tbuckley/cabot-search huggingface dataset:
p53 and p16 expression profiles reveal three prognostically relevant subgroups in vulvar cancer: A TMA based study by the AGO-CaRE-translational study group.
Authors: Linn Lena Woelber, Katharina Prieske, Christine Eulenburg, Nikolaus de Gregorio, Rüdiger Klapdor, Matthias Kalder, Elena Ioana Braicu, Sophie Fuerst, Maximillian Klar, Hans-Georg Strauss, Grit Mehlhorn, Werner Meier, Atanas Ignatov, Alexander Mustea, Julia Kathrin Jueckstock, Georg Schmidt, Dirk Bauerschlag, Martin Hellriegel, Sven Mahner, Eike Burandt
Journal: Journal of Clinical Oncology (2019)

5592 Background: Currently, there are two major pathways for tumorigenesis of vulvar squamous cell carcinoma (VSCC) – an HPV-dependent with p16 overexpression as a surrogate for HPV-associated transformation and an HPV-independent route linked to lichen sclerosus, characterized by p53 mutation. A possible correlation of HPV dependency with a favourable prognosis has been proposed. Methods: The AGO CaRE-1 study is a retrospective survey of pts with primary VSCC FIGO stage ≥1B (UICC-TNM version 6) treated at 29 gynecologic cancer centers in Germany 1998-2008 (n = 1,618). For this CaRE-translational sub-study available FFPE tissue was collected centrally (n = 648). A tissue micro array (TMA) was constructed; p16 and p53 expression was determined by immunohistochemistry (IHC). HPV status and subtype were analyzed by PCR. Results: p16 IHC was interpretable in 550 TMA spots and considered positive in 166/550 (30.2%). HPV DNA was detected in 78.4% of the p16+ tumors, with HPV 16 being the most common subtype (88.3%) . Pts with p16+ tumors were younger at diagnosis (63 vs. 70 yrs for p16- tumors; p = 0 &lt; 0.01) and showed lower rates of lymph-node involvement (29.0% vs. 39.7%; p = 0.021). p53 IHC was interpretable in 597 spots, 187/597 (31.3%) were considered positive. Pts with p53+ tumors were older at first diagnosis (71 vs. 66 yrs; p = 0.001 for p53- tumors) and showed lymph-node involvement more often (43.3% vs. 31.1%; p = 0.007). There was a relevant number of tumors with neither p16 nor p53 overexpression (221/535); while co-expression of p53 and p16 was rare (12/535). For survival analyses, three groups were defined: p53+ (n = 163), p16+/p53- (n = 151) and p16-/p53- (n = 221). 2-y-disease-free (DFS) and overall survival (OS) rates were significantly different between the groups: DFS: p53+ 47.0%; p16-/p53- 53% and p16+/p53- 65.5% (p &lt; 0.001); OS: 70.4%, 72.6% and 82.7% (p = 0.003), respectively. Adjustment for age and nodal status showed consistent p16 and p53 effects regarding DFS. Conclusions: p16 overexpression is associated with an improved prognosis in VSCC while p53 positivity is linked to an adverse outcome. Our data provide evidence of a clinically relevant third subgroup of VSCC with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
Oxfordshire councillors criticise NHS England over outsourcing of cancer scanning services
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A group of councillors from Oxfordshire have launched a stinging attack on NHS England over plans to outsource local cancer scanning services to a private company.

