tbuckley/cabot-search huggingface dataset:
Flow limitation during resting breating is associated with reduced exercise capability in COPD
Authors: Bernt Aarli, Tomas Mikal Lind Eagan, Jon Andrew Hardie
Journal: European Respiratory Journal (2014)

The hallmark of COPD is flow limitation (FL) caused by peripheral airway collapse during expiration. In this case an oscillatory pressure signal applied at the mouth fails to reach the distal airways, creating a within-breath reactance difference. We used forced oscillation technique (FOT) to measure inspiratory-expiratory reactance at 5 Hz, ΔXrs over 30 seconds of resting breathing, and hypothesize that COPD patients with flow limitation have reduced exercise capacity.

Methods 

374 COPD patients from the Bergen COPD Cohort study performed FOT, spirometry and 6-minute-walk test (6MWT). 229 controls performed FOT and spirometry. ΔXrs 99th percentile of healthy controls was 0.1 kPa/L/s. COPD patients with ΔXrs exceeding this threshold were defined as likely to experience FL breaths.

Results 

FL COPD patients had significantly lower 6MWT than the non-flow limited (NFL), p<0.001. The two groups differed significantly in BMI, MMRC, and FEV1. Separated by GOLD grade significant difference was only found in GOLD 2, though similar trends were seen in GOLD 3 and GOLD 4.

View this table:

Demographics and 6-minute-walk test





Conclusion 

COPD patients likely to experience flow limitation during resting breathing have significantly poorer exercise capability than NFL COPD patients, p<0.001. While FL is more common in advanced disease, GOLD 3-4, significantly differences in the 6MWT was only found in GOLD 2, p=0.02.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in men with prostate cancer previously treated with taxane.
Authors: Daniel Peter Petrylak, Philip W. Kantoff, Anthony E. Mega, Robert Dreicer, Richard C. Frank, Neal D. Shore, Stephen Morris, William C. Olson, Robert Joseph Israel
Journal: Journal of Clinical Oncology (2012)

107 Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in patients (pts) with taxane-refractory metastatic castration-resistant prostate cancer (metCRPC). Methods: Eligibility requirements include metCRPC after taxane-containing regimen and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS. Dosing cohorts have ranged from 0.4 mg/kg to 2.2 mg/kg. Results: 26 pts have enrolled in six dosing cohorts (0.4, 0.7, 1.1, 1.6, 1.8, 2.0 mg/kg). Treatment has to date been generally well tolerated with the most commonly seen adverse event being fatigue and the most common laboratory abnormalities being reversible changes in liver and hematological parameters. Antitumor activity manifested as reductions in PSA, circulating tumor cells and/or bone pain has been observed in the higher dose cohorts and appears to be dose-related. Exposure to PSMA ADC increased with dose and was ∼1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.2 mg/kg cohort is continuing and an MTD has not yet been reached. Conclusions: In pts with metCRPC previously treated with taxane PSMA ADC has exhibited dose-related antitumor activity. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.
Impact of PNPLA3 variants on liver histology of 168 patients with HIV infection and chronic hepatitis C
Authors: C. Sagnelli, M. Merli, C. Uberti-Foppa, H. Hasson, G. Cirillo, A. Grandone, S. Salpietro, C. Minichini, E.M. Del Giudice, A. Lazzarin, E. Sagnelli, N. Coppola
Journal: Clinical Microbiology and Infection (2016)
Prognostic significance of cathepsins B and L in primary human breast cancer.
Authors: J A Foekens, J Kos, H A Peters, M Krasovec, M P Look, N Cimerman, M E Meijer-van Gelder, S C Henzen-Logmans, W L van Putten, J G Klijn
Journal: Journal of Clinical Oncology (1998)

