tbuckley/cabot-search huggingface dataset:
The prognostic impact of level I lymph node involvement in oropharyngeal squamous cell carcinoma.
Authors: Roy Xiao, Matthew C Ward, Kailin Yang, David J. Adelstein, Shlomo A. Koyfman, Brandon Prendes, Brian Burkey
Journal: Journal of Clinical Oncology (2018)

6072 Background: Current staging for oropharyngeal squamous cell carcinoma (OPSCC) may not capture the implications of regional lymph node involvement (LNI). We investigated the impact of level I LNI on survival for patients with OPSCC. Methods: We used the National Cancer Database for a cohort study of patients with OPSCC who underwent surgical resection from 2010-2014. The primary outcome was level I LNI, modeled by multivariable logistic regression. Overall survival (OS) was modeled by Cox proportional hazards regression. Results: Among 7,231 patients with OPSCC, 1,061 (14.7%) had level I LNI. Most patients had pT1 (3,412, 47.2%) or pT2 (2,860, 39.6%) tumors with pN2 (5,482, 75.8%) lymph node stage by AJCC 7th Edition. Independent predictors of level I LNI included higher pT stage (pT3 v. pT1, OR 1.82, 95% CI 1.44-2.31; pT4 v. pT1, OR 2.92, 95% CI 2.28-3.75) and higher number of positive regional lymph nodes (OR 1.06, 95% CI 1.05-1.08). Among included patients, 5,543 had known survival status. Level I LNI was a significant predictor of inferior OS (HR 1.83, 95% CI 1.56-2.15) after adjusting for covariates. Subset analysis by pT and pN stage revealed level I LNI to be a consistent predictor of OS for pN2 patients regardless of pT stage (Table 1). For patients with confirmed HPV status, level I LNI significantly predicted OS among HPV(-) patients (N = 888, HR 1.99, 95% CI 1.43-2.74) but not among HPV(+) patients (N = 2,339, HR 1.38, 95% CI 0.89-2.05). Level I LNI remained a significant predictor of OS within additional analyses subset by age, Charlson/Deyo Comorbidity Score, number of positive regional lymph nodes, and adjuvant treatments. Conclusions: Level I lymph node involvement in OPSCC is a significant and independent predictor of mortality. Patients with HPV(-) OPSCC and level I LNI may warrant intensified therapies. Adjusted hazard ratio of mortality for level I nodal involvement subset by pT/pN. Stage: pN1 pN2 N HR (95% CI) p-value N HR (95% CI) p-value pT1 685 0.94 (0.46-1.95) 0.877 1,906 1.80 (1.22-2.66) 0.003* pT2 512 1.76 (0.97-3.19) 0.064 1,678 1.91 (1.42-2.57) <0.001* pT3 109 3.64 (1.31-9.84) 0.014* 338 1.92 (1.19-3.03) 0.008* pT4 76 1.72 (0.58-4.74) 0.315 239 2.03 (1.34-3.03) <0.001* *Statistically significant, p<0.05
Cardiotoxicity of tyrosine kinase inhibitors among veterans diagnosed with renal cell carcinoma.
Authors: Kristine E. Lynch, Julie Ann Lynch, Olga Efimova, Jiwon Chang, Brygida Berse, Donna Rivera, Daniel Jacob Becker, Scott L. DuVall, Kelly Kristin Filipski
Journal: Journal of Clinical Oncology (2017)

