tbuckley/cabot-search huggingface dataset:
Metastases from lobular breast cancer as an unusual source of GI bleeding.
Authors: Emily Clarke, James George, Andrew Peter Dean
Journal: Journal of Clinical Oncology (2017)

e12557 Background: With the exception of malignant melanoma, metastases to the GI tract are rare, especially as a first presentation of malignancy. We report a series of patients with GI metastases from lobular breast carcinoma as an unusual source of symptomatic GI bleeding. Methods: We conducted an electronic database search to identify solid tumour patients (excluding melanoma) with metastases to the GI tract. We then analysed the database by tumour type. Results: 3 cases of proven metastasis to the GI tract were identified. All had lobular breast cancer metastases. The database contained 240 patients with breast cancer, identifying 63 with infiltrating lobular carcinoma, 2 with micropapillary and 175 with invasive ductal carcinoma The 1st case had had invasive ductal breast carcinoma 6 years previously and presented with fatigue and shortness of breath from anaemia. Colonoscopy revealed a polyp which was removed. Histopathology showed metastatic lobular breast carcinoma. Further investigation then confirmed an occult breast mass with identical pathology. The 2nd case presented with 18 months of abdominal pain, previous colonoscopy was normal. After onset of anaemia and 25kg weight loss, upper GI endoscopy showed a markedly thickened stomach with evidence of recent bleeding and biopsies confirmed metastatic lobular breast carcinoma. The 3rd case presented with abdominal pain, subsequent blood tests showing a raised CA125 with omental and ovarian masses. Surgical debulking showed metastatic lobular breast carcinoma, though no primary breast lesion was detectable with mammography, ultrasound and MRI. 3 years later, investigation of anaemia with colonoscopy showed a caecal polyp with histology confirming lobular breast carcinoma. Conclusions: Despite all common tumour types being represented in the database it is notable that all 3 cases with mucosal GI metastases had lobular breast cancer. Previous evidence suggests a long latent period from initial diagnosis of breast cancer to development of GI metastases however our report suggests it can occur earlier in the illness. Clinicians should consider this as a rare cause of GI bleeding and further research to understand the mechanism of mucosal metastasis in lobular breast cancer is needed.
Disease presentation and clinical outcomes of breast cancer (BC) in black women (BW) 40 yrs and under at a single urban hospital.
Authors: Sireesha Datla, Padma L. Draksharam, Harry He, Charles Mupamombe, Gurinder Singh Sidhu, Evelyn Oluwatoyin Taiwo
Journal: Journal of Clinical Oncology (2016)

e12044 Background: BC is the most common cancer in women of all ages; but less common under 40 years (6.6%). Younger BC patients (pts) are known to have Triple negative or Her2neu positive, advanced and aggressive disease. Methods: This is a retrospective study, conducted at KCHC. Data regarding the clinical and pathological profile, treatment outcomes were analyzed; and compared to SEER data. Results: Total of 1273 BC pts were screened from 2001-2013, of which 124 (9.74%) were 40yrs and under. Of 124 pts, 12% with noninvasive BC and 11% with unknown pathology were excluded. Of the remaining 96 pts (7.5%) with invasive cancer, 91.6% were of Afro-Caribbean descent. At the time of presentation, mean age was 36yrs, 7% were pregnant, 22% had positive family history of BC. 36% of pts were ER+/Her2neu+, 27% were ER+/Her2neu negative, 19% were ER-/Her2neu+, and 15% were Triple negative. High grade disease was noted in 65% pts. Early stage disease was seen in 7%, 62% had locally advanced and 15% had metastatic disease. Lymph node (LN) involvement at presentation was seen in 58% pts. All pts received standard treatment. Pts were followed for 155months, 33% had progression of disease, in about 36months with 20% mortality (Table 1). Conclusions: In our analysis, BW were noted to have similar disease characteristics with white women (WW) less than 40yrs. Our study population primarily Afro Caribbean, noted to have higher percentage of BC occurence (7.5% vs 6.6%) compared to young BC pts in the general population. They presented with advanced stage and higher grade similar to BW, however noted to have higher triple positive (36 % vs 18%) disease suggesting a different natural history of disease. Disease characteristics in our population vs SEER Data Base (SDB). Age in years Grade Hormone receptor (%) Stage (%) LN+ (%) Median Survival in months L I H ER + H2- ER- H2 + ER +H2 + TripleNeg I II III IV With out LN+ 1-4 LN+ >4 LN+ Institution 36 3 22 65 27 19 36 15 7 33 29 15 42 75 25 34 SDB BW 37 5 28 65 61 8 18 14 44 34 17 6 65 71 29 36 SDB WW 37 8 34 57 70 5 10 15 44 34 17 6 66 69 31 32 BW: Black Women; WW:White Women; L-low, I-intermediate, H-high; ER-estrogen receptor, H2-Her2 neu, LN-lymph node.
Improved Prognostic Significance of Genomic and Transcriptional Biomarkers By Examining Enriched Populations of AML Blasts: A SWOG Report
Authors: Era L. Pogosova-Agadjanyan, Anna Moseley, Brent L. Wood, Frederick R. Appelbaum, Thomas Chauncey, I-Ming L. Chen, Harry P. Erba, John E. Godwin, Min Fang, Kenneth J. Kopecky, Alan F. List, Megan Othus, Jerald P. Radich, Cheryl L. Willman, Soheil Meshinchi, Derek L. Stirewalt
Journal: Blood (2016)
Abstract P315: S-Glutathiolation of Low-Molecular-Weight PTP Regulates VEGF-Angiogenic Signal
Authors: Mohammed A Abdelsaid, Azza El-Remessy
Journal: Circulation Research (2011)

