tbuckley/cabot-search huggingface dataset:
A genetic UGT1A1 polymorphism oriented phase I study of irinotecan (CPT-11) and doxifluridine (5’-DFUR: An intermediate form of capecitabine for metastatic colorectal cancer (MCRC)
Authors: S. Hazama, A. Nagashima, H. Kondo, R. Shimizu, A. Araki, S. Yoshino, N. Okayama, Y. Hinoda, M. Oka
Journal: Journal of Clinical Oncology (2006)

3602 Background: 5-Fluorouracil plus CPT-11 is one of the standard 1st-line therapies in patients (pts) with metastatic colorectal cancer (MCRC). Although it has been reported that individuals carrying the (TA) 7 allele in the TATAA promoter of UGT1A1 increased risk of severe toxic event occurrence after CPT-11 administration, there is no report about phase I study based on the polymorphism of UGT1A1. Here we report the results from a genetic UGT1A1 polymorphism oriented phase I study of CPT-11 and 5’-DFUR to determine the maximum tolerated dose (MTD) and the recommend doses (RD) for each UGT1A1 genotypes. Methods: Eligibility criteria were as follows; histologically proven CRC with unresectable metastatic lesions, PS 0–2, age&lt;76, adequate organ functions, and written informed consent. CPT-11 was infused (level 1, 2, 3 and 4: 70, 100, 120, 150 mg/m 2 , respectively) biweekly and 5’-DFUR was administered orally (800 mg/body, &lt;1.39 m 2 ; 600 mg/body) on 5 consecutive days with 2 days’ rest for more than 12 weeks. DLT were determined as grade 3 hematological and non-hematological toxicities. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from pts. Results: Eighteen pts with wild 6/6 allele and 9 pts with mutated 6/7 allele were registered. In pts with 6/6 allele, MTD was not observed up to level 4 (150 mg/m 2 ). In pts with mutated 6/7 allele, on the other hand, MTD was observed at level 2 (100 mg/m 2 ). We recommend doses of 70 mg/m 2 of CPT-11 for pts with mutated 6/7 allele and 150 mg/m 2 of CPT-11 for pts with wild 6/6 allele, respectively. Conclusions: The recommended phases II/III starting doses of biweekly CPT-11 administration are 150 mg/m 2 for pts with wild 6/6 allele and 70 mg/m 2 of CPT-11 for pts with mutated 6/7 allele, and 5’ -DFUR 800 mg/body on every 5 days per week. This combination therapy may be administered safely for all pts according to the TATAA promoter polymorphism of UGT1A1. The gene polymorphism should be taken into consideration to provide more precise information to guess the individual toxicities. No significant financial relationships to disclose.
Methadone Treatment of Randomly Selected Criminal Addicts
Authors: Vincent P. Dole, J. Waymond Robinson, John Orraca, Edward Towns, Paul Searcy, Eric Caine
Journal: New England Journal of Medicine (1969)

The potential motivation of criminal addicts for methadone treatment was tested in the New York City Correctional Institute for Men. Of 165 inmates seen, all with records of five or more jail sentences, 116 (70 per cent) applied for treatment after a single interview. None of them had previously made application to the methadone program. Of 18 randomly selected from all applicants with release dates between January 1 and April 30, 1968, 12 were started on methadone before they left jail and then referred to the program for aftercare. None of them became readdicted to heroin, and nine of 12 had no further convictions during the 50 weeks of follow-up study. All of an untreated control group became readdicted after release from jail, and 15 of 16 were convicted of new crimes during the same follow-up period.
Effects of high-dose chemotherapy (HDCT) and stem cell transplant (SCT) on cardiac function: A prospective study
Authors: G. Vallabhaneni, F. Momin
Journal: Journal of Clinical Oncology (2007)

