tbuckley/cabot-search huggingface dataset:
Abstract P2-12-09: histopathologic correlation of residual tumor in breast with residual mammographic microcalcification and magnetic resonance imaging after neoadjuvant systemic treatment
Authors: E Um
Journal: Cancer Research (2018)

Abstract Introduction. In patients with advanced breast cancer, neoadjuvant chemo-therapy is performed to increase breast conserving surgery. Although MRI is known to be accurate in predicting residual cancer after treatment, if calcification remains, the issue of whether to perform surgery based on the residual tumor prediction range in mammography and MRI has not yet been solved. The objective of this study was to estimate the accuracy of residual mammographic (MMG) microcalcification and enhancing lesion in magnetic resonance imaging (MRI) in predicting residual tumor after neoadjuvant systemic treatment (NST). Method. This is a single-center, retrospective study. We included patients with breast cancer who underwent NST and have microcalcifications in the post NST mammogram and had the surgery from January 2, 2013 to December 30, 2014. All the patients had post NST imaging exams of MMG and MRI. Final pathologic tumor size with histopathology and biomarker status was obtained after surgery. Analysis of correlation between image findings and pathology was evaluated. Result. Of 151 patients that were included in this study, 125 patients (82.8%) had residual invasive tumor and 26 patients (17.2%) had pathologic complete response. In overall, MRI correlated better than MMG in predicting tumor size (intraclass correlation coefficient [ICC] = 0.769 vs 0.651), but for HR+/HER2- subtype, MMG had higher correlation than MRI (ICC = 0.747 vs 0.575). Specially in HR- subtype, MRI had strong correlation with pathology (ICC for HR-/HER2+ = 0.939 and TN = 0.75), while MMG tend to overestimate the tumor size (ICC for HR-/HER2+ = 0.543 and TN = 0.479). Discussion. Overall post-NST residual microcalcifications on MMG have lower correlation with residual tumor size than MRI. In other than HR+/HER2- subtype, the extent of calcifications on pre-OP evaluation may not be accurate in evaluating the residual extent of the tumor after NST. Citation Format: Um E. histopathologic correlation of residual tumor in breast with residual mammographic microcalcification and magnetic resonance imaging after neoadjuvant systemic treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-09.
Exposure-Response of Idelalisib Administered in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Chronic Lymphocytic Leukemi
Authors: Vinay Manu Daryani, Shringi Sharma, Guan Xing, Jeffrey Silverman, Adeboye Henry Adewoye, Anita Mathias
Journal: Blood (2017)
Alcoholism and intrahepatic cholangiocarcinoma in a low rate population
Authors: Katherine A. McGlynn, Gloria Gridley, B. J. Stone, Lene Mellemkjaer, Ann W. Hsing, Jorgen H. Olsen
Journal: Cancer Research (2004)

476  Intrahepatic cholangiocarcinoma (ICC), the second most common form of primary liver cancer in the world, is characterized by wide variability in incidence and in risk factors. In high-rate areas, such as northeast Thailand (male rate: 88/100,000; female rate: 35/100,000), the primary risk factor for ICC is infestation with liver flukes. In low-rate rate areas, such as Denmark (male rate: 3.7/100,000; female rate: 1.8/100,000), the risk factors are poorly understood. One suggested risk factor is excessive alcohol consumption. The results of prior studies on alcohol and ICC, however, are quite conflicting, perhaps due to the small size of most of the studies. In order to examine the association in a sizable number of cases, we conducted a record-linkage study in Denmark. All cases of ICC diagnosed between 1977 and 1991 were identified using the Danish Cancer Registry. The total case group of 767 individuals was composed of 411 females and 356 males; the great majority of whom were at least 65 years old at diagnosis. Population controls (n=3068) were identified from the Danish Central Population Register and matched at a 4:1 ratio on sex and year of birth. Controls were eligible if they were free of any liver cancer and alive on the date of diagnosis of the matched case. Cases and controls were linked to the Danish Hospital Discharge Register to determine prior hospital diagnoses. Thirteen cases and 10 controls had a hospital diagnosis of alcoholism at least one year prior to the case’s diagnosis of cancer (RR= 5.27, 95% CI = 1.85-14.96). An analysis stratified by date of diagnosis of alcoholism (1-3 yrs. before cancer, 4-5 years before cancer, 6+ years before cancer), showed no difference in relative risks among the intervals. When stratified on sex, however, males were at significantly greater risk (RR= 5.85, 95% CI= 1.73-19.78) than females (RR=4.02, 95% CI= 0.52-30.99), consistent with the fact that the majority of alcoholism diagnoses were in males. While is has been previously suggested that alcohol only acts as a cofactor in the presence of pre-existing cholangitis, our data did not support this postulate. Cholangitis was present in fewer than half of the male ICC cases who had alcoholism. In addition, pre-existing cholangitis was a stronger risk factor in women (RR= 8.1, 95%CI= 1.5-43.1) than in men (RR= 4.0, 95%CI= 0.7-23.7), indicating that the ICC risk imposed by various factors may vary by sex. In conclusion, these data suggest that excessive alcohol consumption is a significant risk factor for ICC and that the risk imposed by alcohol does not require the presence of pre-existing cholangitis.
Seizures and high-grade gliomas: a UK single centre retrospective analysis
Authors: Oliver Riley, Nicholas Allcroft, Melissa Maguire, Louise Saukila
Journal: Neuro-Oncology (2018)

