tbuckley/cabot-search huggingface dataset:
Your advice to new medical students
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2015)

The application process for medical school entry is long and tough. For this month’s new university entrants, it began over two years ago with selection of A-Level topics, followed by AS Level exams a year later, and then university application and BMAT and UKCAT exams. They probably attended courses on how to pass exams and embarked on relevant work placements. A few months ago, they sat A-Level exams in pursuit of A* and A grades. Last month, the culmination of that effort was rewarded with results that opened the door to a medical career.

But how must these young people feel when any news about their new profession is dominated by unhappiness and discontent? The organisations that they will eventually join are demoralised and on the brink of financial collapse. The representatives of their profession are in a poisonous daily battle with the government. From the press and media reports, from speaking to doctors, they will learn that medical practice is in turmoil. The stock of doctors is so low that they are even berated by football managers for caring for their patients. Might today’s new medical students not feel cheated? Have they been a sold a future of uncertainty and insecurity?

Medicine was once a career that offered a predictable career path for the wide spectrum of personalities it attracted. Social revolutionaries and free marketeers felt equally comfortable that medicine was a vehicle to fulfil their ambitions. There was some sense of what you were letting yourself in for. At the very least, it was a job for life, with respect from the public and your patients, and the prospect of job satisfaction. Today’s medical students will need to prepare themselves for constant change and uncertainty, as technology, finances and politics force innovation and efficiencies. Medical practice may be transformed in five years as new delivery models like integrated care become widespread and funding models evolve.1 The NHS may survive in name, but how it will work is difficult to know.

My guess though is that this year’s new intake of medical students will be unworried. Young people tend to be optimistic about their future and their ability to succeed. Medical students are brighter than they have ever been; their exam results speak for themselves. Whether exam machines become the best doctors or not is a separate debate. Medicine, despite the prevailing doom and gloom, remains a well-paid, highly desirable profession.

These constants, however, do not hide the transformation in medicine that is underway. How much will the practice of medicine change in five years and what advice would you give new medical students? In these uncertain times, can you predict the future of medicine? Can you summon the wisdom of Lord Polonius to benefit the next generation of doctors as the wind sits in the shoulder of their sail? Write to us and we’ll publish the best submissions in our Podium section.
PICOT gene expression levels can predict survival and recurrence among malignant pleural mesothelioma patients
Authors: Anil Wali, Patrice J. Morin, Colleen D. Hough, Fulvio Lonardo, Deepa Kanakapalli, Zhandong Liu, Julia Sluchak-Carlsen, Sorin Draghici, Michele Carbone, Amon Altman, Harvey I. Pass
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

878 

Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by rapid progressive local growth, late metastases, and poor prognosis despite aggressive strategies involving surgery, chemotherapy, and radiation. Upregulation of the thioredoxin/thioredoxin reductase system has been implicated in cell growth, differentiation and apoptosis in MPM. We have studied gene expression pattern differences between a surgically resected MPM and the patient’s autologous normal peritoneum using Serial Analysis of Gene Expression (SAGE) and Affymetrix U133AB microarrays. SAGE revealed a significant induction of 38-fold in the expression of thioredoxin-like 2, PKC-Interacting Cousin Of Thioredoxin (PICOT) gene in the tumor compared to normal peritoneum. PICOT is a novel Ca2+-independent protein kinase C-interacting protein which has an N-terminal thioredoxin homology domain required for its interaction with protein kinase C. We have validated PICOT over expression in 23/44 mesothelioma tumor samples by immunohistochemical (IHC) studies and confirmed in vitro differential PICOT gene expression levels in MPM cell lines and cultured mesothelial cells. Five out of six MPM derived cell lines had significantly higher (>2-fold) levels of PICOT gene expression compared to three normal mesothelial cultures. PICOT overexpression in mesothelioma tumor samples was reflective of shorter survival (p<0.006) and rapid recurrence (p<0.007) among a group of twenty-four MPM patients who underwent cytoreductive surgery. These data are suggestive of a critical role for PICOT gene expression during pathogenesis of mesothelioma which might have potential prognostic, and therapeutic implications in the management of this disease.
MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue
Authors: Xinghui Sun, Jibin Lin, Yu Zhang, Sona Kang, Nathan Belkin, Akm K. Wara, Basak Icli, Naomi M. Hamburg, Dazhu Li, Mark W. Feinberg
Journal: Circulation Research (2016)