PURPOSE Evaluation of the clinical significance of cytosolic tumor levels of the lysosomal cysteine proteases cathepsin B (catB) and cathepsin L (catL) in patients with primary breast cancer. PATIENTS AND METHODS CatB (n = 1,500) and catL (n = 1,391) levels were determined by enzyme-linked immunosorbent assay (ELISA) in cytosols routinely prepared from frozen-tissue samples that were submitted to our laboratory for the assessment of steroid-hormone-receptor status. The median duration of follow-up of patients still alive at the time of analysis was 93 months. RESULTS Relating catB and catL levels with classical prognostic factors, the proteases were positively correlated with the number of positive lymph nodes (P &lt; .01), and negatively with the level of steroid-hormone receptors (P &lt; .01). We did not find a significant relationship between catB or catL levels with age and menopausal status of the patients or with the size of the primary tumor. The levels of catB and catL were positively correlated with each other and with the rates of relapse and death (all, P &lt; .0001). In multivariate regression analysis for relapse-free survival (RFS) and overall survival (OS), corrected for the contribution of age/menopausal status, tumor size, the number of positive lymph nodes, and steroid-hormone-receptor status, catB and catL were significant predictors of the rates of relapse and death (all, P &lt; .01). No statistically significant interactions of catB or catL with any of the classical prognostic factors or with each other were observed in their associations with the rates of relapse and death. CONCLUSION CatB and catL levels measured in routinely prepared cytosols are strong parameters to predict the rate of relapse and the length of survival after treatment of the primary breast tumor.
Getting through OSCEs
Authors: Valerie Wass
Journal: BMJ (2000)

Valerie Wass argues that the OSCE is the fairest assessment method The objective structured clinical examination (OSCE) is becoming the favoured method of clinical competence testing in undergraduate and postgraduate examinations. The examination, however, requires a high level of funding - more examiners, patients or role players, and equipment are necessary. The traditional long and short case examinations were more fun for the examiner, who could interact freely with the candidate, and they were, perhaps, more true to life. The new examinations may feel artificial and rather reductionist.

### Key issues

#### Study the curriculum

Look carefully at the curriculum and course books. Well planned OSCEs aim to cover the course content as widely as possible. Make sure you know what is being assessed

#### Understand the skills

Make sure you understand the criteria for the skill. Work these out yourself rather than learn a checklist. Get a good demonstration of the skill to model on

#### Practise the skills with as many patients as possible

Observe each other. Revise together. Observe and give feedback. It can be fun

#### Remain confident

You need the right mentality. You will undoubtedfly flunk some stations. Forget it immediately and move confidently on to the next

So why the change? The answer hinges on reliability. The stakes are high …
Paraffin-based molecular diagnosis of lung cancer reproduces morphologic and molecular subtypes of lung cancer
Authors: D. N. Hayes, J. Schallheim, P. Roberts, C. Lee, L. Thorne, C. Perou, A. Parsons, M. A. Socinski, W. Funkhouser, P. Bernard
Journal: Journal of Clinical Oncology (2007)

7579 Background: Molecular profiling of lung cancer by gene expression analyses has documented potential to guide therapy. However, quality ‘fresh’ tissue for RNA analyses is generally unavailable in clinical practice. We introduce a (q)RT-PCR assay and analytic method for profiling lung cancers from clinically obtained formalin-fixed paraffin-embedded tissues. Methods: Approximately 1,000 DNA microarrays were analyzed to select genes distinguishing the major histological variants (adenocarcinoma, small cell carcinoma, etc) and previously described molecular subtypes of lung cancer. Based on gene expression, a classifier of 62 genes was constructed to assign each sample to its morphologic tumor type, as well as to risk stratify by molecular subtypes. A real-time qRT-PCR assay was developed to evaluate the expression of the 62 genes from paraffin-embedded samples. This assay was used to profile RNA extracted from a cohort of surgically treated lung cancer patients. Samples were procured as fresh frozen and formalin-fixed, paraffin-embedded and were archived between 1–15 years. Results: Fifty-eight of 62 genes passed performance criteria and were used for analyses. Normalized gene expression was used for sample classification. The cohort contained a broad spectrum of tumors in proportions consistent with clinical practice. Gene amplification was successful in 139 of 142 (98%) lung cancer samples. Matched frozen-paraffin and replicate paraffin samples had mean correlations of approximately 80%. Linear discriminant analysis of gene expression data agreed with morphologic classification by light microscopy in &gt;99% of cases. More importantly, the method successfully re-identified molecular subtypes of lung cancer for the first time through the use of a paraffin-based assay. Clinical outcomes previously associated with molecular tumor subtypes, including differential survival and metastatic patterns, were again seen in our cohort. Conclusions: We describe for the first time a clinically meaningful and robust molecular diagnosis of a clinical cohort of lung cancer patients which is complementary to morphologic cancer diagnosis. This assay is easily implemented using specimens routinely collected in current patient care. No significant financial relationships to disclose.
The risk of cholecystitis in patients with cancer and the general population in a population-based cohort study in Western Denmark, 1995–2003
Authors: J. P. Fryzek, R. W. Thomsen, H. F. Thomsen, M. Nørgaard, K. Cetin, J. K. McLaughlin, R. E. Tarone, H. T. Sørensen
Journal: Journal of Clinical Oncology (2008)