High-grade gliomas (HGG) originate de novo (primary) or following transformation of a low-grade glioma (secondary), and can be considered as two different pathologies, influencing clinical behaviour. Despite this, both tumour types are currently managed similarly. Limited evidence exists investigating the two as separate entities in relation to seizure activity and biochemical markers, therefore forming the focus of our study. Retrospective analysis of 132 confirmed HGG cases in a single neurosciences centre. Variables recorded: patient demographics, tumour features (cytogenetics, location, primary or transformational, grade), seizure characteristics (type/onset), anti-epileptic drugs (AED) prescribed (prophylaxis/post-seizure) and operative intervention. 132 patients analysed: mean age at diagnosis 56 (range 21–82), 1.75:1 male:female, 48% males: 40% females experienced seizures. 105:27 primary:transformational HGG. Most common tumour location: frontal (38%) and temporal (23%). 30% HGG patients initially presented with seizures, 14% developed seizures post-diagnosis. 62/132 were prescribed AEDs; 84% post-seizure, 16% prophylactically. Compared to temporal lobe, frontal lobe HGG was a significant predictor of seizures (p<0.05). Transformational HGG was significantly more likely to present with seizures (p<0.05) compared to primary HGG (88%:58%). HGG with IDH1-IDH2 mutation was significantly more likely to present with seizures (p<0.05), with a 2:1 prevalence of IDH1-IDH2 mutation in transformational:primary. Right-sided HGG was significantly more likely to cause seizures (p<0.01). No significant difference was found between seizures and MGMT hypermethylation/1p-19q co-deletion. The differing HGG pathologies appear to influence the likelihood of developing seizures. Transformational HGG and the presence of IDH1-IDH2 mutation are associated with increased likelihood of seizure at presentation. Right-sided and frontal lobe HGG are associated with both increased seizures at presentation and overall occurrence. With further analysis of AED impact, this could potentially lead to a change in management of patients with HGG. However, conclusions drawn remain complicated by the limitations of a retrospective analysis.
I work as a part time general practitioner and staff grade in genitourinary medicine. I have a background in microbiology (BSc and PhD) as well as membership of the Royal College of General Practitioners (MRCGP). I am considering the possibility of a specialist registrar position in medical microbiology but wonder about salary retention. Any advice?
Authors: Andrew Wilson
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
A phase Ia study of safety and clinical activity of atezolizumab (atezo) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Joseph W. Kim, David R. Shaffer, Christophe Massard, Thomas Powles, Lauren Christine Harshman, Fadi S. Braiteh, Paul R. Conkling, Indrani Sarkar, Edward E. Kadel, Sanjeev Mariathasan, Carol O'Hear, Christina Schiff, Marcella Fasso, Susheela Carroll, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2018)