NHS England’s decision to award a contract to provide the combined positron emission tomography and computed tomography (PET-CT) scanning service to the company InHealth has led to a dispute with Oxford University Hospitals NHS Foundation Trust, which has provided the …
Effector T-cell cytolytic activity modules derived from CD3+ single cells from human primary triple-negative breast cancer (TNBC) in multiple solid tumors to predict response to immune checkpoint blockade therapy (ICB).
Authors: Chaitanya Ramanuj Acharya, Herbert K Lyerly
Journal: Journal of Clinical Oncology (2019)

1073 Background: The prognostic and predictive value of tumor infiltrating lymphocytes for ICB has been recognized in a variety of tumor types, including TNBC. Nonetheless, our understanding of the mechanistic aspects of T cell activation remains incomplete. We hypothesize that a specific effector phenotype of T cell cytolytic activity (ECA) is a consistent feature of epithelial tumors, possibly varying by tumor types with a range of inflammatory features. Methods: We evaluated 6,311 purified CD3+ single cells from human primary TNBC and computed sample set enrichment scores of a set of previously published immune metagenes. Following unsupervised clustering of the enrichment scores of the entire single cell population, two subgroups of cells with highest and lowest average enrichment score of T cell cytolytic activity formed a basis for detecting functional gene expression modules. Spectral decomposition and Jackstraw analysis estimated eight modules with overlapping sets of genes. Each gene expression module was then used to train a Random Forest classifier of ECA phenotype. Results: We discovered that our module-derived classifiers were prognostic not only in TNBC samples obtained from both TCGA (N = 150) and METABRIC (N = 320) datasets but also in 14 other tumor types encompassing 6,000 samples. For example, patient samples from TCGA dataset predicted to be in group ECA ‘High’ have better progression-free survival (p-value: 0.0098l; HR: 0.30) and better overall survival (p-value: 0.0066; HR: 0.17). In both breast datasets, gene within the classifier are relatively under-expressed in ER+ tumors as opposed to HER2+ and TNBC (p-value &lt; 2.2e-16). In a dataset of normal, pure DCIS and mixed DCIS (GSE26304;N = 114), the same genes were relatively under-expressed in DCIS samples relative to invasive tumors (p-value &lt; 2.2e-16). Additionally, in a pre-therapy tumor dataset of fifty-one advanced melanoma patients treated with Nivolumab, who previously either progressed on ipilimumab or were ipilimumab-naïve, our module-derived classifier was able to classify responders and non-responders with 77% accuracy (p-value = 0.02) and was associated with progression-free survival (p-value = 0.03; HR: 0.28). Conclusions: Our study highlights one important application of single-cell genomics in our understanding of immune microenvironment and potentially identify new immunotherapy targets.
Abstract 9240: Activation of PPARγ Converts the Mechanism of Flow-Mediated Dilation in Human Microvessels from H2O2 to NO by a Telomerase Dependent Mechanism
Authors: Andreas M Beyer, David D Gutterman
Journal: Circulation (2012)

Reactive oxygen species (ROS) are important modulators of vascular reactivity. Coronary artery disease (CAD) changes the mechanism of human arteriolar flow-mediated dilation (FMD) from NO to hydrogen peroxide (H2O2), a signaling ROS. Increasing evidence shows that mitochondrial ROS (mtROS) production and the longevity of a cell or organism are inversely related. Telomerase activity (TA), prominent in cellular senescence and tissue aging, shows a reciprocal relationship with mtROS production. Rosiglitazone (Rosi) activates peroxisome proliferator-activated receptor γ (PPARγ) resulting in increased telomerase expression. This could mitigate mtROS production, leading to increased NO bioavailability, improved vascular function, and retardation of atherosclerosis. We hypothesized that PPARγ reduces elevated ROS levels in CAD and converts the mechanism of FMD from H2O2 to NO by increasing telomerase activity. Human adipose arterioles (~200 µm) from discarded pericardial tissue were cannulated for videomicroscopy. Dilation to graded degrees of shear was measured in vessels constricted with endothelin-1. Pharmacological inhibition of TA (BIRBR 1532 10 μM 15-20 h) in vessels from healthy individuals shifted the mechanism of FMD from NO to H2O2 (Panel A+B). In arterioles from patients with CAD, Rosi (10 μM 15-20 h) shifted the mechanism of FMD from H2O2 to NO (Panel C). In vessels from patients with CAD, BIBRB1532 prevented the ability of Rosi to convert the mediator of FMD from NO to H2O2 (D). We conclude that PPARγ signaling increases telomerase activity in the vasculature, which plays a critical and acute role in modulating microvascular function.
Improve: A community-based physical activity intervention to improve functional and health outcomes in older breast cancer survivors: Rationale, design, and methods.
Authors: Cynthia Owusu, Nora Nock, Paul Hergenroeder, Kris Austin, Beth Bennett, Stephen Cerne, Halle C. F. Moore, Jean Petkac, Mark D. Schluchter, KATHRYN H. SCHMITZ, Lindsay Atkins, Oghenerukeme Asagba, Leonard Wimbley, Nathan A. Berger
Journal: Journal of Clinical Oncology (2019)