7106 Background: The effects of HDCT on Cardiac function have not been well defined. In our experience the deleterious effect of HDCT on cardiac function has been overestimated. There is recent evidence that infused peripheral blood progenitor cells have a reparative effect on the myocardium. We prospectively analyzed cardiac function in adult recipients of HDCT and stem cell transplantation before and 100 days after they received HDCT and SCT. Methods: From 1997 to 2004, 109 adult patients received HDCT and SCT. Of these, 34 were male and 51 were female. 55 patients received autologous SCT and 30 patients received allogeneic SCT from HLA matched siblings. Cardiac function was measured by 2D-ECHO two weeks prior to and 100 days post-HDCT and SCT. HDCT was administered according to standard protocols. An ejection fraction [E.F] of greater than 45% was defined as normal. Post-HDCT E.F decrease was defined as reduction of &gt; 10% from baseline. An increase in the EF of greater than 10% from baseline was considered an improvement in cardiac function. Results: 85 patients were evaluable. Median age was 56 years. Auto SCT: Pre-HDCT E.F was normal in 53 auto- SCT and was &lt; 45% in 2 patients. EF declined by 15 and 20% in 2/53 patients (3.7%) who had a normal E.F at baseline. Neither were symptomatic. There was no change in E.F, in patients who had a decreased E.F at baseline. Allogeneic SCT: Pre-HDCT was normal in 29 patients and was &lt; 45% in 1 patient. Post-HDCT E.F remained unchanged in all 29 patients, who had a normal E.F at baseline. The EF improved to normal in the recipient who had a low EF prior to transplant. Conclusions: There was no significant change in cardiac function after HDCT and SCT by 2D-ECHO. The improvement in cardiac function in one of our allogeneic recipients was quite impressive and long lasting and seemed to coincide with engraftment of healthy donor stem cells suggesting that there may be a role for healthy stem cells in improving myocardial dysfunction. No significant financial relationships to disclose.
Conservative treatment with alternative routes of drug administration
Authors: J G Llewelyn
Journal: BMJ (1995)

There seems little doubt that this unfortunate young person has unusually severe diabetic gastroparesis, a condition thought to be due to vagal denervation of the stomach. It is important, however, to identify and correct factors that may be aggravating the gastroparesis to cause such a difficult problem that required admission to hospital for one whole year.

Swings in blood sugar concentrations, in particular hyperglycaemia, and fluctuation in serum potassium concentrations, may slow gastric emptying. Also dietary fat is known to impair gastric motility. Certain drugs may worsen the situation. With severe gastric …
Abstract 9: The Virtually Mature BNP1-32 Is a Precursor for the Biologically More Active BNP1-30
Authors: Anja Schwiebs, Yong Wang, Xudong Zhu, Wolf E Siems, Thomas Walther
Journal: Circulation Research (2012)

The mature B-type natriuretic peptide (BNP1-32), mainly released from ventricular myocardium, has antifibrotic effects and exerts vasorelaxant and natriuretic activity leading to a reduction of blood volume and pressure. Thus, BNP is used as a drug for the treatment of decompensated heart failure. Here we show the discovery of a new murine BNP metabolite, BNP1-30, exerting higher biological activity compared to the mature BNP1-32, in vitro and in vivo. By mass spectrometric analysis of murine lung tissues incubated with BNP1-32 and of elution fractions of BNP1-32-perfused livers, we discovered a distinct BNP1-32 cleavage product, identified as the C-terminally truncated BNP1-30. We identified endothelin-converting enzyme (ECE) as the peptidase generating BNP1-30 from BNP1-32 by the hydrolysis of the two C-terminal leucine. This new metabolite is significantly more efficient compared to BNP1-32 in stimulating the natriuretic peptide receptor (NPR) A. Interestingly it is also stimulating the C-type natriruretic peptide specific receptor NPRB. In parallel, dose-response curves in NPRA &amp; -B co-transfected cell lines and stimulation of primary smooth muscle cells, endothelial cells and mesangial cells showed better efficacy for BNP1-30. In vivo, BNP1-30 reduced the mean arterial blood pressure of normotensive mice after acute infusion significantly more than BNP1-32. Additionally, BNP1-30 was also significantly more potent compared to the rodent derived pro-BNP cleavage product BNP1-45. Even more important, in a 3-day infusion experiment using spontaneously hypertensive rats (SHR), BNP1-30 was able to reduce systolic blood pressure by 30 mmHg and decreased cardiac BNP mRNA, a marker for cardiac failure, while BNP1-32 was without significant effect. We show for the first time the occurrence of a BNP metabolite being a more efficient antihypertensive peptide than the virtually mature BNP1-32 that has been described as ‘the’ circulating biologically active form of BNP. Our results suggest that BNP1-32 is only the precursor for the more biologically active BNP1-30 leading to a fundamental revision of the natriuretic peptide system and also opens the avenue for the identification of more effective targets in the treatment of cardiovascular diseases.
Maternal sleep-disordered breathing and the risk of delivering small for gestational age infants: a prospective cohort study
Authors: Sushmita Pamidi, Isabelle Marc, Gabrielle Simoneau, Lorraine Lavigne, Allen Olha, Andrea Benedetti, Frédéric Sériès, William Fraser, François Audibert, Emmanuel Bujold, Robert Gagnon, Kevin Schwartzman, R John Kimoff
Journal: Thorax (2016)