While reparative angiogenesis improves outcome of stroke and myocardial infarction; pathological angiogenesis aggravates tumors, psoriasis and diabetic retinopathy. We have previously shown that low levels of peroxynitrite (PN, 1µM) are required to mediate VEGF’s angiogenic signal. Prior studies showed that low molecular weight protein tyrosine phosphatase (LMW-PTP) can regulate activation of VEGFR2 and focal adhesion kinase (FAK), key proteins involved in VEGF angiogenic signal. Here, we test the hypothesis that VEGF-induced peroxynitrite regulates LMW-PTP activity via reversible S-glutathiolation. Our results using human microvascular endothelial (HME) cells showed that VEGF (20 ng/ml) caused immediate (1,5 min) and transient negative shift in redox-state assessed by reduced-glutathione (GSH) level that was restored back to baseline by 15–30 minutes. In parallel, total free thiols of LMW-PTP; assessed by 5-iodoacetamide; were immediately oxidized (1, 5 min) and recovered after 15–30 minutes. PN (1μM) mimicked VEGF’ actions by inducing oxidative inhibition of LMW-PTP and FAK phosphorylation that peaked at 15 min. Studies using anti-GSH antibody demonstrated strong s-glutathiolation of LMW-PTP thiols that peaked at (5–10min) under non-reducing conditions and were completely abrogated in DTT-treated samples. These effects were associated with impaired tyrosine phosphorylation of LMW-PTP. PN caused concentration-dependent significant inhibition of LMW-PTP phosphatase activity reaching maximum at 0.5mM. Under pathological conditions recapitulated by combining with peroxynitrite (0.5mM), VEGF caused immediate yet permanent negative shift in cellular redox-state, LMW-PTP inactivation and sustained FAK activation in HME cells. Modulating cellular redox-state to reductive stress using N-acetyl cysteine (NAC, 1mM) or FeTPPS (2.5μM) prevented VEGF-induced angiogenesis in vitro and in vivo using hypoxia-induced neovascularization mouse model. Taken together, shifting redox-state to oxidative stress or reductive stress can impair VEGF’s signal and achieving a balanced redox-state is critical to facilitate VEGF’ angiogenic signal.
T-cell inflamed phenotype gene expression signatures to predict clinical benefit from pembrolizumab across multiple tumor types.
Authors: Sarina Anne Piha-Paul, Jaafar Bennouna, Andrew Albright, Michael Nebozhyn, Terrill McClanahan, Mark Ayers, Jared K. Lunceford, Patrick Alexander Ott
Journal: Journal of Clinical Oncology (2016)