TPS11629 Background: African-Americans (AA) and lower socioeconomic status (SES) older breast cancer survivors (BCS) are more likely to experience poor functional and health outcomes. Promotion of healthy behaviors, such as physical activity (PA), is critical to addressing these health disparities. Here we describe the rationale, design and methods of a randomized controlled trial testing the effectiveness of a physical activity intervention among older BCS from diverse racial and SES backgrounds. Methods: The IMPROVE Study is a community-based randomized-controlled trial designed to recruit 320 BCS, 80 in each of four strata defined by race (AA vs. Non-Hispanic Whites [NHW]) and SES (low vs. high). Participants are aged ≥ 65 years, AA or NHW and are within five years from treatment completion for stage I-III breast cancer. Participants are recruited utilizing the Ohio Cancer Incidence and Surveillance System database or directly from three area hospitals in Cleveland, Ohio and randomized to one of two arms: a 52-week moderate intensity aerobic and resistance group training intervention (n = 160) versus attention-control (support group sessions), (n = 160). The first 20 weeks of the PA intervention includes 3x per week 60-minute supervised sessions. The last 32 weeks of the PA intervention are unsupervised. Each of the 60-minute supervised PA sessions include 30 minutes of moderate intensity aerobic activity at 50%-70% of HRmax (maximum heart rate) and 30 minutes of resistance training based on 1-RM (repetition maximum) for chest and leg press. The attention-control group attend a once per week 60-minute support group session for the first 20 weeks and have unsupervised group sessions during the last 32 weeks. Exit interviews are being conducted at 52 weeks. The primary outcome is change in Short Physical Performance Battery (SPPB) Scores at 20 weeks. Secondary outcomes include change in SPPB scores at 52 weeks, and change in body composition and biomarkers of breast cancer prognosis at 20 and 52 weeks. One hundred and seventy-four participants have been enrolled as of 02/07/2019. Discussion: This study includes three underserved populations, (older BCS in general, older AA BCS and older low SES BCS) in one study. Results may contribute to a better understanding of factors associated with recruitment, sustained participation and acceptability, and will inform physical activity programs that will optimally improve the functional and health outcomes for older women during breast cancer survivorship. Clinical trial information: CNCT02763228.
The Neat-HER Virtual Registry: A novel registry following HER2+ ESBC patients receiving neratinib in the extended adjuvant setting.
Authors: Debu Tripathy, Gregory A. Vidal, Deepa Lalla, Richard Bryce, Gillian Hanson, Melissa Brammer, Feng Xu, Hope S. Rugo
Journal: Journal of Clinical Oncology (2019)

