tbuckley/cabot-search huggingface dataset:
Are we overtreating subclinical hypothyroidism in pregnancy?
Authors: Kate Sophie Wiles, Sheba Jarvis, Catherine Nelson-Piercy
Journal: BMJ (2015)

#### The bottom line

Overt hypothyroidism is diagnosed with a high serum thyroid stimulating hormone (TSH) concentration in conjunction with a low serum thyroxine concentration or an isolated TSH concentration above 10 mU/L. Subclinical hypothyroidism is a biochemical diagnosis based on a high TSH concentration with normal thyroxine.

The benefits of treating overt hypothyroidism during pregnancy include improved obstetric and neonatal outcomes. However, evidence for the management of subclinical hypothyroidism and appropriate treatment targets in pregnancy are lacking. Despite this, international guidelines have set a low TSH threshold for the diagnosis and treatment of both new and pre-existing hypothyroidism in pregnancy.1 2 This threshold potentially increases the prevalence of subclinical hypothyroidism in pregnancy and may “medicalise” women despite a lack of clear evidence that treatment improves outcome.

We reviewed the evidence used to produce international guidelines on hypothyroidism and pregnancy.1 2 In addition, we searched PubMed, Web of Science, and Google Scholar by using the terms subclinical hypothyroid*, thyroxine, thyroid, and thyrotropin in combination with pregnan* and miscarriage to find additional data from randomised trials, cohort studies, systematic reviews, and meta-analyses published between 1990 and 2014.

### What is a “normal” TSH in pregnancy?

The upper limit for TSH outside of pregnancy is 4.12 mU/L.3 However, guidelines recommend a TSH concentration of less than 2.5 mU/L in the first trimester,1 despite the fact that observational studies give a much broader normative range for TSH, especially when …
Combination of intravenously delivered cavatak (coxsackievirus A21) and immune-checkpoint blockade significantly reduces tumor growth and tumor rechallenge
Authors: Min Yuan, Yvonne Wong, Gough Au, Darren Shafren
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Coxsackievirus A21 (CAVATAKTM) is a bio-selected oncolytic immunotherapy virus. Following intravenous (i.v) administration, CAVATAK can preferentially infect ICAM-1 expressing tumor cell, resulting in tumor cell lysis and generate a potential systemic immune-mediated anti-tumor
Consistent variation in amino-acid substitution rate, despite uniformity of mutation rate: protein evolution in mammals is not neutral.
Authors: S Easteal, C Collet
Journal: Molecular Biology and Evolution (1994)

Variation in mutation rate, attributed to differences in both generation time and in metabolic rate, has been invoked under the neutral theory of molecular evolution to account for differences in substitution rate among mammalian lineages. We show that substitution rates at fourfold-degenerate sites and at sites in noncoding regions do not vary between the primate and rodent lineages, implying mutation-rate uniformity. In contrast, the substitution rates at nondegenerate sites vary both within and between lineages. This difference in substitution-rate pattern between the two types of site is incompatible with neutral theory but may result from substitutions occurring by fixation of slightly deleterious mutations. Variation in the rate of protein evolution among mammalian lineages appears to be due more to differences in population fixation rates than to biochemical or physiological differences affecting mutation rates.
Timing of metastatic dissemination in primary colorectal cancer correlates with tumor aggressiveness
Authors: S. D. Finkelstein, P. A. Finkelstein, M. M. Wilson, A. Radfar
Journal: Journal of Clinical Oncology (2005)