e18248 Background: Renal cell carcinoma (RCC) accounts for 3% of cancers diagnosed in the Department of Veterans Affairs (VA). Each year, 15% of the 1,600 veterans diagnosed with RCC have advanced disease. Until a decade ago, there were few non-surgical treatments for advanced RCC. Approval of multi-targeted tyrosine kinase inhibitors (TKIs), sorafenib, sunitinib, and pazopanib significantly improved outcomes for patients. However, several studies demonstrated increased risk of congestive heart failure, stroke, and thromboembolic events in patients treated with TKIs. We sought to understand whether veterans, who have a high prevalence of comorbidities, have increased risk of cardiac events following TKI treatment. Methods: This was a retrospective study of patients diagnosed with advanced RCC from 2006 to 2015. The outcome variable was whether the patient had congestive heart failure, cardiomyopathy, acute myocardial infarction, stroke, or cardiovascular related death after initiation of at least one TKI. Clinical, demographic, and pharmacy data came from the VA Central Cancer Registry and Corporate Data Warehouse. Patient characteristics across treatments were evaluated using chi square tests, t-tests and ANOVAs, as appropriate. We used multivariate logistic regression to determine the likelihood of cardiac event in patients treated with TKIs. Results: We identified 3,510 patients eligible for treatment who did not have a prior cardiac event. Overall, 1,840 patients were treated with at least one TKI prior to any cardiac event: 953 (27.1%) were treated with only sunitinib, 179 (5.1%) with sorafinib, 289 (8.2%) with pazopanib, and 419 (11.9%) treated with a combination. There were 909 who had a cardiac event (25.9% of all patients). Only 259 (28.49%) were treated with a TKI. On multivariate analysis, statistically significant predictors of a cardiac event were having diagnoses of dyslipidemia (Odds ratio [OR] 2.1, 95% confidence interval [CI] 1.7-2.5) or diabetes (OR 1.5, 95% CI 1.3-1.8). Patients treated with TKIs had a lower likelihood of a cardiac event (OR 0.3, CI 0.2-0.3). Conclusions: Among veterans, treatment with TKIs do not pose as great a risk for cardiac events as underlying comorbid diagnoses.
TCT-727 Relevance of type and dose of beta-blockers in prognosis among patients with ischemic heart disease: Data from GRAND-DES Registry
Authors: Jiesuck Park, Jung-Kyu Han, Jeehoon Kang, Han-Mo Yang, Kyung Woo (KW) Park, Hyun-Jae Kang, Bon-Kwon Koo, Hyo-Soo Kim
Journal: Journal of the American College of Cardiology (2018)
Pancreatitis: summary of NICE guidance
Authors: Eleanor Samarasekera, Shama Mahammed, Sophie Carlisle, Richard Charnley
Journal: BMJ (2018)

### What you need to know

Pancreatitis can severely reduce quality of life and may reduce life expectancy.12 Acute and chronic pancreatitis are characterised by inflammation of the pancreas, and table 1 outlines their features. Acute pancreatitis can recur if the cause is not identified and addressed. Over time, such patients may develop chronic pancreatitis. In its early stages this is characterised by acute exacerbations but also chronic pain, along with exocrine insufficiency, associated with fat malabsorption and malnutrition. Diabetes is also common. As chronic pancreatitis progresses, patients tend to experience fewer exacerbations but more chronic pain.

View this table:

Table 1 
Features of acute and chronic pancreatitis



Specialists almost always manage acute pancreatitis because it is an acute abdominal emergency requiring hospital admission. However, non-specialists, including those in primary care, may be the first clinicians to identify chronic pancreatitis. Non-specialists may also manage and monitor symptoms including pain, endocrine and exocrine insufficiency, and make appropriate referrals.

Interventions used for management of acute pancreatitis show wide variation.3 Advice on management is often conflicting, and some patients have had difficulty accessing appropriate care. The new national guideline from the National Institute for Health and Care Excellence (NICE) on pancreatitis aims …
Retrospective analysis of patients with high-grade soft-tissue sarcoma treated with interdigitated neoadjuvant MAI chemotherapy and radiation.
Authors: Kevin Rakszawski, Francis R LeBlanc, Edward J Fox, Heath B. Mackley, Colette Pameijer, Joseph J. Drabick
Journal: Journal of Clinical Oncology (2018)