1536 Background: Two multigene expression signatures previously derived in melanoma patients (pts) and confirmed to be associated with clinical outcome in head and neck and gastric cancer pts, were evaluated in 5 additional cancer types. Methods: We conducted a meta-analysis of the 2 multigene expression signatures in PD-L1+ pts from 5 tumor type cohorts of study KEYNOTE 028. A total of 109 cancer pts (20 anal canal, 18 biliary tract, 22 colorectal, 23 esophageal, 26 ovarian) treated with pembrolizumab on the trial had RNA expression profiling and survival data available; 107 were evaluable for objective response (OR). FFPE-extracted RNA was analyzed on the Nanostring nCounter system and signature scores were calculated as an average of housekeeping normalized expression values of the signature member genes. Statistical regression models tested the association between the predefined signature scores and clinical outcome, adjusted for cancer type for the 2 multigene signatures: 1) IFN-γ and 2) Expanded-immune. Results: Both signature scores showed statistically significant (P< 0.05) association with OR and progression free survival (PFS). Signature scores exhibited the same hallmark pattern seen in head and neck and gastric cancer where the lower end of the signature score distributions had very few patients with OR or prolonged times to progression. The area under the ROC curve for the IFN-γ signature was 0.65 (95% CI: 0.50 - 0.79). Conclusions: This RNA profiling data set from 5 cancers adds to the growing body of evidence that tumor infiltration with activated T-cells is a prerequisite for response to PD-1 checkpoint blockade, and demonstrates that T-cell inflamed gene expression signatures are pan-cancer predictors of clinical benefit from anti-PD-1 treatment; the results suggest that this holds true in pts with PD-L1+ tumors. Such signatures may represent a useful tool for identifying patients who are likely to respond to anti-PD-1 therapy. Clinical trial information: NCT02054806.Signature Nominal 1-sided P valuea OR N = 107 PFS N = 109 IFN-γ (6 gene) 0.010 0.003 Expanded-immune (18 gene) 0.028 0.009 aFrom logistic or Cox regression for OR and PFS, respectively; both regression models included terms adjusting for cancer type.
Baseline cancer screening findings from the NCI Li-Fraumeni syndrome study.
Authors: Phuong L. Mai, Rosamma M Decastro, Payal Khincha, Jennifer T. Loud, Renee C Bremer, June A Peters, Sharon A. Savage
Journal: Journal of Clinical Oncology (2016)

1526 Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome primarily caused by germline TP53 mutations. LFS is associated with very high lifetime cancer risk and early onset of a wide range of cancers. Cancer surveillance is challenging given the tumor spectrum, although an MRI-based regimen has shown promise. An important aim of NCI’s LFS cohort study (NCT01443468) is to establish an effective cancer-screening regimen. Methods: Individuals with a germline TP53 mutation were eligible for screening with annual rapid sequence whole-body (WB) MRI, brain MRI, and breast MRI if applicable, colonoscopy every 3 years, and blood tests every 4 months; children < 17 years also have abdominal ultrasound every 4 months. Here we report the findings at baseline screening of the first 100 participants. Results: Twenty of the 100 WB MRIs had abnormalities requiring additional imaging. Subsequent biopsies in 3 individuals led to the diagnosis of 1 stage Ib lung cancer and 1 osteosarcoma. Of the brain MRIs, 1 required additional imaging, 1 required a 6-month follow-up brain MRI, 1 showed abnormalities consistent with Multiple Sclerosis in an asymptomatic individual, 1 was positive for a frontal lobe Grade II astrocytoma, and 1 showed a small thalamic lesion with a biopsy positive for pilocytic astrocytoma. Fifteen participants had breast MRI; 2 required 6-month follow-up breast MRI, and 2 required biopsies which were found to be DCIS. None of the labs or abdominal ultrasounds showed any abnormalities. A gastric cancer was diagnosed 8 months after a negative baseline screening in a 68 year-old woman. All cancers detected were completely resected, except the pilocystic astrocytoma, which is being closely monitored. Conclusions: Of the first 100 participants enrolled in the LFS cancer screening protocol, there were 6 prevalent and 1 interval cancers; we did not expect WB MRI to detect gastric cancer. Most abnormalities identified on baseline WB MRI (18/20) did not lead to a cancer diagnosis. The frequency of false-positive MRI findings should decrease with subsequent screening. The NCI cancer screening protocol is well-tolerated and showed promise in early cancer detection. Annual screening is on-going.
Effectiveness and feasibility of neoadjuvant hormonal therapy for breast cancer patients in community setting.
Authors: Martin Majer, Tu Quach, Randell Skau, Elizabeth Johnston, Rebecca Vierra, Milton Conley, Ravi Nagubandi, Edward J. Ordorica, Tien Nguyen, Susan Schmidt, Lucie Tomanova, Steve DeMartini, Greg Schneringer, Steve Fletcher
Journal: Journal of Clinical Oncology (2016)