<h3>Objective</h3> It is unclear whether objectively measured maternal sleep-disordered breathing (SDB) leads to poor fetal outcomes. In this study, we prospectively assessed whether polysomnography-based diagnosis of SDB in the third trimester is associated with the delivery of small for gestational age (SGA) infants. <h3>Study design</h3> Participants were recruited from a multicentre pregnancy cohort study. Eligible participants were evaluated for SDB based on symptoms (snoring and/or witnessed apnoeas assessed using the Pittsburgh Sleep Quality Index questionnaire) and in-home complete polysomnography in the third trimester. SGA was defined as &lt;10th centile using customised birthweight centiles adjusted for maternal parity, prepregnancy body mass index (BMI), ethnicity, gestational age and infant sex. <h3>Results</h3> Of the 234 pregnant participants who completed a sleep study, 82% were Caucasian, with mean (SD) age of 31 (4.3) years and a prepregnancy BMI of 23 (4) kg/m<sup>2</sup>. The delivery of SGA infants occurred in 27 (12%) of the study participants. The symptoms of SDB had poor overall sensitivity and specificity for diagnosing SDB identified by polysomnography. Symptoms of SDB in the third trimester demonstrated a potential association with delivering an SGA infant, however this did not reach statistical significance (OR 2.36 (95% CI 0.85 to 6.54, p=0.10)). However, the odds of delivering an SGA infant were significantly increased with polysomnography-based diagnosis of maternal SDB (using apnoea-hypopnoea index cut-off of 10, OR 2.65 (95% CI 1.15 to 6.10, p=0.02)). <h3>Conclusions</h3> Objectively measured SDB in the third trimester is significantly associated with the delivery of SGA infants.
Depression and depressive symptoms in preschool children from the general population
Authors: J H Kashani, W R Holcomb, H Orvaschel
Journal: American Journal of Psychiatry (1986)

This multiphasic study used four independent sources of information to investigate depression and depressive symptoms in a sample of preschool-age children from a general population. The study provides evidence that major depressive disorder exists in preschoolers and that stressful life events are associated with depressive symptoms; it underscores the importance of the teacher's report for identifying the presence of depression in this age group. Details of the findings, including a new scale for rating depression in young children, are discussed.
Hereditary Thrombocytopenia with an Intrinsic Platelet Defect
Authors: Scott Murphy, Frank A. Oski, Frank H. Gardner
Journal: New England Journal of Medicine (1969)

Thrombocytopenia, inherited as a dominant trait, was present in three generations of a kindred. The clinical picture was quite similar to that of idiopathic thrombocytopenic purpura, but thrombokinetic studies clearly distinguished the two diseases. Platelet-survival studies after labeling with 51Cr demonstrated shortened life-spans of the patients' platelets both in themselves and in normal volunteers. Platelets from healthy volunteers, however, survived normally in the patients, showing that the accelerated platelet destruction resulted from an intrinsic platelet defect and not one extrinsic to the cell. Morphologic and biochemical studies have not as yet elucidated the nature of the defect. Splenectomy in two patients was followed by improvement in the thrombocytopenia, but the postoperative platelet survival remained short.
SAT0251 Is There Clinical Association Between Radiologic Progression of Spine and Radiologic Changes of Foot in Ankylosing Spondylitis?
Authors: J.J. Kim, I.H. Sung, S. Lee, K.B. Joo, T.H. Kim
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the axial skeleton, the enthesis and peripheral joints. The most prominent and common enthesitis occur in the lower extremities, especially the foot at the insertion of Achilles tendon. Peripheral arthritis is uncommon in AS, but it usually occurs in the lower extremities presenting asymmetric oligoarthritis, too. Some suggested that when peripheral arthritis develop early in the disease course it can be a predictor of more aggressive disease and enthesitis may be associated with high disease activity. <h3>Objectives</h3> The aim of this study was to investigate the association between radiologic changes of foot and radiologic progression of spine. <h3>Methods</h3> We enrolled two-hundred patients with AS who had both feet and whole spine x-ray in similar periods at one tertiary center of rheumatology from 2005 to 2014. We collected demographic findings including sex, age and disease durations. The foot x-ray was reviewed about presence of radiologic changes such as joint space narrowing (JSN) and erosion in ten metatarsophalangeal (MTP) joints and Achilles tendinopathy such as calcaneal spur, retrocalcaneal bursitis and soft tissue thickening by orthopedic surgeon. The radiologic damage of spine was scored by modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS) by two radiologists. And the annual progression rate was calculated by difference of mSASSS divided by x-ray intervals. <h3>Results</h3> There were 149 males (73.8%) and 51 females (25.2%). Their mean age and disease duration were 38.5±12.8 years old and 45.9±59.4 months. The 26.5% of patients showed the radiologic changes of MTP joints, and 25.5% of patients had Achilles tendinopathy. There was significant difference between mSASSS in AS patients with radiologic changes of foot (8.2±6.9) and without (10.6±10.9) changes (P=0.036). The mSASSS was significantly increased in patients with Achilles tendinopathy (13.2±14.1) compared to without Achilles tendinopathy (8.8±8.0) (P=0.007). However, there was no significant difference of annual progression rate of mSASSS according to presence of radiologic damages at MTP joints and Achilles tendinopathy, respectively. The risk of radiologic changes of foot in patients without Achilles tendinopathy was more increased than patients with Achilles tendinopathy [OR=2.268 (1.146-4.487), P=0.026]. <h3>Conclusions</h3> The mSASSS was increased in patients with Achilles tendinopathy, and without radiologic damage of MTP joints, respectively. However, each findings did not associate with annual progression rate of mSASSS. Therefore, the radiologic changes of foot did not show the associations with radiologic progression of spine in this study. <h3>Disclosure of Interest</h3> None declared
Lithogenic Bile among Young Indian Women
Authors: Johnson L. Thistle, Leslie J. Schoenfield
Journal: New England Journal of Medicine (1971)