e12035 Background: While data from traditional registries are limited to patients (pts) treated at study sites, virtual registries can enroll a more diverse real-world population. Neat-HER is a US-based, non-interventional pilot virtual registry through PicnicHealth that will enroll 100 pts with HER2+ BC receiving neratinib as extended adjuvant therapy. Methods: Neat-HER will evaluate the feasibility of enrolling pts &amp; answering research questions using this novel methodology. Eligibility includes receipt of neratinib, signed informed consent for medical record retrieval/data abstraction &amp; &gt; 18 years age at study consent. Pts who fail to complete enrollment procedures, are participating in a clinical trial, have metastatic disease, or who lack adequate medical records will be excluded. For each pt discontinuing neratinib within 60 days of starting treatment, an additional pt will be recruited, but all pts will be included in the analysis. Pts are recruited through multiple mechanisms incl. private social media groups, treating clinicians &amp; pts enrolled in the Puma texting program. PicnicHealth will collect &amp; structure medical records from medical practices in the United States for ~7 years prior to enrolment up to 1 year after enrolment. Research questions focus on descriptive pt characteristics &amp; demographics, breast cancer history [(neo)adjuvant treatment/outcomes], use of diarrhea prophylaxis, incidence of diarrhea &amp; duration of neratinib. Results: Enrollment began in 12/2018 with target completion in 4/2019. As of 2/2019, 42 pts have initiated enrolment. Of these, 19 pts completed enrolment &amp; 69,750 data points have been extracted from medical records. Descriptive statistics will be used to characterize the pt cohort. Duration of treatment, receipt &amp; type of prophylaxis, incidence of diarrhea, treatment discontinuation &amp; reasons for discontinuation will be summarized for all pts. Conclusions: A virtual registry allows assessment of medication use &amp; outcomes in a diverse population in a rapid timeframe. Neat-HER will provide comprehensive information on clinical history &amp; treatment patterns in a real-world cohort of pts receiving extended adjuvant neratinib.
Postoperative adjuvant chemotherapy for thoracic pathological T3N0M0 esophageal cancer: A propensity score-matched analysis (APEC Study 1).
Authors: Qifeng Wang, Tao Li, Yongtao Han, Qiang Li, Lin Peng, Tianpeng Xie, Qiang Fang, Xiaojun Yang, Xiang Zhuang, Wei Dai, Yingchun Jiang, Yi Wang, Jiahua Lv, Lei Wu, Bangrong Cao, Mei Lan, Jinyi Lang
Journal: Journal of Clinical Oncology (2019)

e15537 Background: The role of postoperative chemotherapy (POCT) in thoracic esophageal squamous cell carcinoma (TESCC) has not been addressed . The aim of this study was to investigate whether POCT after an R0 resection improves outcomes in pT3N0M0 TESCC compared with operation alone. Methods: This study included 604 patients with pT3N0M0 TESCC who were treated at Sichuan Cancer Hospital from January 2009 to December 2017. The patients were divided into two groups: a surgery plus postoperative chemotherapy group (PORT group) comprising Surgery alone patients who underwent after an R0 resection and a surgery group (S group). Propensity score matching was used to create patient groups that were balanced across several covariates (n= 246 in each group). Outcome measures included overall survival (OS), disease free survival (DFS). Results: In the whole group 5-year OS and PFS were 58.4% and 56.0%. In the overall study cohort, 5-year OS (68.3% versus 50.4%, p &lt; 0.0001) and DFS (65.5% versus 45.8%, p &lt; 0.0001) rates were significantly higher in the POCT group than in the S group. These data were confirmed in the matched samples (5-year OS, 68.3% versus 49.5% [p &lt; 0.0001]; DFS, 65.5% versus 42.5% [p &lt; 0.0001]). Multivariate Cox analyses in the matched samples revealed that surgery and postoperative POCT were independently associated with longer OS (hazard ratio = 0.553, 95% confidence interval: 0.391–0.726, p &lt; 0.0001) and longer DFS (hazard ratio = 0.556, 95% confidence interval: 0.416–0.744, p &lt; 0.0001) than resection alone. Subgroup analysis found : POCT with IIA in pT3N0M0 have not longer OS and DFS ( p = 0.122 and p = 0.193). POCT with IIB in pT3N0M0 have the longer OS and DFS(p &lt; 0.0001 both). Conclusions: Postoperative adjuvant Chemotherapy is strongly associated with improved OS and DFS in patients with pT3N0M0 TESCC. A multicenter, randomized phase III clinical trial is warranted to confirm these findings.
Unlocking the full potential of lipid-based formulations using lipophilic salt/ionic liquid forms
Authors: Hywel D. Williams, Leigh Ford, Annabel Igonin, Zhenhua Shan, Paolo Botti, Michael M. Morgen, Guixian Hu, Colin W. Pouton, Peter J. Scammells, Christopher J.H. Porter, Hassan Benameur
Journal: Advanced Drug Delivery Reviews (2019)
Case 36-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Michael A. Lew, Joanne K. Rutgers
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 29-year-old woman was admitted to the hospital because of left flank pain and gross hematuria.There was a 14-year history of insulin-dependent diabetes mellitus, with poor compliance and 15 previous admissions to a hospital, the majority for control of diabetes mellitus and management of diabetic ketoacidosis. The patient was in her usual state of health until several weeks before entry, when she began to experience diffuse pains. Fifteen days before admission she was seen at a second hospital because of left flank pain. The blood glucose was in excess of 800 mg per 100 ml (40 . . .
Tumor size and location affecting the treatment selection for solitary small recurrent hepatocellular carcinoma (≤3.0 cm) after initial hepatectomy.
Authors: Shu-Ling Chen, Zhenwei Peng, Han Xiao, Mengchao Wei, Ming Kuang
Journal: Journal of Clinical Oncology (2019)

