Miracle-dz/UniFAR-FTUs huggingface dataset:
Hidden biases in an observational study of bevacizumab beyond progression.

TO THE EDITOR: Grothey et al 1 recently reported a prospective observational study that monitored oncologists’ use of bevacizumab after patients experienced disease progression while receiving a prior bevacizumab-containing regimen. The conclusion formed on the basis of this study was that there was a suggested survival benefit from continuing bevacizumab after failure of a first-line bevacizumabcontaining regimen, with a hazard ratio (HR) of 0.46 on multivariate analysis. Generally, observational studies can provide important data on toxicities and practice patterns, but these types of studies have significant limitations when they are used to answer comparative questions of efficacy. Grothey et al 1 clearly acknowledge the potential bias with this study design and attempt to adjust for several factors. Unfortunately, it is impossible to quantify the extent to which this bias formed or altered the outcome of the trial. Several important sources of bias cannot be controlled for in the absence of randomization to treatment in this study, as will undoubtedly be delineated in this space by other readers of this journal. As a result, factors that are correlated with survival also affect the oncologist’s decision to continue bevacizumab. Several poor prognosis factors that may decrease an oncologist’s enthusiasm to continue bevacizumab include poor performance status at progression, higher vascular comorbidities, rapid tumor growth while receiving the prior bevacizumab-containing regimen, or peritoneal disease. Each of these factors would generally have predicted shorter survival in patients in whom bevacizumab was discontinued. However, in lieu of enumerating the number and reasoning for such biases in greater detail, we conducted similar analyses that may help to highlight the extent to which the conclusions in this observational trial may have been formed by these unseen biases. Since the US Food and Drug Administration’s approval of bevacizumab in 2004, most previously untreated metastatic colorectal patients at our institution have been treated with a bevacizumab-containing regimen. We chose to retrospectively examine these sequential patients to determine if patients treated again with bevacizumab as part of a later-line regimen had improved outcomes than those who did not receive a later-line bevacizumab-containing regimen. Indeed, we were able to demonstrate a similar HR of 0.62 (P .01) in favor of patients receiving bevacizumab after failing a prior bevacizumab-containing regimen.
Clinically driven diagnostic antifungal approach in neutropenic patients: a prospective feasibility study.

PURPOSE Preemptive strategies in neutropenic patients based on serum galactomannan (GM) -guided triggering of diagnostic work-up may be time-consuming and expensive when applied to the entire population. We have assessed the feasibility of a clinically driven diagnostic strategy without GM screening. PATIENTS AND METHODS Patients with neutropenic fever underwent a baseline diagnostic work-up (BDWU; three blood cultures and other examinations as indicated). An intensive diagnostic work-up (IDWU; GM for 3 days, chest computed tomography and other examinations as indicated) was reserved for patients with 4 days of persisting or relapsing fever or with other clinical findings possibly related to an invasive fungal diseaser (IFD). Antifungal therapy was administered to patients diagnosed with IFD and empirically (negative IDWU) only to those with persisting neutropenic fever and worsening clinical conditions. RESULTS Of 220 neutropenia episodes, fever occurred in 159 cases and recurred in 28 cases. Overall, 49 IFDs were diagnosed (two by BDWU and 47 by IDWU) during 48 episodes (21.8%). Diagnostic-driven therapy was administered to 48 patients with IFDs; one patient with zygomycosis died without treatment. Only one patient received empirical therapy. IDWU was required in 40% of neutropenia episodes, and only 1.4 mean blood samples per neutropenia episode were tested for GM. Our strategy allowed a 43% reduction in antifungal treatments compared with a standard empirical approach. At 3-month follow-up, 63% of patients with IFD survived, and no undetected IFDs were found. CONCLUSION A clinically driven diagnostic approach in selected neutropenia episodes offered effective antifungal control and reduced the exposure to unnecessary antifungal treatment.
Phase III trial of casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

PURPOSE The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC). PATIENTS AND METHODS Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC. RESULTS A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms. CONCLUSION All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.
Toward Unification of Synthesis and Verification in Topologically Constrained Logic Design