20598 Background: Little information is available on the risk of cholecystitis among patients with cancer. Methods: We conducted a population-based retrospective cohort study of 51,350 patients with incident cancer, identified in medical databases of Western Denmark between 1995 and 2003. A general population comparison cohort of 513,500 persons frequency-matched on the age and sex distribution of the cancer cohort was assembled from the Danish Civil Registration System. The incidence of cholecystitis in the two cohorts was determined by linkage to the regional Hospital Discharge Registry covering all hospitals in the region. Results: We identified 230 incident diagnoses of cholecystitis in our cancer cohort during 130,628 person-years of follow-up, corresponding to an incidence rate of 1.8/1000 person-years. After adjustment for potential confounders, the adjusted relative risk (aRR) for cholecystitis among cancer patients compared with the general population cohort was 1.38 (95% confidence interval (CI) 1.20–1.58). Overall, the aRR for cholecystitis was doubled during the first six months after cancer diagnosis (aRR=1.95, 95% CI 1.50–2.54), at which point the aRR declined but remained greater than 1 throughout the rest of the follow-up period (aRR=1.23, 95% CI 1.05–1.45). Age-specific adjusted RRs ranged from 1.44 to 2.11 among cancer patients up to 70 years of age but were only marginally increased in cancer patients aged greater than 70 years. There were no major differences in aRRs between metastatic and non-metastatic cancer patients. Pancreatic cancer (aRR=6.71, 95% CI 3.82–11.76), thyroid cancer (aRR=3.83, 95% CI 1.60–9.22), and colorectal cancer (aRR=2.06, 95% CI 1.33–3.20) conferred the highest adjusted relative risks for subsequent cholecystitis. Conclusions: Cholecystitis occurs more often in cancer patients than in the general population. Pancreatic, thyroid and colorectal cancer seem to confer an especially high relative risk for subsequent cholecystitis, particularly during the first six months following diagnosis and among younger patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen Inc.
Response to physical exercise in sarcoidosis
Authors: Katarzyna Hildebrand, Tadeusz Przybylowski, Marta Maskey-Warzechowska, Joanna Wiwala, Ryszarda Chazan
Journal: European Respiratory Journal (2012)

The aim of this study was to analyze the response to exercise in untreated patients with pulmonary sarcoidosis. We recruited 39 patients (15 females) at mean age 39±9 years to undergo lung function testing (spirometry, bodyplethysmography, CO diffusing capacity) and symptom limited cardiopulmonary exercise test on a treadmill. Histological confirmation of sarcoidosis was obtained in 64% of patients; on the basis of radiologic findings 37% of patients were diagnosed with stage I, 51% with stage II and 11% with stages III and IV. Muscle fatigue was the main reason for exercise termination (82% of patients), followed by ECG abnormalities, blood pressure increase or vertigo and dyspnea reported by 10% and 5% of patients, respectively. Decreased exercise tolerance (defined as V'O2max < 82% of predicted) was diagnosed in 15 (38%). V'O2max in patients with decreased exercise tolerance was significantly lower than in patients with normal response to exercise (32.6±7.8 vs 27.6±6.6 ml O2/kg/min; p<0.05). Patients with impaired response also had a lower PaO2 at peak exercise (87.8±18.5 vs 100.1±7.6 mmHg; p< 0.05) and widened alveolar-capillary oxygen gradient (17.5±10.1 vs 7.9±8.1 mmHg; p<0.05). Some significant correlations between V'O2max and FEV1 % pred. (r=0.40; p<0.05), FVC % pred. (r=0.43; p=0.008), RV/TLC (r=-0.41; p<0.01) were also noted.