187 Background: In the past decade, several therapies have been approved for mCRPC. However, most pts develop resistance and experience disease progression. Thus, there remains a high unmet need. Atezo (anti–PD-L1) blocks the interaction between PD-L1 and its receptors, PD-1 and B7.1, thereby restoring anti-tumor immunity. Atezo has demonstrated clinical efficacy in many tumor types. Here we report the clinical safety and activity of atezo in pts with mCRPC from a Phase Ia study (PCD4989g; NCT01375842). Methods: Eligible pts previously received enzalutamide and/or sipuleucel-T for mCRPC. Pts also had PSA or radiographic progression prior to enrollment. Atezo 1200mg was administered IV q3w. CT and bone scans were performed q6w for 24w and q12w thereafter (q6w if treatment beyond disease progression). Primary objectives were safety and tolerability; OS was an exploratory objective. mCRPC cohort–specific objectives included PSA response, radiographic progression per PCWG2 criteria, soft tissue response per RECIST v1.1 and immune-related response criteria (irRC). Survival follow-up data was collected ≈ every 3 mo until death or loss to follow-up. Results: The 15 pts in the initial mCRPC cohort were evaluated (clinical cutoff: December 31, 2016). 13 pts (87%) had received ≥ 2 prior lines of therapy for mCRPC. Median survival follow-up was 15.8 mo (range, 2.3-23.0). 9 pts (60%) had a treatment-related AE (TRAE); only 1 pt (7%) experienced a Gr 3 TRAE (hyponatremia). No Gr 4-5 TRAEs were reported. The landmark 12-mo OS rate was 55.6% (95% CI: 27.4, 83.7); median OS was not reached (range, 2.3-23.0 mo). Median PFS was 3.4 mo (95% CI: 2.3, 5.7); the 6-mo PFS rate was 26.7% (95% CI: 4.3, 49.1). 1 pt (9%) had a PR per irRC (irPR); 5 pts (45%) had SD per RECIST v1.1 and irRC. 2 pts (13%) had a ≥ 50% decrease in PSA from baseline. The pt who experienced an irPR had increased CD8 expression and expansion of T-cell clones on study treatment. Conclusions: Atezo was well tolerated and demonstrated long-term disease control in pts with heavily pretreated mCRPC, with a 12-mo OS rate of 55.6%. Preliminary biomarker analyses from the pt who experienced an irPR were suggestive of an activated immune response. Clinical trial information: NCT01375842.
Peripheral artery disease
Authors: Rachael L Morley, Anita Sharma, Alexander D Horsch, Robert J Hinchliffe
Journal: BMJ (2018)

What you need to know• Most people with peripheral artery disease are asymptomatic • Peripheral artery disease is associated with a high risk of vascular complications such as myocardial infarction, stroke, vascular dementia, renovascular disease, and mesenteric disease• Few patients with intermittent claudication develop limb-threatening complications (1-3% in 5 years)• Management of risk factors-including smoking, diabetes, and dyslipidaemia-is key to reducing the risk of vascular complications• Patients with critical limb ischaemia are at high risk of limb amputation and premature death
Profile of programmed death ligand-1 (PD-L1) expression and <i>PD-L1</i> gene amplification in Indonesian colorectal cancer patients.
Authors: Akterono dwi Budiyati, Teguh Pribadi Putra, Gita Dewi Kusumo, Fritzie Rexana, Antonius Kurniawan, Aru Wisaksono Sudoyo, Ahmad Rusdan Utomo, Andi Utama
Journal: Journal of Clinical Oncology (2018)

82 Background: The presence of the programmed death ligand-1 (PD-L1) has been used as biomarker to select patients and analyze responses to anti-PD-1/L1 antibodies. PD-L1 positivity may be a result of genetic mechanism leading to constitutive PD-L1 expression or inducible mechanism by T-cell presence. Each mechanism may have different significance and response to such therapy. In colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). This study aimed to investigate the mechanism of PD-L1 gene activation in colorectal cancer (CRC) patients, particularly in MSI population. Methods: We have investigated 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using Single Tube TaqMan CNA Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Results: Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) patients (15%; 8/53) (P = 0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). We found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlated with PD-L1 expression. Conclusions: Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.
Nucleosidic DNA demethylating epigenetic drugs – A comprehensive review from discovery to clinic
Authors: Khushboo Agrawal, Viswanath Das, Pankhuri Vyas, Marián Hajdúch
Journal: Pharmacology & Therapeutics (2018)

DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.
Evaluation of the timing of adjuvant mitomycin C following nephroureterectomy for urothelial carcinoma of the upper urinary tract.
Authors: Blake Noennig, Shahab Bozorgmehri, Russell Terry, Brandon Otto, Mike Blute, Li-Ming Su, Paul Crispen
Journal: Journal of Clinical Oncology (2018)