e15660 Background: We aimed to investigate the optimal treatment modality between radiofrequency ablation (RFA) and repeated hepatectomy in the treatment of solitary recurrent HCC (rHCC) after hepatectomy, considering the influence of tumor size and location. Methods: From Jan 2009 to Dec 2016, 630 consecutive patients with solitary small rHCC (≤3.0cm) after initial hepatectomy who underwent RFA or repeated hepatectomy were enrolled in three tertiary referral centers. Patients were divided into four groups according to tumor size (≤ 2.0cm or &gt; 2.0cm) and location (central or peripheral) respectively. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between RFA and repeated hepatectomy in these four groups. Results: For central rHCC ≤ 2.0cm, the OS and RFS rates at 5 years after RFA were significantly higher than those after repeated hepatectomy (69.9% vs 53.1%, P= 0.001; 56.2% vs 42.6%, P= 0.038). For central rHCC &gt; 2.0cm, the 5-year OS and RFS rates were not significantly different between repeated hepatectomy and RFA (55.9% vs 48.2%, P= 0.080; 27.0% vs 19.2%, P= 0.103). For peripheral tumors ≤ 2.0cm (58.8% vs. 47.7%, P= 0.001; 45.2% vs. 25.6%, P= 0.001) or &gt; 2.0cm (62.6% vs. 45.4%, P= 0.001; 44.7% vs. 21.1%, P= 0.010), the OS and RFS rates at 5 years after repeated hepatectomy were both significantly higher than those after RFA. Complications were more common in patients after repeated hepatectomy than RFA, especially for central tumors. Conclusions: RFA might be the optimal treatment for patients with central rHCC ≤ 2.0 cm whereas repeated hepatectomy should be recommended for patients with peripheral tumors.
Everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer patients previously treated with CDK4/6 inhibitor based therapies.
Authors: Madeline Cook, Luai Al Rabadi, Zahi Ibrahim Mitri
Journal: Journal of Clinical Oncology (2019)