Conclusions. Impaired exercise tolerance can affect up to 40% of patients with sarcoidosis. Lower PaO2 and widened alveolar-capillary oxygen gradient suggest an important role of gas exchange abnormalities in the pathogenesis of impaired response to exercise.
The quality-of-life impact of osteonecrosis of the jaw: Implications for bisphosphonate use in metastatic breast cancer
Authors: R. A. Miksad, S. Come, M. Weinstein
Journal: Journal of Clinical Oncology (2007)

6620 Background: Osteonecrosis of the jaw (ONJ) has been linked to bisphosphonates used to prevent skeletal related events (SREs) in metastatic breast cancer (MBC). The primary aim of this decision-analysis study is to determine the preference threshold at which the quality of life (QOL) impact of ONJ may change bisphosphonate treatment decisions. Methods: We developed a Markov decision- analysis model of bisphosphonate use in MBC that includes the risk of ONJ. For the base case we estimated the QOL impact of ONJ by evaluating published ONJ reports with the Oral Health Impact Profile (OHIP). OHIP scores were transformed to EQ5D utilities and adjusted for MBC (published utility for MBC=0.63). We used published utility values for SRE: 0.46 for the month in which SRE occurs. Based on published data, we estimated that bisphosphonates reduce the incidence of SREs by 41% and that the incidence of SRE rises with increased bisphosphonate exposure: year 1=0.004/month; year 2=0.022/month; year 3=0.034/month. We inspected 2 treatment strategies: treat all patients with bisphosphonates (treat all) and treat no patient with bisphosphonates (treat none). Results: 18 published cases were adequate for evaluation. The mean OHIP score=27 (possible range 14–70), s.d.=1.8. We calculated that patients with MBC and ONJ have a utility=0.53 (s.d.=0.04) for the base-case. The model predicted a mean survival of 22 months for both strategies. In the treat all strategy each patient received a mean of 19 months of bisphosphonates and suffered 2.4 SREs. In the treat none strategy each patient suffered 4.0 SREs. In the base case, the treat all strategy maximized net quality-adjusted life, although by less than 1/2 month per patient. The treat all strategy was optimal for only 33% of patients. The treat all strategy does not maximize net quality-adjusted life if the risk of ONJ is 4.5 times higher than the base case or the ratio of the utility for ONJ to the utility for SRE is less than 0.4 (base-case ratio=1.152). Conclusions: The QOL impact of ONJ alters the decision to use bisphosphonates when 1) the incidence of ONJ is 4.5 times higher than published estimates; or 2) the long-term preference for ONJ is 60% lower than the short-term preference for SRE. Further QOL research may refine these estimates. No significant financial relationships to disclose.
From genomic medicine to precision medicine: highlights of 2015
Authors: Charles Auffray, Timothy Caulfield, Julian L. Griffin, Muin J. Khoury, James R. Lupski, Matthias Schwab
Journal: Genome Medicine (2016)

2015 has been an exciting year for genomic medicine.We asked our Section Editors to discuss the breakthroughs in their fields of expertise, and what these might mean for the future.As in previous years, exome and whole-genome sequencing are leading the way in our understanding of disease mechanisms, their diagnosis and treatment, while information about the protein products of the genome has also grown, driven by novel technological advances.Precision medicine is now taking off as an important topic in the public health sphere and in education, and no discussion of 2015 would be complete without a mention of the huge advances in gene editing technologies, the implications of which have dominated ethics and policy debate.
Biomarker analyses from an open-label study of erlotinib in advanced non-small-cell lung cancer (NSCLC)
Authors: N. van Zandwijk, W. Su, R. Rooneem, B. Mehi|Dc, F. A. Franke
Journal: Journal of Clinical Oncology (2008)