e12018 Background: Numerous studies have shown that neoadjuvant hormonal therapy improves breast-conservation and reduces tumor growth in hormone sensitive breast cancer patients. However, there are not many studies on the effectiveness and feasibility of this therapy in community settings. Our goal is to predict future clinical effectiveness using decrease in Ki-67, a proliferation biomarker, after short neoadjuvant hormonal treatment as an option in a regular standard oncological care in medically underserved, rural, low income community. Methods: This is a retrospective observational study where data was collected from 70 hormone sensitive breast cancer patients at Oroville Hospital in Oroville, California over a 5 year period (2011 to 2016) with ages ranging from 40 to 91 year old (median of 69.5) and an median oncotype Dx is 13 (from 48 patients). Hormone sensitive patients were offered a minimum of 2-week neoadjuvant treatment of either tamoxifen (11 patients) or an aromatase inhibitor (59 patients) during the interval between their diagnostic core biopsy and curative surgery. Five patients had stage 4 and biopsy for comparison was repeated ideally from same location for Ki-67 response value. Out of 54 patients, 49 patients had either stage 1 or 2 cancer and 5 patients had stage 4 cancer. Our primary endpoint is the number of patients with at least 50% Ki-67 reduction and proportion of patients accepting offered neoadjuvant hormonal treatment. Results: Sixteen patients had only one Ki-67 measurement and 44 out of 54 patients (81%) had at least 50% Ki-67 reduction after 2 weeks of neoadjuvant hormonal treatment (6 patients from tamoxifen group and 44 patients from aromatase inhibitor group). One patient out of the 44 achieved complete pathological response. Acceptance of neoadjuvant hormonal exposure was 70/71 (98%). Patient rejecting neoadjuvant treatment refused any medical or surgical treatment. Conclusions: Neoadjuvant hormonal therapy is a feasible option for hormone sensitive breast cancer patients of all backgrounds including rural and low income communities. Availability of mTOR inhibitors and cyclin dependent kinase 4/6 inhibitors might rekindle interest in neoadjuvant hormonal studies.
Reply to Eugenio Ventimiglia, Paolo Capogrosso, Walter Cazzaniga, Francesco Montorsi, and Andrea Salonia's Letter to the Editor re: Giovanni Corona, Giulia Rastrelli, Abraham Morgentaler, Alessandra Sforza, Edoardo Mannucci, Mario Maggi. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. Eur Urol 2017;72:1000–11
Authors: Giulia Rastrelli, Giovanni Corona, Edoardo Mannucci, Mario Maggi
Journal: European Urology (2017)
Yoga, Physical Therapy, or Education for Chronic Low Back Pain
Authors: Robert B. Saper, Chelsey Lemaster, Anthony Delitto, Karen J. Sherman, Patricia M. Herman, Ekaterina Sadikova, Joel Stevans, Julia E. Keosaian, Christian J. Cerrada, Alexandra L. Femia, Eric J. Roseen, Paula Gardiner, Katherine Gergen Barnett, Carol Faulkner, Janice Weinberg
Journal: Annals of Internal Medicine (2017)

Yoga is effective for mild to moderate chronic low back pain (cLBP), but its comparative effectiveness with physical therapy (PT) is unknown. Moreover, little is known about yoga's effectiveness in underserved patients with more severe functional disability and pain.To determine whether yoga is noninferior to PT for cLBP.12-week, single-blind, 3-group randomized noninferiority trial and subsequent 40-week maintenance phase. (ClinicalTrials.gov: NCT01343927).Academic safety-net hospital and 7 affiliated community health centers.320 predominantly low-income, racially diverse adults with nonspecific cLBP.Participants received 12 weekly yoga classes, 15 PT visits, or an educational book and newsletters. The maintenance phase compared yoga drop-in classes versus home practice and PT booster sessions versus home practice.Primary outcomes were back-related function, measured by the Roland Morris Disability Questionnaire (RMDQ), and pain, measured by an 11-point scale, at 12 weeks. Prespecified noninferiority margins were 1.5 (RMDQ) and 1.0 (pain). Secondary outcomes included pain medication use, global improvement, satisfaction with intervention, and health-related quality of life.One-sided 95% lower confidence limits were 0.83 (RMDQ) and 0.97 (pain), demonstrating noninferiority of yoga to PT. However, yoga was not superior to education for either outcome. Yoga and PT were similar for most secondary outcomes. Yoga and PT participants were 21 and 22 percentage points less likely, respectively, than education participants to use pain medication at 12 weeks. Improvements in yoga and PT groups were maintained at 1 year with no differences between maintenance strategies. Frequency of adverse events, mostly mild self-limited joint and back pain, did not differ between the yoga and PT groups.Participants were not blinded to treatment assignment. The PT group had disproportionate loss to follow-up.A manualized yoga program for nonspecific cLBP was noninferior to PT for function and pain.National Center for Complementary and Integrative Health of the National Institutes of Health.
I am a better doctor for allowing myself to stop, reflect, and grieve
Authors: Helgi Johannsson
Journal: BMJ (2017)

At 3 am on the 14 June 2017 I was woken by the loud, grating ringtone that I use for the St Mary’s Hospital major incident number. After the recent terror attacks in London my colleagues and I had become acutely aware that further major incidents could be on the horizon and I had saved the number into my favourites, allowing it to pierce through my “do not disturb” function.