Chippewa Indian women have a high prevalence of symptomatic gallstones. Lithogenic bile is characterized by a low ratio of bile acids plus lecithin to cholesterol. The ratios of bile acid plus lecithin to cholesterol in duodenal bile among 12 young Indian women without gallstones were significantly lower, 9.4 ± 0.82 (mean ± S.E.), than among white controls, 16.4 ± 1.0 (p less than 0.001), and Indian men, 14.8 ± 2.2 (p less than 0.02), and not different from those previously reported among white women with gallstones: 11.3 ± 1.3. Administration of chenodeoxycholic acid resulted in a bile acid composition of 96 per cent chenodeoxycholic acid and significantly increased the ratio of bile acid plus lecithin to cholesterol to 14.2 ± 1.9, without adverse reactions. These observations suggest that lithogenic bile precedes gallstone formation in Chippewa women and that administration of chenodeoxycholic acid decreases this lithogenic potential.
A phase I/II study of radiochemotherapy in extrahepatic bile duct carcinoma
Authors: K. Schoppmeyer, S. Miethe, H. Witzigmann, J. Hauss, J. Moessner, G. Hildebrandt, K. Caca
Journal: Journal of Clinical Oncology (2005)

4233 Background: The 5-year survival rate of patients with curatively resected extrahepatic bile duct carcinoma is less than 25%. Despite the poor prognosis there is a lack of adjuvant therapies. Phase II trials demonstrated that advanced extrahepatic bile duct carcinomas respond to both chemotherapy with gemcitabine and radiotherapy. Our objective was to define a feasible and effective radiochemotherapy in bile duct cancer. Methods: Patients with histologically confirmed adenocarcinoma of the distal or hilar extrahepatic bile ducts were prospectively enrolled after non-curative operations (R1/R2-resection or surgical exploration). Treatment consisted of a fractionated radiotherapy with 40 Gy + 9.6 Gy Boost accompanied by gemcitabine 100 mg/m2 weekly x 5. After a two week rest gemcitabine (1000 mg/m2 IV weekly x 2 q3w) and capecitabine (1500 mg/m2 PO D1–14 q3w) were given. Treatment continued for 6 cycles in nonmeasurable disease or until disease progression or intolerable toxicity. Primary endpoint was toxicity; secondary endpoints were response rate in measurable disease and overall survival. Results: 11 Patients (hilar/distal carcinoma: 8/3) were enrolled. Radiotherapy was completed in all patients and a total of 49 cycles of chemotherapy were applied. Grade 3/4 toxicity was observed in 7 patients and consisted of leucopenia (2 cycles), thrombopenia (1), nausea (3), a bleeding ulcer (1) and cachexia in 3 patients. The most frequent mild toxicities were asthenia and nausea in 50% and 40% of cycles, respectively. Therapy was discontinued in 2 patients. Of 8 patients with measurable disease, one each had a complete and a partial response and 3 had stable disease for at least 3 months. Median actuarial survival is 296 days. Conclusions: Radiochemotherapy with gemcitabine followed by gemcitabine and capecitabine is an active regimen with manageable toxicity in postoperative palliative treatment of extrahepatic bile duct cancer. No significant financial relationships to disclose.
A blinded placebo (P)-controlled phase I/II dose-escalation study (DES) of brivanib (B), an oral selective dual inhibitor of FGF and VEGF signaling, in combination with cetuximab (C) and irinotecan (I) in patients (pts) with KRAS wild-type (KWT) advanced or metastatic colorectal cancer (amCRC): Safety, tolerability, and pharmacokinetics (PK) findings.
Authors: Y. Park, A. B. El-Khoueiry, A. C. Gracian, P. Pfeifer, M. Chacon, D. Amadori, T. Fokstuen, J. Chemidlin, G. Kollia, D. S. Nuyten
Journal: Journal of Clinical Oncology (2010)