The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function. To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity. MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression. Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or Pleckstrin homology domain leucine-rich repeat protein phosphatase inhibitors may represent a new therapeutic approach to ameliorate insulin resistance by improving adipose tissue endothelial Akt-endothelial nitric oxide synthase-nitric oxide signaling.
Suicide clustering in a psychiatric hospital with a history of a suicide epidemic: a quantitative study
Authors: T J Taiminen, H Helenius
Journal: American Journal of Psychiatry (1994)

To determine if the suicides in a Finnish psychiatric hospital with a history of a suicide epidemic were clustered and if the sex distribution of the suicides followed a random pattern, the authors conducted statistical analyses of the temporal distribution and sex distribution of 59 consecutive inpatient suicides over the years 1967-1992 in the hospital. They found no statistically significant temporal clustering and that the sex distribution of the suicides was random. They conclude that inpatient suicide epidemics seem to be rare and separate events, related more to temporary micro-social factors and to the psychopathology of individual patients than to permanent characteristics of a particular hospital.
Abstract MP06: Gait Speed is Associated with Subclinical and Clinical Atherosclerosis - Analysis from the AGES Reykjavik Study
Authors: Vilmundur Gudnason, Kristin Siggeirsdottir, Lenore J Launer, Tamara B Harris, Thor Aspelund
Journal: Circulation (2014)

Background: Coronary events are major causes of morbidity and mortality in the population and are consequences of atherosclerotic coronary artery disease. The development of atherosclerosis is a long standing process. Measuring subclinical atherosclerosis allows examination of the determinants of the disease without using hard end points. We studied the functional ability of individuals measured as gait speed and its relationship with prevalent subclinical atherosclerosis and incident coronary events. Material and Methods: Participants were from the AGES Reykjavik Study, a population study of 5174 men and women (57%), mean age 76.5 (SD 5.5) followed for coronary events (MI, PCI, CABG) for a median of 8.1 years. Subclinical atherosclerosis (IMT and plaque) was examined with ultrasound of the carotid arteries and Agatston score of coronary artery calcium (CAC) by CT at entry into the study. Gait speed was measured by time of 6 m walk. Cox proportional hazard was used to assess the effect of gate gait speed, on CHD events, verified from hospital records. Logistic regression was used to estimate the association of subclinical CHD to atherosclerosis, adjusted for baseline age, sex and CHD risk factors. Results: There was a gradual increase in risk of CHD by quintile of 6m walk speed with HR of 2.0 (95% CI 1.7 - 2.4) in the top compared to bottom quintile adjusted for age and sex. After further adjustment for conventional risk factors attenuation to a HR of 1.8 (95% CI 1.5 - 2.2) was seen. When the subclinical markers was examined, there was a gradual increase in CAC by slower gate speed (p&lt; 0.0001), much more pronounced in men, who had higher CAC than women. Similar picture was seen for plaque (p &lt;0.0001) in the carotid arteries, but a statistically significant association was not found for IMT (p=0.09). Conclusion: Gait speed is strongly associated with manifest CHD in this population of free living old people. When subclinical measurements of arterial disease are used, those clearly measuring atherosclerosis - CAC and plaque of the carotid - are associated with worse gait speed. On the other hand gait speed was not associated with IMT, which much less clearly reflects atherosclerosis. The simple physical performance test, of the time it takes to walk 6 m used in this study, captured clinical CHD and subclinical cardiovascular status measured by imaging. This simple performance measurement might therefore be of potential use for peripheral practitioner in selecting those individuals who might benefit from detailed cardiovascular assessment.
Institutional retrospective review of presurgical cisplatin-based chemotherapy (chemo) in patients with urothelial carcinoma (UC): Gemcitabine+cisplatin (GC) versus dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC).
Authors: Lauren Christine Harshman, Susanna J. Jacobus, Stephanie A. Mullane, Hope Feldman, Michelle S. Hirsch, Philip W. Kantoff, Toni K. Choueiri, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2015)