e23539 Background: High-grade soft tissue sarcoma (STS) carries a poor prognosis, and identifying the optimal treatment regimen remains a challenge. We performed a retrospective analysis of patient and disease characteristics and outcomes for patients with high-grade extremity or trunk STS who were treated with interdigitated neoadjuvant chemotherapy (CT) and radiation therapy (RT) before surgical resection at our institution. Methods: Patients with high-grade extremity or trunk STS were planned for treatment with 3 cycles of neoadjuvant CT with MAI – mesna (2500 mg/m2 IV combined with ifosfamide on days 1-3, with additional dose on day 4), doxorubicin (20 mg/m2 IV on days 1-3) and ifosfamide (2500 mg/m2 IV on days 1-3), interdigitated with neoadjuvant RT (44 Gy in two split courses of 22 Gy, with 11 fractions of 2 Gy daily). RT utilized either image-guided 3D conformal or intensity modulated radiotherapy. The cancer control outcomes at 3 and 5 years were analyzed. Results: Seventeen patients with high-grade (grade 2 or 3) STS were analyzed. The median age at diagnosis was 52 years (range 22–72). The median follow-up time from date of diagnosis was 33.2 months (range 11.4-97.0). The estimated 3-year rates for local control (LC), disease-free survival (DFS), and overall survival (OS) are 94.1%, 53.7% and 87.4%, respectively. The estimated 5-year rates for LC, DFS, and OS were 87.4%, 53.6% and 54.6% respectively. All resected tumors were evaluated for response to interdigitated CT and RT. Seven patients had ≥90% tumor necrosis, eight patients had ≥50% but ≤90% tumor necrosis, and two patients had < 50% tumor necrosis. Conclusions: Patients with high-grade STS treated with interdigitated neoadjuvant MAI CT and RT before surgical resection had excellent response rates for LC, DFS and OS at both 3 and 5 years. These results were similar to previously published reports even though we omitted dacarbazine in our CT regimen and did not utilize post-operative CT. This combined interdigitated neoadjuvant chemotherapy-radiation therapy approach before surgical resection therefore continues to have a role in the treatment of high-grade STS.
Clinicopathologic characteristics of endometrial carcinoma metastatic to the ovary compared to endometrial carcinoma with synchronous ovarian carcinoma.
Authors: Natalia Rodriguez Gomez Hidalgo, Robert A. Soslow, Britta Weigelt, Vasileios Sioulas, Alessia Aloisi, Nadeem Abu-Rustum, Jennifer Jean Mueller, Vicky Makker, Mario M. Leitao
Journal: Journal of Clinical Oncology (2017)

e17105 Background: According to recent reports, sporadic synchronous endometrial and ovarian cancers (SEOCs) of endometrioid histology may be clonally related. We sought to characterize the clinicopathologic characteristics and outcomes of patients with SEOC compared to those with endometrial carcinoma felt to have metastasis to the ovaries. Methods: All patients with endometrial cancer who underwent primary surgery at our institution from 06/1993- 09/2014 were identified. We included cases with carcinoma in the endometrium and ovary. Pathology reports were reviewed to determine the pathologist’s assessment of whether the ovarian carcinomas were likely synchronous or metastatic. Patients with stage IV endometrial carcinoma, irrespective of presence of ovarian disease, were excluded. Appropriate statistical tests were performed. Results: We identified 76 eligible cases; 19 were deemed SEOCs and 57 endometrial carcinoma with ovarian metastasis (ECOM). Median age was 52 years (range, 32-71) and 63 years (range, 43-89), respectively (p = 0.4). Non-endometrioid histology was observed in 21% of SEOCs compared with 58% of ECOMs (p = 0.006). There was no myoinvasion in 32% of SEOCs compared with 9% of ECOMs (p = 0.01). Endometriosis was noted in 58% of SEOCs compared with 4% of ECOMs (p &lt; 0.0001). The median follow-up time was 44.2 months (range, 0.4-201.4) for the entire cohort. The 4-year progression-free survival (PFS) rates were 82% (SE+/-9.5) for SEOCs and 51.6% (SE+/- 7) for ECOMs (p = 0.06). The 4-year overall survival (OS) rates were 94.7% (SE+/-5.1) for SEOCs and 69.8% (SE+/-6.2) for ECOMs (p = 0.046). The 4-year PFS rates for cases of endometrioid histology alone were 84% (SE+/-10.6) for SEOCs and 77.8% (SE+/-8.87) for ECOMs (p = 0.97). The 4-year OS rates for cases of endometrioid histology alone were 93.3% (SE+/-8.4) and 81.9% (SE+/-8.2), respectively (p = 0.3). Conclusions: SEOC was associated with more favorable endometrial factors and with the presence of endometriosis, consistent with the notion that these are likely dissemination by retrograde flux. SEOC was associated with better survival outcomes but not when analyzing endometrioid histology alone.
Metabolic intratumor heterogeneity of breast cancer.
Authors: Guro Fanneløb Giskeødegård, Marina Perea Badia, Anna Bofin, Torfinn Støve Madssen, Steinar Lundgren, Hans Fjøsne, Tone Frost Bathen
Journal: Journal of Clinical Oncology (2017)

