R. Hauser, Thomas S. Redding, Kellie J. Sims, Ziad F Gellad, Meghan O'Leary, Ashton Madison, Xuejun Qin, David G. Weiss, A Jasmine Bullard, Christina D. Williams, Brian Sullivan, David A. Lieberman, Dawn T. Provenzale
Journal: Journal of Clinical Oncology (2019)

e18049 Background: Understanding patient trajectories and common sequences of comorbidity accrual among those newly diagnosed with cancer is critical for precision approaches to care and prevention. The Veterans Affairs (VA) Cooperative Studies Program (CSP) #380 cohort includes 3,121 healthy asymptomatic veterans who underwent screening colonoscopy and were followed for at least ten years. The current analysis leverages computational approaches to characterize the temporal relationships of diagnoses in CSP #380 participants following diagnosis of colorectal or other cancers. Methods: Patients enrolled in CSP #380 with at least 5 years of linked electronic health record data from the VA Corporate Data Warehouse (October 1999-December 2015) were included. Cancer diagnoses and their most common subsequent new diagnoses were identified per patient by the first instance of each three-digit ICD-9 diagnosis affecting at least 50 patients. Pairwise chronological relative risks (RR) between subsequent diagnoses were represented as a directed network graph, which maps the probability of developing a diagnosis following a prior diagnosis. Results: A total of 2,210 patients were included. The most common cancer diagnoses were prostate (436), thoracic (169), bladder (120), colon (72), and kidney cancers (65). Most first diagnoses following a cancer diagnosis were related to progressive cancer or acute/subacute treatment toxicity. For prostate cancer, comorbidities with greatest RR were carcinoma in situ (RR 6.85), unspecified (NOS) metastases (2.75), and urethral stricture (2.53). For lung cancer, they were metastases of respiratory and digestive sites (12.24), lymph nodes (6.47), and NOS (5.68), pneumothorax and air leak (4.16), and convalescence and palliative care (3.07). In bladder cancer, they were carcinoma in situ (9.00), cystitis (6.78), kidney or other urinary cancer (6.19), attention to artificial openings (3.40), and urethral stricture (2.78). These and other results were visualized with network graphs. Conclusions: Computational techniques can identify and visualize future health concerns following cancer diagnoses. In this cohort of initially healthy and asymptomatic veterans on a prospective screening colonoscopy study, most subsequent diagnoses were related to cancer or toxicities of therapy, as might be expected in an aging cohort. Future work may focus on streamlining in-clinic identification of potential high likelihood comorbidities.
Confirmation of germline variants identified by tumor testing: A population-based study.
Authors: Alexandra Pender, Aly Karsan, Stephen Yip, Ian Bosdet, Sean Young, Tracy Tucker, Kasmintan A Schrader, Sophie Sun
Journal: Journal of Clinical Oncology (2019)

e13021 Background: Multi-gene panel tumour testing (TT) has been available in British Columbia since mid-2016 for metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), melanoma (MEL), low-grade glioma (LGG), and gastro-intestinal stromal tumours (GIST). TT can detect somatic driver mutations and potential pathogenic germline variants (pPGVs) associated with hereditary cancer susceptibility. We reviewed the frequency of pPGVs identified by TT and examined referral rates to the Hereditary Cancer Program (HCP) for confirmatory germline testing (GT) and therapeutic implications of PGV findings. Methods: All patients (pts) undergoing TT testing from October 1, 2016 to December 31, 2018 were identified. Diagnosis, age, gender, family history and treatment data were obtained. TT was performed by next-generation sequencing for all/selected regions of the following genes: AKT1, ALK, BRAF, BRCA1, BRCA2, CCND1, CCND3, CIC, EGFR, ERBB2, ERBB3, FUBP1, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, ROS1, SDHA, SDHB, SDHC, SDHD. Results: Among 2937 TTs, pPGVs were identified in 83 pts (2.8%) [Table 1]. 50 pts (57%) were referred to HCP, 41 had germline testing, and 14 PGV were confirmed. PGVs were most commonly identified in BRCA1/2 and SDHA and these findings did not influence oncologic treatments. Conclusions: TT detected pPGVs in 2.8% of unselected pts with metastatic cancers. Among 41 pts undergoing germline testing, 34% who would not have otherwise met testing criteria, had a confirmed PGV. Referral rates were low due to lack of patient and clinician awareness and poor health status. Although PGV findings did not directly impact treatment, TT identified 14 new families with hereditary cancer who can benefit from early detection and screening. Future directions include expansion of TT to include additional hereditary cancer susceptibility genes and development of digital tools for pts and clinicians. [Table: see text]
Subcutaneous nicotine delivery via needle-free jet injection: A porcine model
Authors: Bryan P. Ruddy, Chris Bullen, Joanna Ting Wai Chu, Soo Hee Jeong, Bahareh Madadkhahsalmassi, James W. McKeage, Darren Svirskis, Malcolm D. Tingle, Jiali Xu, Andrew J. Taberner
Journal: Journal of Controlled Release (2019)
Case 1-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Joseph M. Mirra, Alan L. Schiller
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 67-year-old man was admitted to the hospital because of progressive weakness of the legs.Ten years earlier, after a fall, x-ray films of the pelvis showed Paget's disease. The patient was free of symptoms until six years before admission, when he noticed a mass in the right buttock that slowly enlarged; pain developed in the mass and radiated down both legs to the knees. He was seen at another hospital, where a biopsy of the mass was reported to show only Paget's disease. An unknown medication was administered, without effect.Four years before entry he was . . .
A general approach to optimizing tumor treating fields therapy.
Authors: Zeev Bomzon, Noa Urman, Hadas Sara Hershkovich, Eilon David Kirson, Ariel Naveh, Reuven Shamir, Eduard Federov, Cornelia Wenger, Uri Weinberg
Journal: Journal of Clinical Oncology (2019)