3666 Background: Microscopic evaluation of colorectal cancer confirms the presence of tumor, classifies degree of differentiation and defines pathology stage. Morphologic analysis does not define tumor biological aggressiveness or treatment responsiveness on an individual patient basis. We developed and evaluated here a tissue microdissection approach targeting multiple microscopic sites with detailed molecular characterization of colorectal cancer that delineates the unique timeline of mutation accumulation and timing of metastatic dissemination for each cancer. Methods: 21 colorectal cancer patients with T1N1 (n=4), T2N1/M1 (n=7), T3N1/M1 with poor outcome (n=5) and T3N1 long survival (n=5) disease were microdissected using unstained formalin fixed, paraffin embedded standard tissue sections. Microdissection targets consisted of one non-neoplastic site, two sites of greatest primary site invasion and multiple lymph node and hepatic metastasis. Each microdissected sample was quantitatively genotyped and time course determined using a broad panel of mutational damage including k-ras-2 point mutation and LOH for 1p,3p,5q, 9p,10q,17p,17q,21q,22q. Results: There was a progressive increase in acquired discordant mutational change between primary and metastatic sites (T1[0–2]<T2[2–4]<T3[4–8] correlating with metastasis from precursor cells at an earlier stage of invasion. Total mutational load was higher in T3N1/M1 patients with poor survival than for those with good survival (p<.001). For T3NI neoplasms, metastatic precursor cell at the time was deeper (more recent) in the bowel wall than for patients with poor overall survival (p<.01). Liver metastasis could be shown to have arisen from precursor cells in the primary site and not from lymph node metastasis. Conclusions: Aggressive colorectal cancer possesses a high cumulative mutational load with timing of metastasis occurring early in bowel wall invasion. Indolent colorectal cancer of equal T stage shows a lower level of mutations with later timing of metastasis. Microdissection based mutational profiling can characterize colorectal cancer biological aggressiveness in a new and biologically meaningful manner. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration RedPath Integrated Pathology RedPath Integrated Pathology RedPath Integrated Pathology RedPath Integrated Pathology
A phase II multicenter trial of paclitaxel and carboplatin in women with advanced or recurrent malignant mixed müllerian tumors (MMMT) of the uterus
Authors: L. M. Ramondetta, R. A. Lacour, E. D. Euscher, R. B. Iyer, E. N. Atkinson, J. B. Gano, M. R. Milam, P. T. Ramirez, C. F. Levenback, T. W. Burke
Journal: Journal of Clinical Oncology (2007)

5589 Background: Systemic therapy for advanced malignant mixed müllerian tumor of the uterus (MMMT) after surgery has been disappointing. Currently, the most common treatment regimen is ifosfamide and platinum. Moderate success has been documented using paclitaxel in MMMT of the ovary. The purpose of this study is to evaluate carboplatin and paclitaxel in patients with advanced (IIIb-IVb) and recurrent MMMT of the uterus. Methods: A single arm, prospective, non-randomized phase II trial opened in October 2001. The planned sample size is 37 evaluable patients, with time to progression and response rate as the primary endpoints. Patients receive carboplatin (AUC 5) and paclitaxel (175 mg/m 2 ) every 21 days. Patients treated adjuvantly receive a total of 6 cycles or until progression or toxicity. Patients with disease present at study entry are treated until progression or toxicity. Results: To date, 18 patients have been enrolled. Seven patients received adjuvant treatment and 11 patients had documented disease at study entry. In the adjuvant group, the median progression-free interval was 15.8 months and median overall survival from treatment initiation was 20.2 months. Four of these 7 patients (57%) continue to be followed with a median follow-up of 19.2 months. In the patients with documented disease, the median progression- free interval was 7.8 months and the median overall survival from treatment initiation was 12.4 months. In this group, there were 3 complete and 4 partial responses (63.6% response rate). Over 45% of patients with disease at study entry are alive with a median follow-up of 14.0 months. Four patients experienced grade 4 granulocytopenia. Only two (11%) had treatment-limiting toxicity, one with grade 3 neuropathy and one with grade 3 fatigue. Conclusions: Carboplatin and paclitaxel appear to have improved tolerability and response rate (63.6%) compared to previous reports of ifosfamide and cisplatin (33% RR) in treating MMMT of the uterus. This regimen seems extremely promising and we are awaiting the final results of this trial. No significant financial relationships to disclose.
Limitation of immunohistochemisty in predicting the outcome of patients treated for germinal center diffuse large B-cell lymphoma
Authors: C. Chini, M. Cergnul, S. Uccella, C. Placidi, I. Proserpio, S. Marchet, C. Capella, G. Pinotti
Journal: Journal of Clinical Oncology (2008)