e23095 Background: Breast tumors are highly heterogeneous due to subpopulations of cancer cells that differ in genetic and phenotypic characteristics. Tumor heterogeneity has been associated with treatment resistance and relapse. Therefore, it can be questioned how representative one biopsy is for the whole tumor. Tumor phenotypic heterogeneity cannot be solely attributed to genetic differences, as epigenetics and interaction with the tumor microenvironment also contribute. In this study we have examined intra-tumor heterogeneity by measuring metabolite expression in breast cancer tissue compared with fibroadenomas. Methods: Fresh frozen tissue slices from surgically removed breast tumors were used. Five cores from different areas of the slices were drilled out from 10 tumors; 6 invasive ductal carcinomas grade 2-3, and 4 fibroadenomas. Histological examination of HES-stained sections from each core was done, and metabolic profiling was performed by magnetic resonance spectroscopy (MRS). The relative concentrations of 23 metabolites were quantified. Metabolic heterogeneity was assessed by coefficient of variation (CoV) and PLSDA classification was used for prediction of tumor origin. Results: Cancer tissue showed significantly higher heterogeneity than fibroadenomas for 16/23 metabolites (mean CoV range: 0.15-0.94 for cancer samples, 0.09-0.37 for fibroadenomas, p &lt; 0.05). However, 23/50 samples did not contain tumor tissue on histological examination. After exclusion of tumor-free samples, the heterogeneity of 3 metabolites (glycine, glycerophosphocholine (GPC) and phosphocholine (PCho) remained significantly different between cancer and fibroadenomas (mean CoV range: 0.12-0.65 for cancer, 0.07-0.42 for fibroadenomas, p &lt; 0.05). GPC and PCho are involved in building of cell membranes and may reflect cell-turnover. Multivariate classification could correctly predict which patient a sample belonged to with 78% accuracy. Conclusions: Metabolic heterogeneity could partly be explained by differences in tumor cell and stromal content, and the origin of an unknown sample could be successfully predicted, showing that metabolic intratumor heterogeneity is smaller than the heterogeneity between patients.
Confounding effects of clonal hematopoiesis in clinical genomic profiling of solid tumors.
Authors: Ahmet Zehir, Ryan Ptashkin, Diana Mandelker, Catherine Callaghan Coombs, Kelly L Bolton, Zarina Yelskaya, David Michael Hyman, David B. Solit, Jose Baselga, Liying Zhang, Maria E. Arcila, Marc Ladanyi, Ross L. Levine, Michael F. Berger
Journal: Journal of Clinical Oncology (2018)

12004 Background: Clonal hematopoiesis (CH) is the somatic acquisition of genomic alterations in hematopoietic stem/progenitor cells, leading to clonal expansion. While a few reports showed CH-derived mutations can contaminate solid tumor sequencing results, a comprehensive analysis has not been reported before. Here, we set out to identify and quantify CH-related mutations in patients with solid tumors using matched tumor-blood sequencing, and to establish the proportion that would be misattributed to the tumor from unmatched analysis. Methods: We retrospectively selected 17,469 solid tumor patients that underwent prospective clinical sequencing of DNA isolated from tumor tissue and matched peripheral blood using the MSK-IMPACT assay between January 2014 and August 2017. We identified the presence of CH-related mutations in each patient’s blood leukocytes by performing mutation calling in the blood and genotyping the tumor DNA at the mutated positions. We then considered variants passing our detection thresholds for somatic mutation calling in tumor NGS data to quantify the prevalence of CH alterations detected in solid tumor specimens. Results: We identified 7,608 CH-associated mutations in the blood of 4,628 (26.5%) patients. 14% of CH-associated mutations (n = 1,075) were also detectable in the matched tumor above established thresholds for calling somatic mutations. In total, 5% of the patients (n = 912) would have had at least one CH-associated mutation erroneously called as tumor-derived in the absence of matched blood sequencing. 99% of these mutations were absent from population scale databases of germline polymorphisms (ExAC and gnomAD) and therefore would have been challenging to filter informatically. Of these, 534 were identified as oncogenic or likely oncogenic based on OncoKB database and 3% of the oncogenic mutations were associated with clinical actionability. Conclusions: Our results demonstrate how CH-derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is employed.
Prognostic value of NK and T-lymphocytes markers in operable non-small cell lung cancer (NSCLC).
Authors: Marcin Tomasz Skrzypski, Amelia Szymanowska-Narloch, Ewa Jassem, Michał Marczyk, Joanna Polanska, Wojciech Biernat, Witold Rzyman, Agnieszka Maciejewska, Ryszard Pawlowski, Jacek Jassem
Journal: Journal of Clinical Oncology (2017)