19012 Background: The global open-label TRUST study of erlotinib in NSCLC provides a valuable opportunity to assess biomarker hypotheses in a large patient (pt) population. A biomarker analysis of German TRUST pts was reported at ASCO 2007. Here we report data from non-German centers. Methods: Eligibility criteria: pts with stage IIIB/IV NSCLC who had previously failed on or were unsuitable for chemo-/radiotherapy. Erlotinib 150 mg/d p.o. was given until disease progression or unacceptable toxicity. Retrospectively-obtained tumor samples were analyzed by immunohistochemistry (IHC; EGFR expression), fluorescent in-situ hybridization (FISH; EGFR gene copy number) and DNA sequencing (EGFR, KRAS gene mutations). Results: 171 pts were included in this analysis. Baseline characteristics (%): male/female 60/40; Caucasian/other 71/29; adenocarcinoma/squamous-cell/other 56/27/17; never-smoker/ever-smoker 30/70; erlotinib 1st/2nd/3rd-line 9/53/38. Of 155 pts with response data, 13% had CR/PR and 57% had SD; disease control rate = 70%. Median progression-free survival (PFS) was 17.3 wks. EGFR IHC+ pts (≥10% membrane staining; 99/135; 73%) tended to have longer overall survival (OS) and PFS than IHC- pts (36/135; 27%); HR 0.73 in both cases, not significant (ns). OS tended to be greater in EGFR FISH+ (Cappuzzo scoring; 32/56; 57%) vs FISH- (24/56; 43%) pts (HR 0.75; ns), but PFS was similar in these two groups (HR 0.91; ns). OS and PFS were significantly greater in pts with EGFR mutations (11/75; 15%) vs pts with wild-type EGFR (64/75; 85%); HR 0.32 (p=0.013) and 0.43 (p=0.016), respectively. All pts with EGFR mutations achieved PR/SD; the response rate was significantly higher in pts with mutations (46% vs 7% for wild-type; p=0.00043). Pts with KRAS mutations (14/92; 15%) had shorter OS and PFS vs wild-type KRAS (78/92; 85%); HR 1.73 and 1.37, respectively (ns). Interestingly, 3 pts with KRAS mutations had PR. Conclusions: Pts with EGFR mutation+, EGFR IHC+ or EGFR FISH+ tumors tend to have better outcomes on erlotinib therapy. However, the single-arm design of TRUST precludes conclusions on the predictive vs prognostic value of these biomarkers, and their predictive value is being assessed prospectively in a randomized phase III study of erlotinib (SATURN). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly, Roche Lilly
Use of Ki-67 in residual disease following preoperative chemotherapy to predict of recurrence and death in breast cancer patients.
Authors: V. Guarneri, M. Chavez-Mac Gregor, L. Hsu, W. F. Symmans, J. K. Litton, E. A. Mittendorf, P. F. Conte, G. N. Hortobagyi, A. M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2010)

621 Background: The achievement of a pathologic complete response (pCR) after preoperative chemotherapy (PCT) is a powerful predictor of long term outcome, while the prognosis in case of less than pCR is heterogeneous. In two independent studies, posttherapy ki67 was a significant predictor of outcome in breast cancer (BC) patients with residual disease after PCT. The aim of the present study was to evaluate the prognostic significance of posttherapy Ki-67 in an independent patient cohort. Methods: Patients with residual disease following PCT and with posttherapy Ki-67 evaluation by IHC were identified by searching the Breast Medical Oncology database. Patient characteristics including clinical stage, hormone receptors and HER2 status, type of chemotherapy and nodal status after PCT were recorded. The 15% cut-off to define high posttherapy Ki-67 was selected from our previous study (Guarneri, Ann Oncol 2009). Survival rates were estimated with the Kaplan-Meier method; hazard ratios (HRs) by Cox model. Results: Ninety-four patients were included. Median age was 48 years. 69% of the patients had clinical stage I-IIB BC. According to the expression of ER, PgR, and HER2, tumors were classified in the following subtypes: hormone receptor positive/HER2 negative (58%), HER2 positive (18%), and triple receptor negative (18%). All the patients received anthracycline-taxane-containing PCT. The mean posttherapy Ki-67 was 27%. In univariate analyses, clinical stage at diagnosis, posttherapy Ki-67 and BC subtypes were significantly associated with disease-free and overall survival. In multivariate analyses, the HRs for relapse were 6.7 in case of clinical stage III (p < 0.001), 2.9 in case of triple negative disease (p = 0.017), and 6.8 in case of high posttherapy Ki-67 (p < 0.001). The HRs for death were 4.4 in case of clinical stage III (p = 0.005), 3.6 in case of triple negative disease (p = 0.004), and 2.7 in case of high posttherapy Ki-67 (p = 0.026). Conclusions: High posttherapy proliferation is confirmed as an independent predictor of disease-free and overall survival in BC patients with residual disease after PCT. No significant financial relationships to disclose.