After a few seconds I worked out what was happening and checked my phone. I had recently set up a WhatsApp group—which was only to be used during a major incident—for my consultant colleagues. I saw it had filled with messages about a fire where we expected mass casualties. I got up, looked out from our balcony and …
Abstract 385: D-2-hydroxyglutaric acid Acutely Impairs Oxidative Decarboxylation in the Heart
Authors: Anja Karlstaedt, Xiaotian Zhang, Hernan Vasquez, Margaret A Goodell, Heinrich Taegtmeyer
Journal: Circulation Research (2015)

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) have been described in low-grade glioma and in acute myeloid leukemia. Accumulation of the oncometabolite D-2-hydroxyglutaric acid (2HG) and its release into the blood is associated with dilated cardiomyopathy. The mechanisms leading to changes in cardiac metabolism and contractile function are unknown. We studied in the isolated working rat heart preparation metabolic consequences of increased 2HG supply and its impact on cardiac energy provision. In combination with physiological levels of glucose (5mM) and lactate (0.5mM), hearts were perfused at different concentrations with 2HG (0.5mM, 1.0mM). We confirmed the uptake and enrichment of 2HG in the tissue through liquid chromatography followed by mass spectrometry (LC/MS). 2HG markedly decreased cardiac power and cardiac efficiency in a concentration dependent manner. At the same time glucose oxidation increased significantly (1.4±0.1 μmol/min/g dry wt, p&lt;0.05) at higher workloads. The alpha-Ketoglutarate Dehydrogenase activity was reduced by two-fold (2.84±0.56 μmol/min/g dry wt, p&lt;0.01) and production of reactive oxygen species (e.g. H2O2) increased by three-fold (1.06±0.07 μmol/min/g dry wt, p&lt;0.01) in presence of 2HG. Consistent with this reduction in oxidative decarboxylation, the cytosolic NAD+/NADH redox state increased (3.1±0.1, p&lt;0.001), while the cellular energy charge declined (AMP:ATP ratio, 0.15±0.1, p&lt;0.001). Together, our results demonstrate a direct impairment of cardiac energy substrate metabolism with a resulting decline in contractile function. The data suggests that 2HG directly suppresses cardiac function by specific metabolic alterations in a range of pathologies.
Underutilization of multigene panels among Ashkenazi Jewish patients.
Authors: Jessica Fields, Dimitrios Nasioudis, Zhen Ni Zhou, Ann Carlson, Melissa Kristen Frey, Kevin Holcomb, Eloise Chapman-Davis
Journal: Journal of Clinical Oncology (2017)

1533 Background: Approximately one in forty Ashkenazi Jewish (AJ) individuals carry a BRCA1/2 mutation and genetic screening in this population has largely focused on these two genes. With the recent rapid uptake of multigene panel testing for cancer genetic assessment, we sought to explore multigene panels in our cohort which is comprised of AJ and non-AJ patients. Methods: The results of all patients with known ancestry who underwent genetic testing and counseling at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Results: One thousand six hundred and fifty patients with known ancestry underwent genetic testing over the study period, including 681 AJ patients. The median age was 49 (range 20-86). AJ patients were more likely to undergo targeted testing than non-AJ patients (74% vs. 61 %, P&lt;0.001). The use of multigene panels in AJ patients increased over time (2013 – 3.2%, 2014 – 18.7%, 2015 – 27.4%, 2016 – 48.4%, P&lt;0.001). Mutations were more common in AJ patients (75, 11% vs. 66, 7%, P=0.003). Variants of uncertain significance (VUS) were less common in AJ patients (40, 6% vs. 124, 13%, P&lt;0.001), even when excluding patients with single gene testing (32, 19% vs. 98, 27%, P=0.05). Among all patients, mutations in BRCA1/2 were most common (75%). The majority (69%) of non- BRCA1/2 mutations were identified on multigene panels. Rates of mutations in non- BRCA1/2 genes were the same among AJ and non-AJ patients (16, 21% vs. 20, 30%, P=0.3, Table 1). Conclusions: AJ patients have equivalent rates of non- BRCA1/2 mutations and on multigene panels have lower rates of VUS compared to non-AJ patients. However, the majority of AJ patients underwent targeted gene testing. These findings suggest consideration of a change in paradigm for genetic assessment of AJ patients with a focus on BRCA and non- BRCAassociated cancer genes through multigene panel testing. [Table: see text]