e13552 Background: B has therapeutic potential in a variety of tumors. B+C treatment is currently being tested in phase III in refractory amCRC. An innovative phase I design was used to separate specific B toxicity (thrombosis-related events [TRE]) from the background rate. Methods: A blinded P-controlled phase I/II DES of B+C+I (BCI) was conducted in pts with KWT amCRC. A minimum of 4 pts/cohort were treated with BCI and 2 pts/cohort were treated with P+C+I (PCI). Standard full-dose I (q3w) and C (qw) were combined with escalating doses of B (200, 400, 600, 800 mg) PO qd. Results: 30 pts were treated with 200 (6), 400 (8), 600 (10), or 800 (6) mg of BCI or PCI for a median of 14 weeks (range 1–38). One dose-limiting toxicity (DLT), grade III diarrhea, occurred at 600 mg. Blinded safety data on 200, 400, and 600 mg (8/10 pts) are presented. The 800 mg cohort is ongoing; a maximum tolerated dose has not yet been reached. Adverse events (AEs; regardless of relationship) occurred in 17/21 pts and are consistent with monotherapy toxicities from B, C, and I (Table). 1/21 pts experienced a TRE (asymptomatic portal vein thrombosis). Most pts (15) discontinued (DC) due to disease progression. No pts DC due to treatment-related AEs. PK data are pending. 11 pts were not evaluable for response (5 DC before first evaluation, 6 in first 6 weeks), 10 pts had stable disease, 6 achieved a partial response, and 2 had progressive disease. Conclusions: The safety profile of BCI in amCRC pts is manageable and seems consistent with monotherapy toxicities; there is no increased rate of TRE. AEs occurring in >25% (any grade) or >5% (grade III-IV) of pts B or P 200 mg (n=6) 400 mg (n=7) 600 mg (n=7) AE Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Diarrhea 4 1 5 2 3 Neutropenia 1 3 2 Hypokal aemia 1 1 1 1 1 Dermatitis acneiform 1 2 1 1 Rash 3 1 3 1 Alopecia 3 3 2 Fatigue 2 1 3 Pyrexia 4 1 1 Abdominal pain 1 4 2 2 Nausea 4 4 1 Vomiting 3 1 4 1 Reduced appetite 3 4 1 1 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Effect of Renal Disease on Renal Uptake and Excretion of Insulin in Man
Authors: Ralph Rabkin, Norman M. Simon, Sheldon Steiner, John A. Colwell
Journal: New England Journal of Medicine (1970)

Renal handling of insulin was studied over plasma insulin levels of 6 to 40 μU per milliliter in 13 patients by renal-vein catheterization. The kidney in normal subjects and 7 patients with moderate renal insufficiency — glomerular filtration rate (GFR) over 22.5 ml per minute per kidney per 1.73 M2 — removed 39 ± 4 per cent (SD) of the insulin from arterial plasma. Severe renal insufficiency (GFR less than 6) reduced insulin uptake to 9 per cent in four subjects, two with diabetic glomerulosclerosis. Mean GFR in normal subjects was 61 ± 11 (SD) and renal insulin extraction —renal plasma flow (RPF) × % uptake — was 106 ± 28 (SD). These findings suggest that a decreased uptake of insulin by damaged kidneys accounts in part for the diminished insulin requirements seen in patients with diabetic glomerulosclerosis and that all the renal uptake of insulin cannot be explained by glomerular filtration alone.
Smokers and overweight patients are denied surgery, royal college finds
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Over a third of clinical commissioning groups (CCGs) in England are restricting access to routine surgery such as hip and knee replacements until patients stop smoking or lose weight, a report by the Royal College of Surgeons has found.

The college said that policies to deny or delay access to surgery for smokers and overweight patients contravened national clinical guidance, and it urged the government to clamp down on the restrictions.

The report compared the commissioning policies of CCGs in England with guidance produced by the National Institute for Health and Care Excellence (NICE), the college, and surgical specialty associations.1 It found that one in three (34%) of the 200 CCGs that responded to a freedom of information request had at least one policy of blocking smokers or overweight patients from being referred for routine surgery, on the …