In logic synthesis, the search space is infinite in the sense that any number of gates can be connected using any topology to come up with the best circuit under performance and other constraints. In formal verification, to achieve full coverage, an n-input circuit must be checked either explicitly or implicitly using the complete set of 2n input values. There are, however, situations when the possible circuit topologies are limited. Logic optimization methods, in general, do not change circuit topologies dramatically. Most of them are based on series of local circuit transformations. In this paper, we discuss formal verification of circuits produced by logic synthesis where the search space is limited, and only gates or subcircuits are transformed whereas their interconnections never change. If there are p possible transformations for each gate or subcircuit, and there are m gates or subcircuits in the entire circuit, the number of all possible transformations for the entire circuit is pm. Logic synthesis with this restriction attempts to find the best circuit among the pm alternatives. The logic synthesis problem can be formulated as a sequence of incremental SAT problems and the complete set of test patterns can be computed, which detects all possible errors in the synthesized circuit. As long as the search space is limited to the pm alternatives, such complete set of test patterns can be used for formal verification. The number of test patterns needed in this case is experimentally shown to be very small, e.g., a few hundred, even for circuits having several hundred inputs and several thousand gates. With the complete set of test patterns generated for the circuit transformations, logic synthesis and formal verification are unified in the sense that the small number of test patterns allows for logic synthesis with 100% correctness.
Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.

PURPOSE Assess toxicity and efficacy of cisplatin (Cis) doublet combinations in advanced and recurrent cervical carcinoma. PATIENTS AND METHODS Patients were randomly assigned to paclitaxel 135 mg/m(2) over 24 hours plus Cis 50 mg/m(2) day 2 every 3 weeks (PC, reference arm); vinorelbine 30 mg/m(2) days 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (VC); gemcitabine 1,000 mg/m(2) day 1 and 8 plus Cis 50 mg/m(2) day 1 every 3 weeks (GC); or topotecan 0.75 mg/m(2) days 1, 2, and 3 plus Cis 50 mg/m(2) day 1 every 3 weeks (TC). Survival was the primary end point with a 33% improvement relative to PC considered important (85% power, alpha = 5%). Quality-of-life data were prospectively collected. RESULTS A total of 513 patients were enrolled when a planned interim analysis recommended early closure for futility. The experimental-to-PC hazard ratios of death were 1.15 (95% CI, 0.79 to 1.67) for VC, 1.32 (95% CI, 0.91 to 1.92) for GC, and 1.26 (95% CI, 0.86 to 1.82) for TC. The hazard ratios for progression-free survival (PFS) were 1.36 (95% CI, 0.97 to 1.90) for VC, 1.39 (95% CI, 0.99 to 1.96) for GC, and 1.27 (95% CI, 0.90 to 1.78) for TC. Response rates (RRs) for PC, VC, GC, and TC were 29.1%, 25.9%, 22.3%, and 23.4%, respectively. The arms were comparable with respect to toxicity except for leucopenia, neutropenia, infection, and alopecia. CONCLUSION VC, GC, and TC are not superior to PC in terms of overall survival (OS). However, the trend in RR, PFS, and OS favors PC. Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.
Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers.

PURPOSE Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. PATIENTS AND METHODS Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. RESULTS Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. CONCLUSION Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.
Training in dealing with child abuse in schools: problems in evaluating course effectiveness

Teachers play an important part in identifying child maltreatment but find dealing with it difficult. This study examines the problems involved with evaluating a countywide training programme on this topic for senior teachers. The course was run 17 times and 60% of the participants attending were sent an evaluation questionnaire three months after taking part. There was a 49% response rate. It was found that the activities undertaken by the participants after the course were a greater reflection of the effort required than of the effectiveness of the course. It is argued that this factor should be taken into account when conducting and interpreting any course evaluation.
Changes in the management of deep sternal wound infections: a 12‐year review

Deep sternal wound infection (DSWI) is a rare but life‐threatening complication following cardiac surgery associated with increased morbidity and mortality. Management of these patients has evolved over the years and can include sternal rewiring, mediastinal irrigation, negative‐pressure wound therapy (NPWT) dressing or repair with flaps. We reviewed changes in our management of DSWI and outcomes.
No weak days? Impact of day in the week on surgical mortality