444 Background: Results of randomized trials support a single dose of intravesical chemotherapy (IVC) following radical nephroureterectomy (RNU) for urothelial carcinoma. Our goal was to evaluate the impact of the timing of intravesical mitomycin C (MMC) administration on the rate of bladder tumor recurrence (BTR) following RNU. Methods: After obtaining IRB approval, we performed a retrospective review of patients who underwent RNU for upper tract urothelial carcinoma (UTUC) and received intravesical MMC between 2008 and 2016 at our institution. Patients were categorized into two separate groups based on the timing of MMC administration: (1) patients who received MMC on the day of surgery (POD0) and (2) patients who received MMC on post-operative day 1 or later (POD1). Our primary endpoint was BTR rate within the first year after surgery. Our secondary endpoint was overall BTR rate. Results: Fifty-one patients met our inclusion criteria: (POD0: n = 30; POD1: n = 21). Mean length of follow-up for each group was 22.1 and 12.5 months, respectively (p = 0.02). There were no statistically significant differences in baseline characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, surgical margins, nodal status, concomitant CIS, or history of bladder cancer. BTR rates at 1 year for the POD0 and POD1 groups were 16% and 33%, respectively (p = 0.17). Overall BTR rates were 23% and 33%, respectively (p = 0.43). Multivariate analysis noted that the POD0 patients had a significantly lower rate of BTR in the first year postoperatively (HR = 0.082, 95% CI = 0.01-0.56, p = 0.01). Other factors that were associated with a higher rate of BTR within the first year were open surgery (HR = 7.9, 95% CI = 1.18-53.88, p = 0.03), positive surgical margins (HR = 37.9, 95% CI = 1.74-825.35, p = 0.02), and concomitant CIS (HR = 10.8, 95% CI = 1.08-108.72). Conclusions: Our results suggest that the timing of intravesical MMC administration may impact the rate of BTR following RNU for urothelial carcinoma. This is the first study of its kind to attempt to identify the importance of timing of MMC administration relative to BTR following RNU. Further prospective studies are warranted to validate our current findings.
VASODILATORY EFFECT OF PERIVASCULAR FAT ON SAPHENOUS VEIN GRAFT FROM PATIENTS UNDERGOING CORONARY ARTERY BYPASS GRAFTING
Authors: Toshiyuki Yamada, Takeshi Adachi, Yasuo Ido, Nobuyuki Masaki, Takumi Toya, Hisao Suda, Motohiko Osako, Tomoya Uchimuro, Kosaku Nishigawa, Masataka Yamazaki, Shuichiro Takanashi, Hideyuki Shimizu
Journal: Journal of the American College of Cardiology (2018)
Nivolumab demonstrates benefit over nomogram-predicted 12-month survival as salvage therapy for metastatic urothelial carcinoma.
Authors: Gregory Russell Pond, Guru Sonpavde, Matt D. Galsky, Padmanee Sharma, Jonathan E. Rosenberg, Toni K. Choueiri, Joaquim Bellmunt, Jae-Lyun Lee, Soon Il Lee, Alex Azrilevich, Shuo Yang, Kyna McCullough Gooden, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2018)

451 Background: Intermediate endpoints of benefit in metastatic urothelial carcinoma (mUC) nonrandomized trials are necessary to identify promising drugs, particularly for checkpoint inhibitors, where response and progression-free survival remain suboptimal. We previously reported a nomogram (Pond GR et al, 2017 GU Cancers Symposium) using 5 prognostic factors (hemoglobin &lt; 10 g/dL, Eastern Cooperative Oncology Group performance status ≥1, presence of liver metastasis, time from last treatment ≤3 months, and albumin &lt; lower limit of normal) from phase 2 trials of historical agents (eg, taxanes) to estimate 12-month overall survival (OS), against which observed survival could be compared. Nivolumab was granted approval as salvage therapy for patients with mUC, based on the CheckMate (CM) 275 trial; it is thus of interest to compare the nivolumab observed survival versus nomogram-predicted survival results. Methods: Data were obtained from CM 275, including survival and all 5 prognostic factors. Nomogram points were calculated and the expected 12-month OS was estimated. Bootstrap analyses based on 2000 replications were used to estimate 95% confidence intervals (CIs) for the median expected, observed, and difference between the expected and observed 12-month OS values. All tests were 2-sided, with statistical significance defined as P≤0.05. Results: Data were available from 270 patients from CM 275. Fifteen patients did not have albumin recorded and were excluded. Among the 255 evaluable patients, 46 (18.0%) patients had 0 adverse prognostic factors, 85 (33.3%) had 1, and 124 (48.6%) had 2 or more. The observed nivolumab 12-month OS from CM 275 (43.3% [95% CI, 37.0%-50.5%]) was 19.8% higher (95% CI, 13.6%-26.4%) when compared with the nomogram-predicted 12-month OS (23.5%; [95% CI, 22.5%-25.5%]) if patients received historical chemotherapy. Across all 2000 bootstrap samples, the observed nivolumab 12-month OS exceeded the nomogram-predicted 12-month OS. Conclusions: Nivolumab was associated with a significantly improved 12-month OS compared with historical chemotherapy based on the value predicted by the validated nomogram incorporating baseline prognostic factors. Clinical trial information: NCT02387996.
Patient groups urge government to implement revalidation this year
Authors: Caroline White
Journal: BMJ (2012)

Patient representative groups have urged the government to “green light” revalidation without further delay, on the grounds that patients need to know that the doctor treating them is competent and safe to practise.

The system of checks of a doctor’s competence and fitness to practise every five years is scheduled to start at the end of this year, with a statement to this effect expected from the health secretary, Andrew Lansley, …