e14668 Background: Tumor Treating Fields (TTFields) are alternating electric fields used to non-invasively treat cancer. TTFields are delivered via transducer arrays placed on the skin close to the tumor. Post-hoc analysis [1] has shown that delivering higher field power to the tumor and increasing usage (percent of time patient is actively treated) improve patient survival. Thus, optimizing the position of arrays to maximize TTFields power at the tumor could improve survival. At the same time, minimizing the array area to maximize patient comfort and consequently maximizing usage is also likely to improve survival. However, optimizing TTFields delivery is non-trivial since the field distribution is influenced by array positioning and geometry, the anatomy of the patient and the heterogeneous electric properties of different tissues. Here we present a general approach to optimizing Tumor Treating Fields using numerical simulations. Methods: Delivery of TTFields to the brains, lungs and abdomens of realistic computational models was investigated. The effect of the transducer array size and position on the field distribution within the phantoms was analyzed, and an approach for optimizing TTFields delivery developed. Results: Field power is generally highest in the region between the arrays, with larger arrays generally delivering higher field power. Anatomical features such as bones, the spine or a resection cavity significantly influence the field within this region. A general approach to optimizing TTFields delivery is: Maximize field power by using the largest arrays possible. To maximize patient comfort, array size are chose so that significant portions of the skin in the region of disease are not covered by the arrays. Place virtual arrays on a realistic computational model of the patient such that the tumor is located between them and simulate TTFields delivery to the patient. Apply an iterative algorithm to shift the arrays around their initial positions until field power in the tumor bed is maximized. Conclusions: We have developed a general approach to optimizing delivery of TTFields to the tumor. Effective TTFields treatment planning is expected to improve patient outcome. [1] Ballo et. al., submitted to RED Journal 2018.
Development and validation of a prediction-score model for distant metastases in major salivary gland carcinoma.
Authors: Jelena Lukovic, Fatima Alfaraj, Michelle Lynn Mierzwa, Gustavo Nader Marta, Wei Xu, Jie Su, Fabio Ynoe de Moraes, Shao Hui Huang, Scott Victor Bratman, Brian O'Sullivan, John Kim, Jolie Ringash, John Waldron, John R. de Almeida, David Paul Goldstein, Andrew Rosko, Mathew E Spector, Luiz Paulo Kowalski, Andrew Hope, Ali Hosni
Journal: Journal of Clinical Oncology (2019)