11556 Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p &lt; 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. &lt; 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.
P05.03 Stereotactic Radiosurgery to Surgical Cavity Post Resection of Brain Metastases: Local Recurrence and Overall Survival Rates. A Single Centre Experience
Authors: M J Higgins, O Burke, K Nugent, C Skourou, M Dunne, M Javadpour, D Fitzpatrick, C Faul
Journal: Neuro-Oncology (2018)

We reviewed local control (LC) and overall survival (OS) post intracranial SRS to cavity post resection of brain metastases at one institution, and factors affecting LC. A retrospective review was conducted of adjuvant SRS at one institution from 2013 to 2016. Patient records, treatment plans, and diagnostic images were reviewed. Local failure was MRI defined. Categorical variables were analysed using chi-square and Fisher’s exact tests. Continuous variables were analysed using Mann-Whitney tests. The Kaplan-Meier method was used to estimate survival times and the log-rank test was used to compare differences in survival. 47 patients with 48 cavities were treated with SRS post operatively. LC rate was 69%, and the distant intracranial failure rate was 47%. The 12 month freedom from local recurrence (FFLR) was 77% (63–91%). Median OS (95% CI) was 22.7 (14.6–30.8) months. Patients with a single metastasis had longer FFLR (30.1 vs 14.4 months; p = .014). Median interval from surgery to SRS was 6.3 weeks. Patients with interval > 7 weeks had increased local recurrence (LR) (62%) than < 7 weeks (37%), p = 0.025.Patients with a margin < 2mm were more likely to experience LR (48%) than those with margin equal to 2mm (20%); this approached statistical significance (p = 0.063). The median follow up for all patients was 15.4 months (2–41). We determined LC and OS using adjuvant SRS at our institution. Based on the findings of this retrospective review SRS should be given promptly post operatively with a 2mm PTV margin.
Development and validation of ColoScape: A new colorectal cancer mutation detection assay.
Authors: Michael Joseph Powell, Elena Peletskaya, Qing Sun, Larry Pastor, Aiguo Zhang, Kamila Koprowska, Walter Bodmer
Journal: Journal of Clinical Oncology (2018)

e24189 Background: Colorectal cancer is a highly preventable disease. Herein we report the development and validation of ColoScape, a novel multigene mutation biomarker real-time PCR based assay for qualitative detection of colorectal cancer associated 'drive' mutations in the following genes: APC (Exon 15), KRAS (Exon 2), BRAF (Exon 15) and CTNNB1 (Exon 3). Methods: The high sensitivity of ColoScape is achieved by xenonucleic acid (XNA) probe technology. XNA probes are backbone modified oligomers with natural nucleoside bases (A,T, C and G) that hybridize by Watson-Crick base pairing to natural DNA and RNA with significantly higher binding affinity. XNA probes bind to the selected wild-type sequences at the respective genetic loci in the target genes. Variant alleles at these loci are selectively amplified since the XNA does not bind tightly to the variant sequence and allows DNA polymerase to copy the mutant allele but no the wild-type allele. For selected mutation sites, primers and FAM-labeled TaqMan probes were designed and tested with the selected XNA oligomers. An internal PCR control selected in the Human Beta-Actin (ACTB) gene was employed utilizing a HEX-labeled TaqMan probe. Performance parameters were established on colorectal cancer patients DNA extracted from FFPE and plasma ctDNA materials. Results: At least 0.5% allelic frequency mutation in the presence of excess wild-type DNA background can be detected by Coloscape for target mutations in APC (exon 15), KRAS (exon 2),BRAF V600 (exon15) and CTNNB1 (exon 3) in 5-10 ng of input DNA/well. No cross reactivity was observed with wild-type up to 320ng purified gDNA and up to 20ng FFPE DNA per reaction. Intra-assay, inter-assay, lot-to-lot and operator variation comparison showed CV between 3% and 8%. Excluding pre-cancer samples, the assay clinical specificity and sensitivity were 95% and 100% respectively. Pre-cancer detection sensitivity was 60% (6 out of 10 FFPE samples) and 62.5% for stool samples. For tested FFPE clinical samples, assay specificity and sensitivity were 95% and 91% respectively while assay clinical specificity and sensitivity were both 100% for plasma samples. Conclusions: The ColoScapeColorectal Cancer Mutation Detection assay is a sensitive tool intended to facilitate research in colon cancer development, early detection, disease recurrence monitoring and therapeutic intervention.