365 Background: Neoadjuvant cisplatin-based chemo is the standard of care for muscle invasive UC. ddMVAC and GC are frequently used regimens but have not been directly compared. The choice is often based on physician preference and toxicity profile. We interrogated a pre-existing database of UC patients (pts) for differences in efficacy and toxicity among them. Methods: From 2007-2013, consecutive pts who had received presurgical chemo prior to primary tumor resection for muscle invasive, non-metastatic UC were identified. Tolerability, toxicity and efficacy were evaluated. Rates were calculated by regimen and compared using Fisher’s exact test. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by regimen using logrank test. Cox regression estimated hazard ratios (HR) in univariate and adjusted models. Results: Of the96 patients eligible for analysis (GC: 40, ddMVAC: 56), 42% of GC pts had ≥cT3 and 23% had cN+ compared to 62% and 39% with ddMVAC. pCR rate was 18% for GC and 27% for ddMVAC (p=0.33). With a median follow-up of 28 mo., 2-yr OS probabilities were 59% [95% CI:(39-74)] on GC and 77%[95%CI:(60-87%)] on ddMVAC (p=0.1). Conclusions: Despite having more clinical ≥T3 and node positive disease at baseline, ddMVAC is at least as active as GC and achieved a numerically higher rate of pCRs/≤pT1 than GC in our cohort. No unexpected toxicities surfaced. Dose delays, discontinuations, and most selected toxicities appeared higher with GC. Neither DFS or OS significantly differed between the two regimens, however, there was a trend to greater benefit with ddMVAC. [Table: see text]
Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy.
Authors: I F Ciernik, U Meier, U M Lütolf
Journal: Journal of Clinical Oncology (1994)

Stage III and stage IV thymomas with significant macroscopic infiltration to the neighboring structures are rarely completely resectable. It therefore remains unclear to what extent tumors must be surgically debulked to improve prognosis.We reviewed the cases of 31 patients with incompletely resected invasive thymoma and residual macroscopic disease who were referred to postoperative irradiation. Survival and local tumor control were analyzed. All patients were treated between 1958 and 1990 with megavoltage irradiation at doses ranging from 42 to 66 Gy. The shortest follow-up time for living patients was more than 5 years.The overall median 5-year survival rate was 45%. Eighteen stage III patients had a 5-year survival rate of 61% and a 10-year survival rate of 57%. Thirteen patients had stage IV disease and 5- and 10-year survival rates of 23% and 8%, respectively. Univariate and multivariate analyses confirmed a worse prognosis for stage IV disease. Epithelial or spindle-cell thymoma was associated with stage IV disease. Twenty-two percent of patients with stage III disease had epithelial or spindle-cell thymoma, versus 69% of patients with stage IV disease (P = .02 for univariate and P = .05 for multivariate analysis). Initial tumor diameter greater than 10 cm correlated with poor prognosis in the univariate analysis (P = .05). However, more importantly, debulking of tumor did not significantly improve outcome when compared with patients who received biopsy only. The median survival rate of patients with stage IVa disease did not differ from that of those with stage IVb disease. Mediastinal control was achieved in 23 patients (74%). Stage IV disease did not correlate with an increase in local treatment failure after irradiation, although epithelial or spindle-cell thymoma predisposed for local treatment failure (46% v 11%; P = .04 in univariate and P = .055 in multivariate analysis).Tumor debulking leaving macroscopic residual thymoma, as opposed to biopsy alone, does not improve prognosis when followed by radiation. Radiation therapy for local tumor control is most effective in nonepithelial-predominant thymomas.
Over half of eligible people don’t go for bowel cancer test in pilot areas
Authors: Jacqui Wise
Journal: BMJ (2015)

Overall uptake for a pilot bowel cancer screening programme in England using flexible sigmoidoscopy was 43%, dropping to 33% in the most deprived areas, an analysis has shown.

The report, published in the Journal of Medical Screening , covered 21 187 invitations sent to eligible people in six pilot areas during the first 14 months of the programme—March 2013 to May 2014.1 The six screening centre areas were in London, Norwich, Surrey, Tyneside, west Kent, and Wolverhampton. An explanatory letter was sent to all men …
Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth
Authors: Ditte Mølgaard-Nielsen, Henrik Svanström, Mads Melbye, Anders Hviid, Björn Pasternak
Journal: JAMA (2016)

Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information.To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth.Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group.Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression.Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.
Intratumoral chemotherapy as an adjunct to endobronchial brachytherapy
Authors: D. Nader, P. Ketterl, D. Kelly, J. Flynn, J. J. Stark, E. D. Staren, D. P. Braun
Journal: Journal of Clinical Oncology (2009)