Studies show increased rates of mortality for admissions on the weekend (WE) versus the weekday (WD). However, scepticism exists of this so‐called ‘weekend effect’ on patient outcome. It remains poorly investigated, particularly the timing of the day of surgery and post‐operative outcomes. A UK study found higher odds of death when operated on Friday and the WE, versus WD. This relationship was investigated by interrogating the Australian and New Zealand Audit of Surgical Mortality database.
Dirucotide (MBP8298) for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a chronic and debilitating disease affecting approximately 2.5 million people worldwide, and safe and effective treatment options are sorely lacking. While there are several currently approved drugs that have shown some efficacy at reducing the relapse rate in patients with the relapsing–remitting form of the disease, the impact of this outcome relative to long-term disease progression is unknown. Effective treatment for those with primary or secondary progressive MS is practically nonexistent. Dirucotide (MBP8298) is a synthetic peptide that has shown promise at increasing time to progression with little or no associated toxicity in Phase II studies. The drug is specifically designed to induce tolerance in patients with HLA types DR2 and/or DR4, although patients with other HLA subtypes may also benefit. Dirucotide is now being evaluated in two large Phase III secondary progressive MS trials, as well as a smaller Phase II relapsing–remitting MS trial.
Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.

PURPOSE Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. PATIENTS AND METHODS Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. RESULTS The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses > or = 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. CONCLUSION IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.
Hepatotoxicity Due to Pemoline

Pemoline, a central nervous system stimulant, has been used extensively in Great Britain and Europe for a variety of conditions including memory failure and depression. In the 10 years that the drug has been used no report of hepatotoxicity has appeared. A prospective study of efficacy and safety of pemoline was started in the United States approximately 3 years ago. This report describes two patients who developed reversible liver abnormalities while receiving pemoline during the study and following rechallenge with the drug.
High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller.

PURPOSE To evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) -positive breast cancer. METHODS We reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3+ by immunohistochemistry or if it had a ratio of 2.0 or greater by fluorescence in situ hybridization (FISH). Patients who received adjuvant chemotherapy or trastuzumab were excluded. Kaplan-Meier product was used to calculate recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). Cox proportional hazard models were fit to determine associations between HER2 status and survival after adjustment for patient and disease characteristics. Additionally, 350 breast cancers from two other institutions were used for validation. RESULTS Ten percent of patients had HER2-positive tumors. At a median follow-up of 74 months, there were 72 recurrences. The 5-year RFS rates were 77.1% and 93.7% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). The 5-year DRFS rates were 86.4% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). In multivariate analysis, patients with HER2-positive tumors had higher risks of recurrence (hazard ratio [HR], 2.68; 95% CI, 1.44 to 5.0; P = .002) and distant recurrence (HR, 5.3; 95% CI, 2.23 to 12.62; P < .001) than those with HER2-negative tumors. Patients with HER2-positive tumors had 5.09 times (95% CI, 2.56 to 10.14; P < .0001) the rate of recurrences and 7.81 times (95% CI, 3.17 to 19.22; P < .0001) the rate of distant recurrences at 5 years compared with patients who had hormone receptor-positive tumors. CONCLUSION Patients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy.
Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes.

PURPOSE The sixth edition of the American Joint Committee on Cancer (AJCC) rectal cancer staging subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III as a result of improved survival with T1-2N2 versus T3-4N2 and survival of T4N1 more similar to T3-4N2 than T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion interacts with nodal status to affect survival. METHODS Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 35,829 patients with rectal cancer were compared with rectal pooled analysis data (3,791 patients). T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of positive nodes as follows: N1a/N1b (one v two to three nodes) and N2a/N2b (four to six v > or = seven nodes). Five-year observed and relative survival rates were obtained for each TN category. RESULTS SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2, T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. CONCLUSION This SEER population-based rectal cancer analysis validates the rectal pooled analyses and supports the shift of T1-2N2 lesions from IIIC to IIIA or IIIB and T4bN1 from IIIB to IIIC. SEER outcomes support subdividing T4, N1, and N2 and revised substaging of stages II and III. Survival by TN category suggests a complex biologic interaction between depth of invasion and nodal status.
Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer.

PURPOSE Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC. PATIENTS AND METHODS Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients. RESULTS Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction > or = 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment. CONCLUSION Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.