1058 Background: The combination of everolimus (EVE) and exemestane (EXE) is approved as second line endocrine therapy for metastatic hormone receptor positive breast cancer (mHRBC) patients who progressed on non-steroidal aromatase inhibitor (NSAI) therapy based on the BOLERO-2 trial. However, none of the patients in BOLERO-2 received prior CDK4/6 inhibitors, which have since become standard of care for metastatic HRBC. As such, the clinical benefit of EVE + EXE in mHRBC patients previously treated with CDK4/6 inhibitors remains unknown. Methods: We reviewed patients ≥18yo with mHRBC treated with EVE + EXE following NSAI alone or NSAI + CDK 4/6 inhibitor at our institution between 2012-2018. Data collected included patient and tumor characteristics, therapies in the metastatic setting, special interest adverse events, and clinical outcomes. The primary objective was comparing PFS for EVE + EXE therapy between patients who received prior CDK4/6 inhibitor therapy and those who did not. Secondary endpoints included overall survival (OS). Patient features were summarized with descriptive statistics and time-to-event measures were estimated using the Kaplan-Meier method. Differences between groups were tested with Fisher’s exact, Kruskal-Wallis, or log-rank test. Results: Thirty-three patients were included in the study; 17 had prior CDK4/6 inhibitor therapy and 16 did not. Subjects that took EVE + EXE for &lt; 28 days were excluded. Patient characteristics, including prior therapies and sites of metastatic disease, were not significantly different. There was no significant difference in PFS (median 5.7 vs 4.7 months, p = 0.890) or OS (median 17.8 vs 11.4 months, p = 0.177) between patients who received prior CDK4/6 inhibitors and those who did not, respectively. Steroid mouthwash use was associated with a reduced incidence of stomatitis. Conclusions: EVE + EXE is well tolerated and shows similar efficacy in metastatic HRBC patients who received CDK4/6 inhibitor therapy and those who did not. There was a non-significant trend towards improved OS in the CDK4/6 inhibitor group that needs to be further evaluated in larger patient cohorts.
Case 5-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely
Journal: New England Journal of Medicine (1984)

Presentation of Case A 21-year-old man was admitted to the hospital because of a draining appendectomy incision. He was well until five months earlier, when he began to experience fever and intermittent colicky pain in the right lower abdominal quadrant, accompanied by anorexia; there was no nausea, vomiting, or diarrhea. His symptoms persisted, and eight days later he entered another hospital. Physical examination showed guarding in the right lower abdominal quadrant, with a question of rebound tenderness. Rectal examination revealed tenderness anteriorly on the right side. The white-cell count was 13,600, with 75 per cent neutrophils. A urinalysis and a . . .
Predictors of mortality following cardiac surgery for carcinoid heart disease.
Authors: Cezar Iliescu, Dinu Valentin Balanescu, Saamir Hassan, Juan Lopez-Mattei, Nicolas Palaskas, Arvind Dasari, Daniel M. Halperin, James C. Yao, Biswajit Kar, Igor Gregoric, Sriram Nathan, Jean-Bernard Durand, Kaveh Karimzad, Peter Y. Kim, Gloria Iliescu, Serban Mihai Balanescu, Konstantinos Marmagkiolis, Teodora Donisan
Journal: Journal of Clinical Oncology (2019)

e15692 Background: Carcinoid Heart Disease (CHD) complicates 50% of carcinoid syndrome cases and represents a major cause of mortality in these patients. Surgery continues to be the only strategy to improve survival in CHD. We aimed to evaluate predictors of mortality following surgery for CHD. Methods: We retrospectively analyzed patients with CHD and a history of valve surgery presenting at a tertiary cancer center between November 2005 and March 2018. Data regarding symptoms, clinical findings, and CHD treatment were collected. Overall survival (OS, time interval from heart surgery to death) was calculated. Univariate Cox proportional hazards regression analyses were conducted to identify variables that were associated with OS. Results: We identified 25 patients with CHD who underwent surgical replacement with bioprosthetic valves: 10 (40%) the tricuspid valve (TV), 11 (44%) TV and pulmonary valve (PV), 3 (12%) TV, PV, and aortic valve, and 1 (4%) all 4 valves. Among them, 19 (76%) survived at least 12 months after the surgery. Clinical factors associated with decreased OS are presented in Table 1. Conclusions: OS following surgery is dictated by the severity of CHD at the time of surgery. Worse outcomes are predicted by a history of congestive heart failure, the number of symptoms, and ascites. Better selection criteria are needed in order to choose the candidates for surgery who will benefit the most. [Table: see text]