7591 Background: NSCLC patients (pts) with clinically significant endobronchial obstruction have a poor prognosis and quality of life in both locally advanced and metastatic stages of disease. Radiation therapy (RTx) in conjunction with chemotherapy (CTx) improves survival compared to either modality alone but produces greater toxicity and morbidity. Significant clinical benefit with respect to disease management and quality of life could be realized with improved methods for controlling obstructing endobronchial lesions. The hypothesis for this study is that optimal clinical control of endobronchial lesions can be achieved by intratumoral injection of a drug with both clinical activity against NSCLC and synergy with RTx. Cisplatin (CPt), an active agent in NSCLC and a known radiosensitizer is an ideal drug for this objective. Thus, the goal of this exploratory study was to determine the clinical efficacy and tolerance to intratumoral CPt injection in combination with HDR brachytherapy (BTx) in NSCLC patients with obstructing endobronchial lesions. Methods: NSCLC pts (n=16) with &gt; 75% endoluminal obstruction of a main or lobar airway were evaluated. Intratumoral CTx consisted of CPt (1 mg/ml; 0.5–2.0 ml/session) injected into the entire visible tumor through a flexible 21 gauge needle through the bronchoscope. BTx was given as 500 cGy/session at one cm diameter for 4 sessions concomitant with CTx. Results: All pts completed the entire 4 sessions of planned local therapy. There was complete resolution of injected lesions in 14/16 pts confirmed bronchoscopically and cytologically. In the other 2 pts, necrotic tissue occupying &lt; 10 and 20% of the airway, cytologically negative for tumor was seen. There were no adverse events or complications related to bronchoscopy or local CTx. Conclusions: The results of this study demonstrate that intratumoral administration of CPt, as an adjunct to endobronchial BTx for the management of endobronchial obstructing lesions in patients with NSCLC is safe and effective. This approach offers the possibility of superior local tumor control while reducing toxicity to normal lung and esophagus as compared to conventional external beam radiation therapy modalities. Further studies evaluating the impact of this approach on survival and quality of life are warranted. No significant financial relationships to disclose.
Osteonecrosis of the jaw (ONJ) among intravenous (IV) bisphosphonate- and/or bevacizumab-treated patients (pts) at Memorial Sloan-Kettering Cancer Center (MSKCC)
Authors: H. L. McArthur, C. Estilo, J. Huryn, T. Williams, M. Fornier, T. A. Traina, J. Howard, C. A. Hudis, M. N. Dickler
Journal: Journal of Clinical Oncology (2008)

9588 Background: ONJ is diagnosed with increasing frequency among IV bisphosponate (IVBP)-treated cancer pts, in the range of 1–10 per 100 treated pts depending on duration of therapy (Khosla 2007). The etiology and specific incidence of this phenomenon is uncertain. However, ONJ pathogenesis may reflect defects in bone remodeling or wound healing (Ruggiero 2006). Bevacizumab (B) is an anti-vascular endothelial growth factor (VEGF) antibody that has demonstrated significant benefits alone or in combination with chemotherapy for several cancers. As an anti-angiogenesis molecule, B may exacerbate IVBP-induced ONJ. We report the results of a retrospective, single institution study of incident ONJ cases among IVBP- and/or B-treated pts. Methods: Institutional databases were surveyed to identify the 8,681 pts treated with IVBPs (pamidronate and/or zoledronic acid) and/or B between January 1, 2001 and October 24, 2007 at MSKCC. Incident ONJ diagnoses were identified from the MSKCC dental database and described by treatment cohort. Results: Of the 80 IVBP- and/or B- treated patients diagnosed with ONJ within the study period, the median age at ONJ diagnosis was 64.2y (range 25.9–91.6y) and 47 (59%) were female. 38 (47.5%) had breast cancer, 20 (25%) multiple myeloma, 14 (17.5%) prostate cancer, 4 (5%) lung cancer, and 4 (5%) another primary. The incidence of ONJ by treatment cohort was 72 (1.1%) of the 6,561 patients treated with IV pamidronate and/or zoledronic acid alone; 0 (0%) of the 1,711 pts treated with B alone; and 8 (2.0%) of the 409 patients treated with the combination of B and IV pamidronate and/or zoledronic acid. Conclusions: There is a modest risk of ONJ with IVBP administration which may be compounded by B administration. However, B administration alone does not appear to be associated with significant ONJ risk. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Novartis, Abraxis, Roche Genentech, Amgen, GlaxoSmithKline, Novartis, Abraxis, Roche Genentech, Novartis, Abraxis, Roche