8604 Background: Although International Prognostic Index (IPI) actually represents the most useful prognostic score in patients (pts) with diffuse large B-cell Lymphoma (DLBCL), pts at same risk could show a different outcome. Germinal center (GC) subtype defined by tissue microarrays in DLBCL has been found as a good prognostic parameter compared to non-germinal center (n-GC) profile. These data, valuated with immunohistochemistry, were confirmed by some but not all authors. Methods: On 105 consecutive pts with DLBCL referred to our institution between 1990 and 2005 and treated with an antracycline based regimen with or without rituximab, we undertook a retrospective immunohistochemical study on 3 μm-thick section obtained from 73 well preserved paraffin block. We analyzed the expression of CD10, Bcl-6, mum1 and Bcl-2 and classified the pts as GC or n-GC according to the Hans’ algorithm. The sample was scored positive for Bcl-6, mum1, CD10 if 30% or more of tumor cells were stained and for Bcl-2 if there was at least 50% of tumor cells positive. Combining Bcl-2 with the GC/n-GC markers we also classified pts in 2 prognostics group as proposed by Muris’ algorithm. Results: We identified 30 GC type DLBCL pts (41%) and 43 n-GC type DLBCL pts (59%) according to the Hans’ algorithm, while 33 GC type DLBCL pts (45%) and 40 n-GC type DLBCL pts (59%) were found with the Muris’ system. Pts characteristics were well balanced between the two subtypes. With a median follow-up time of 29 months, PFS and OS was not different between GC an n-GC pts (p=0.4 and p=0.6 respectively); Same results occurred with the Muris’ algorithm. Multivariate analysis confirmed that only IPI score (p<0.001), bcl-6 (p=0.03) and treatment arm including rituximab (p=0.04) influence the OS and PFS. Although rituximab was delivered only in 20 pts no differences between GC and n-GC were observed dividing the patients according the treatment regimens. Conclusions: The immunohistochemical determination of the GC/n-GC immunophenotype, proposed as a less expensive technique, failed to predict the outcome of DLBCL pts in our study. Randomized trials, including the identification of new markers and the determination of the optimal cut-offs, are needed. No significant financial relationships to disclose.
The reliability and validity of the M. D. Anderson Symptom Inventory (MDASI-HN) as a measure of symptom burden in the head and neck cancer (HNC) patient population
Authors: D. I. Rosenthal, M. S. Chambers, T. R. Mendoza, J. A. Asper, M. S. Kies, R. S. Weber, A. S. Garden, K. K. Ang, X. S. Wang, C. S. Cleeland
Journal: Journal of Clinical Oncology (2005)

8097 Background: The aims of this study are to validate a symptom inventory in patients with HNC for reliability in identifying the occurrence and severity of symptoms, and overall symptom burden. Methods: Multiple cancer related symptoms impact quality of life, mood, disease progression, and survival. Symptom burden is not routinely measured in HNC patients. The MDASI measures multiple symptoms in patients with other tumor types. No patient completed instrument has been validated that includes both symptoms specific to HNC together with those more generally associated with cancer and its treatment. The previously validated solid tumor MDASI was adapted by adding 11 HNC-specific items selected by patient survey and interviews with health care workers to constitute the MDASI-HN. Results: 160 adult patients with HNC presenting to MDACC are being accrued. Preliminary analysis from 57 patients completing the MDASI-HN shows coefficient alpha reliabilities of 0.90, 0.84 and 0.91 for the 13 core MDASI items, 11 HNC-specific items and the 6 interference items, respectively. The most prevalent symptoms are difficulty chewing or swallowing, dry mouth, problems with tasting food, problems with mucus, pain and fatigue with 42%, 41%, 32%, 32%, 25% and 25% of the patients reporting them to be severe (ratings of 7 or greater), respectively. 72% patients are male, 61% married, 75% White Non-Hispanic and there is a median 12th grade education. Diagnoses were pharynx (40%) and larynx (24%) cancers. 62% had recurrent tumors. 78% had ECOG of 0 and 1. Conclusions: The study gives preliminary evidence of the reliability and validity of the MDASI-HN in HNC patients, and identifies a subset of specifically distressing symptoms. The larger data set will be used to explore further issues related to construct and predictive validity. Finally, we will examine the relationship of symptom severity to diagnosis, concomitant medications, performance status, and where the patient is in treatment. No significant financial relationships to disclose.
Tissue sampling and digital histologic imaging for the National Lung Screening Trial.
Authors: W. A. Franklin, C. D. Berg, S. Tze, S. Groshong, R. D. Achcar, F. Duan, A. Adams, G. Marquez, D. B. Seligson, D. R. Aberle
Journal: Journal of Clinical Oncology (2010)