6085 Background: We developed and validated a prediction-score for distant metastases (DM) in major salivary gland carcinoma (SGC). Methods: Patients with SGC treated with curative-intent surgery +/- postoperative radiation therapy (PORT) at 4 tertiary cancer centers were divided into discovery (institution A&amp;B) and validation (institution C&amp;D) cohorts. Multivariable analysis using competing risk regression was used to identify predictors of DM in the discovery cohort and create a prediction score. The optimal score cut-off for high vs low-DM risk was determined using a minimal p-value approach. The results were subsequently evaluated in the validation cohort. The cumulative incidence and Kaplan-Meier methods were used to analyze DM and overall survival (OS), respectively. Results: Overall, 1035 patients were included (Table). In the discovery cohort, DM predictors (risk score coefficient) were: positive margin (0.6), pT3-4 (0.7), pN+ (0.7), lymphovascular invasion (LVI; 0.8), and high risk histology* (1.2). High DM-risk SGC was defined by sum of coefficients greater than 2. In the discovery cohort, the 5-year cumulative incidence of DM for high vs low risk SGC was 50% vs 8%; p &lt; 0.01; these results were similar in the validation cohort (44% vs 4% at 5 years; p &lt; 0.01). In the combined cohorts, this model predicted distant-only failure (40% vs 6%, p &lt; 0.01) and late ( &gt; 2yr post surgery) DM (22% vs 4%; p &lt; 0.01). Patients with high DM-risk SGC had an increased incidence of DM in the subgroup receiving PORT (46% vs 8%; p &lt; 0.01) or concurrent chemotherapy (71% vs 34%; p &lt; 0.01). The 5-yr OS for high vs low risk SGC was 48% vs 92% (p &lt; 0.01). Conclusions: This validated prediction score model may be used to identify SGC patients at increased risk for DM and select those who may benefit from prospective evaluation of treatment intensification and/or surveillance strategies. Baseline characteristics. [Table: see text]
Investigation of enhanced antitumor effects via co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR signaling pathways in human gastric cancer.
Authors: Moon Young Choi, Min-Hee Cho, Hye Jung Chang, Soon-Nam Lee, Kyoung Eun Lee
Journal: Journal of Clinical Oncology (2019)

e15553 Background: Gastric cancer, a highly aggressive malignancy, frequently recurs despite curative surgery and metastasizes to lymph node and distant sites. Epithelial-mesenchymal transition (EMT) is the main phenomenon of cancer progression, including invasion and metastasis. It is regulated by crosstalks between diverse intracellular signaling pathways such as Wnt/β-catenin and phosphatidylinositol-3-kinase(PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways. Here, this study elucidated the effects of co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways on gastric cancer. Methods: It is known that Wnt/β-catenin signaling pathways are constitutively activated in two of gastric cancer cell lines, AGS and MKN-28. ICG-001 (β-catenin transcription inhibitor) and rapamycin (mTOR inhibitor) were used for dual blockade, and then the combinatory effects were examined. Results: As a result, both cell lines were significantly affected by the β-catenin transcription inhibitor, ICG-001, and addition of the mTOR inhibitor, rapamycin induced marginal inhibitory effects on cancer cell proliferation and target gene expression. In addition, invasive activity was 62.3 ± 15.7% and 53 ± 14.4% inhibited by single treatment, but it was 79 ± 13.3% inhibited by co-treatment. Moreover, migratory activity was 33 ± 13%, 42 ± 9% inhibited by single treatment, but it was 82 ± 4% by co-treatment. Interestingly, Snail, one of the important regulatory protein during EMT process, was significantly decreased by co-treatment. Conclusions: Taken together, these results suggest that co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways could effectively enhance antitumor effects on gastric cancer via the inhibition of invasion and migration as well as decrease of Snail expression.
Prediction of trifluridine/tipiracil (TAS-102) effectiveness in patients with refractory metastatic colorectal cancer (mCRC): Real-life data from the Czech Republic.
Authors: Peter Grell, Josef Dvorak, Michal Vocka, Stanislav John, Helena Tuskova, Tomas Buchler, Simona Borilova, Iveta Selingerova, Rostislav Vyzula, Lubos B. Petruzelka, Igor Kiss, Radka Obermannova
Journal: Journal of Clinical Oncology (2019)