e12032 Background: Tissue samples from tumors diagnosed in patients enrolled in the National Lung Screening Trial (NLST) have been gathered from widely dispersed geographical locations for histological assessment and selection of tumor rich regions by an innovative digital microscopy protocol. This protocol was designed to take advantage of multi-institutional centers of expertise to create tissue microarrays and molecular extracts that will be available for testing to NLST-approved investigators. Methods: Blocks containing primary tumor, metastasis, lymph node and/or normal lung tissue were forwarded to the UCLA Tissue Array Core Facility. Hematoxylin and eosin-stained histological sections (4-5 microns) from these blocks were forwarded to the University of Colorado Denver, where they were imaged using an Aperio Scanscope, creating a high resolution scan of the whole slide. The digital image of the slide was then manually annotated and printed onto transparency film at the actual size of the matching donor tissue block. The transparency image was then forwarded to UCLA where the core facility closely superimposed the transparency onto the block and sampled the regions of interest guided by the detailed annotations. Sample cores taken were placed in a receiver tissue microarray (TMA) block. Information regarding exposure to neoadjuvant therapy was used to determine the placement of tissue cores in the TMA. Results: Three cores were obtained from each region of interest including tumor, nonmalignant lung tissue, premalignant lesions, if present, and lymph node. Each of these regions of interest was also sampled in triplicate for extraction of DNA, RNA and/or protein. Digital images of the scanned slides have been stored in a barcoded image warehouse for future review by expert panelists. The tissue microarray and DNA, RNA and protein archives created from NLST samples will permit efficient distribution of samples to qualified investigators. Conclusions: An innovative tissue sampling protocol that uses telepathology to take advantage of widely distributed expertise proved effective in creating tissue microarrays and molecular extracts from archival NLST tumor samples. No significant financial relationships to disclose.
Phase II study of perifosine in metastatic renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor
Authors: N. J. Vogelzang, T. E. Hutson, W. Samlowski, B. Somer, S. Richey, C. Alemany, D. Loesch, P. Richards, L. Gardner, P. Sportelli
Journal: Journal of Clinical Oncology (2009)

5034 Background: Perifosine, a synthetic alkylphospholipid, inhibits or modulates a number of different signal transduction pathways (AKT, MAPK and JNK). In a prior trial, 15 RCC patients (pts) were enrolled in a randomized dose finding study, 9 were evaluable for response and 3 (33%) had a partial response (PR). Thus phase II trials were begun for pts who had been treated with one prior VEGFr inhibitor (Group A) or with a prior VEGFr inhibitor and prior mTOR inhibitor (Group B). We report the results of Group A (closed), and Group B (enrollment open). Methods: To measure the objective response rate (RECIST) and PFS to single agent perifosine (100 mg qhs with food) after 3 mos of Rx; Prior Rx with vaccine therapy, bevacizumab and/or cytokines was permitted. Normal organ/marrow function was required. Results: From 12/07–12/08, 46 pts (31 Group A/ 15 Group B) were treated at 13 sites. Median age 64 (range 46–80) and 36 were male; Median prior Rx was 2 (range 1 - 5); Clear cell = 37, non clear cell = 6, data n/a = 3. Prior sunitinib = 35, prior sorafenib = 10, 1 unknown due to blinded study. Prior mTOR; Tem = 9 and Rad001 = 6. As of 12/08, 44 pts were evaluable for response and PFS (two pts not eval; 1 withdrew consent, 1 toxicity &lt; 5 days on Rx). Results listed in the table below. As of 12/08, 12/44 pts (5 Group A/ 7 Group B) remain on treatment. Median survival; not reached. Most common toxicity was grade 1 &amp; 2 nausea (56%), arthralgia (47%), vomiting (36%), fatigue (33%) and cognitive changes (28%). Grade 3 &amp; 4 toxicity was uncommon; arthralgia (14%) and hyperuricemia/gout (8%). Conclusions: Perifosine, similar to mTOR inhibitors, appears to have clinical benefit in mRCC as reflected by the PR rate and a 15 wk median overall PFS. This is most notably in patients who failed both a prior VEGFr and mTOR inhibitor where 7/14 remain on study as of 12/08. Randomized studies are under consideration to further evaluate perifosine's clinical benefit as 2 nd or 3 rd line therapy of mRCC. [Table: see text] [Table: see text]
Use of sex-specific genomic profile to predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5- fluorouracil/oxaliplatin
Authors: M. A. Gordon, W. Zhang, D. Yang, F. Nagashima, H. Chang, G. Lurje, E. Borucka, H. J. Lenz
Journal: Journal of Clinical Oncology (2007)

4122 Background: There is increasing evidence that gender plays a significant role in the development and progression of colorectal cancer (CRC). Rates of CRC incidence are higher among males, and it has been shown that hormone replacement therapy in postmenopausal women reduces the risk of developing CRC, indicating a protective effect of female hormones. These findings indicate that physiological differences between the sexes may contribute to differential tumor development and progression. In the current study, we tested the hypothesis whether males and females would have different genomic profiles that would predict clinical outcome in 5-FU/oxal-treated mCRC. Methods: One hundred seventy-three patients were enrolled in this phase II study. One hundred fifty-two patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). Twenty-four polymorphisms in 12 genes involved in cancer progression were tested by PCR. CART analysis was used to test for association of polymorphisms with overall survival (OS), time to tumor progression (TTP), and tumor response. Separate regression trees were developed for males and females. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. CART analysis by gender generated significantly different regression trees for men versus women. For TTP, males carrying polymorphisms in the ER-β and SCN1A genes had improved TTP, while females carrying polymorphisms in the XPD and EGFR genes had improved TTP. For OS, male patients carrying ER-β and MTHFR polymorphisms had improved OS, while female patients carrying polymorphisms in SCN1A and PLA2 had improved OS. It is notable that analysis of males and females in combination produced a different regression tree than when separated by gender. Conclusions: Our results suggest for the first time that genomic profiling to predict clinical outcome of patients with mCRC depends on gender. Taking gender into account when examining the genetic profile of patients may help to more specifically identify those who will benefit from 5-FU/oxal chemotherapy. No significant financial relationships to disclose.
Shane Warne takes money to give up smoking
Authors: S Chapman
Journal: BMJ (1999)

Shane Warne, the Australian spin bowler who recently admitted that he took money from an Indian bookmaker in exchange for providing basic cricketing information, has found yetanother novel way to rake in the dollars. For $A200000 (US$130800; $76900), he has agreed to try to give up smoking and to use the smoking cessation aid Nicorette …
Abstract 13156: Survivin Inhibition Reverses Cardiac and Pulmonary Remodeling in Monocrotaline-Induced Pulmonary Arterial Hypertension
Authors: Manuel J Ferreira-Pinto, Ana Filipa Silva, Joana Justino, Rita Nogueira-Ferreira, Ana Isabel Padrco, Daniel Moreira-Goncalves, Fabio Carneiro, Raquel Costa, Adelino F Leite-Moreira, Tiago Henriques-Coelho
Journal: Circulation (2013)

Introduction: Cardiac and pulmonary expression of the inhibitor of apoptosis survivin and its endogenous inhibitor smac was characterized throughout the progression of monocrotaline (MCT)-induced p...
인공간 시스템 적용을 위한 돼지 간세포의 대량 분리 및 배양
Authors: 정유정(Yu Jeong Chung), 이혁준(Hyuk Joon Lee), 고영택(Young Taeg Koh), 김상범(Sang Beom Kim), 김성훈(Seong Hoon Kim), 최석호(Seok Ho Choi), 이남준(Nam Joon Yil), 장성환(Seong Hwan Chang), 양은란(Eun Lan Yang), 서경석(Kyung Suk Suh), 이윤신(Yoon Shin Lee), 이건욱(Kuh)
Journal: Clinical and Molecular Hepatology (2002)

목적: 전격성 간부전 환자의 유일한 치료법인 간 이식술은 공여간의 부족으로 제한된 환자에게서만 시술이 가능하다. 이러한 이유로 여러 가지 간기능 보조 장치가 개발 중인데 이중 체외 순환형 인공간 시스템 연구가 가장 활발히 진행되고 있다. 인공간 시스템의 연구에 있어서는 간 고유의 기능을 장기간 유지할 수 있는 간세포의 분리, 배양법이 집중적으로 연구되고 있다. 이에 본 연구진은 돼지에서 간세포 분리 및 배양 방법을 확립하고 단층 배양과 구 상체 배양의 기능을 비교 분석하고자 하였다. 방법: 10kg내외의 암퇘지에서 전간을 적출한 후 2단계 효 소관류 분리 방법에 의해서 간세포를 분리한 후 생존율을 검사하고 단층배양과 구상체 배양을 시도하였다. 암모니아 농도와 요소 농도를 측정해서 배양된 간세포의 기능을 규명하였다. 결과: 총 23마리 돼지 실험 결과 86.84± 8.04%의 생존율과 7.82± 5.40×109개의 세포 수를 얻었고, 단층 배양과 구상 체 배양 결과 암모니아 제거율과 요소 생성능에 있어서 구상체 배양이 단층 배양에 비해 우수하였음을 확인할 수 있었다. 결론: 본 연구를 통해 대량의 돼지 간세포 분리법을 확립하였고, 배양한 간세포는 기능상으로 안정된 세포로 인공간에 적용 가능하였다. 하지만 이상적인 인공간의 세포 충진 형태인 구 상체 간세포를 적용하기 위한 더욱 다양한 시도가 요구되리라 사료된다.