e15102 Background: TAS-102 is effective in refractory mCRC and significantly improved survival versus placebo. Currently no predictive biomarkers are established and used in clinical practice. Methods: We analyzed data of 160 patients treated with TAS-102 in real clinical practice in Czech Republic. Different factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated. Results: Baseline patients’ characteristics: median age 66 years (range 28-83), 106 patients were male (66.3 %), ECOG PS 0 had 38.1 %, RAS wt 45 %. Anti-VEGF treatment had 83.1 %, anti-EGFR 43.8 %. Median number of TAS-102 treatment line was 3 (range, 2 – 8), median TAS-102 cycles 3 (range 1 – 27). At the time of analysis 15 % continued in treatment, 73.7 % discontinued due to progression, 6.9 % due to toxicity, 3.8 % decided to discontinue in treatment. Median PFS was 3.3 months (95% CI, 3.0 – 3.5), and median OS 10.2 months (95% CI, 8.9 – 11.8). Factors significantly associated with PFS and/or OS were: PS, time from diagnosis of mCRC, initiation of TAS-102 treatment &gt; 3 months from last fluoropyrimidine, baseline CRP, WBC, neutrophils count, monocytes count, NLR, neutropenia ≥ G2, diarrhea ≥ G1, thrombocytopenia ≥ G2, required TAS-102 dose reduction and cycle delay. We developed a scoring system TAScore from factors at the beginning of treatment (PS 0, initiation of TAS-102 &gt; 3 months from fluoropyrimidine, time from diagnosis of mCRC, baseline CRP, WBC, monocytes count &lt; 0.5 × 10 9 /L). For each factor patient received 1 point, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS according to risk group was: 5.7 months for high risk (11 patients), 8.7 for intermediate (63), 12.8 for favorable (59) (P &lt; 0.0001). TAScore was also associated with PFS: 2.4 months for high risk, 2.9 intermediate and 3.9 for favorable risk group (P &lt; 0.0001). Conclusions: TAS-102 is effective in patients with refractory mCRC. We propose simple scoring system TAScore to help with precise patient selection at the beginning of TAS-102 treatment.
New hypertension guidance has major implications for countries with low resources
Authors: Nadarajah Sreeharan, T Kumanan, K Sujanitha, M Guruparan
Journal: BMJ (2019)

Haase and colleagues discuss the dangers of overdiagnosis and overtreatment that may result from lowering the 10 year cardiovascular risk in patients with stage 1 hypertension.1 The National Institute for Health and Care Excellence guidance takes a more pragmatic approach in retaining the threshold for diagnosis and target for treatment at a clinic blood pressure …
Hypermetabolic activity by FDG-PET after immunogenic chemotherapy and multi-peptide immunotherapy in ovarian cancer.
Authors: Juan Pablo Marquez-Manriquez, Pedro Alejandro Lucero-Diaz, Alberto Durazo, Jose Antonio Matute-Briseno, Dolores Gallardo-Rincon, Mario ALBERTO Perez-Astorga, Michelle ANTONIA Gutierrez-Marquez, Alejandro Camacho-Hernandez
Journal: Journal of Clinical Oncology (2019)

e17079 Background: There are several reports of increased of SUV in the lymph nodes of cancer patients after immune manipulation such as the administration of vaccines and checkpoint inhibitors. However the clinical importance of these phenomena is poorly understood. The administration of two immunogenic drugs and eight peptides in HGSOC induced atypical bright zones in multiple lymph nodes and, in areas with microscopic disease where potentially we can have cancer stem cells (CSC’s). Methods: We enrolled N = 10 HGSOC after the local IRB ethic committee approval. All the patients had 3 recurrences with mPFS = 8 months of the third relapse. The last FDG-PET scan was used as basal image for the study. Blood was collected for cellular and humoral immunology analysis such as Granzyme B ELISPOT and ELISA. Tissue was used for IHC analysis for the evaluation of CD8, FOXP3, Th1, and proteins related with CSC’s. The patients received 50 mg of oxaliplatin and 30 mg of doxorubicin total dose every week four times simultaneously with multi peptide immunotherapy. A second FDG-PET scan was performed after the termination of the treatment. Results: After the treatment 100% of the patients showed intense atypical bright uptake areas in lymph nodes and in the peritoneum. There was a correlation between the brightness intensity (SUV), and the Granzyme B production (p = 0.001). We found multiple bright small lesions in the peritoneum that were not visible before treatment. We demonstrated the presence of proteins related with CSC’s in the original tumor tissue and an antibody immune response against EGFR (P = 0.005), Ape-1 (p = 0.003) and Bcl-2 (p = 0.05). Conclusions: Immunotherapy may produce hypermetabolic activity that could lead to overtreatment when evaluated by FDG-PET in HGSOC. Vaccination may activate lymph nodes and anti-cancer immune interventions may also activate CD8 and Th1 cells able to accumulate in CSC’s clusters and increased notably the SUV, which may lead to false relapse interpretation by the radiologists and oncologists.