Outcome Of Untreated Patients Research Articles

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing–remitting multiple sclerosis, the ProVal-MS study

IntroductionIn Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients.MethodsProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing–Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing–Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed.PerspectiveClinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage.Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)—ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034

929 Case Report -Post Cataract Surgery Fungal Infection Presenting as a Mass Lesion

Abstract Purpose Fungal endophthalmitis is rare and usually causes poor outcome in untreated patients. It is important to document and be aware of uncommon presentation of fungal endophthalmitis. Case report 68-year-old male presented with complaints of redness, pain, and blurry vision in the right eye for the past 5 months. He underwent an uneventful cataract surgery in the right eye 5 months ago elsewhere and in the post operative follow-up was found to have high intraocular pressure for which he was started on antiglaucoma medications. Aqueous tap did not reveal growth of any microorganism. On examination his vision in both the eyes were 20/20. Slit lamp examination revealed congested conjunctiva, corneal superficial punctate keratitis, anterior chamber 2+ cells and 1.2mm white mass over the iris which was encroaching towards the pupillary margin. Ultrasound bio microscopy revealed 0.8mm x 1.5mm mass in the iris at 11 -12 o’clock position. Since there was a diagnostic uncertainty, excision biopsy was done which revealed fungal filaments on KOH staining. The patient was started on tablet voriconazole and advised to review in 1 month. Conclusions Due to the rare frequency, there is a lack of understanding of presentation of fungal endophthalmitis. Many cases series analysis have suggested that the late fungal endophthalmitis presents as clumpy anterior chamber or posterior chamber inflammation [1], white plaque over the lens [2], peripheral vitreous lesion or as chorioretinitis. Our case report shows a rare presentation of fungal endophthalmitis in the form of mass lesion on the iris.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan

AimsIn Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026.Materials and methodsWe constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts’ opinions.ResultsIn 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively.LimitationsOnly those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered.ConclusionsThe present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

Association of non-alcoholic fatty liver disease fibrosis score with proprotein convertase subtilisin/kexin type 9 and combined impact on cardiovascular outcomes in untreated patients with angina-like chest pain: A Prospective cohort study

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is the most common non-invasive score for evaluating fibrosis severity of NAFLD and proprotein convertase subtilisin/kexin type 9 (PCSK9) is linked to NAFLD, which has been reported to be associated with cardiovascular outcomes. We aim to investigate the association of NFS with PCSK9 and their combined effects on cardiovascular outcomes.

Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients

In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo controlled studies in early-stage COVID-19. The present analysis aimed to elucidate, through a comparative analysis with two control groups, whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable. The Active group (AG) consisted of patients enrolled in the Pre-AndroCoV-Trial (n = 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5–36.5% in viral shedding (p < 0.0001), 70–85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilation, deaths and post-COVID manifestations (p < 0.0001 for all). For every 1000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with the well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19.

Serum IgG4 levels at diagnosis can predict unfavorable outcomes of untreated patients with IgG4-related disease

The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921–1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094–8.977, P = 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index.

P53 expression and clinical outcomes in untreated and treated breast cancer patients after long-term follow-up.

e14745 Background: p53 alteration represents one of the hallmarks of malignant transformation. However, its role on treatment outcome remains controversial and is unknown in untreated patients in breast cancer. This study aims to evaluate p53 expression in association with clinical outcomes in untreated patients relative to those undergoing homogeneous therapy. Methods: p53 protein was examined by immunohistochemistry in 956 patients with stage I, II and III breast cancer. Overall survival (OS) and relapse-free survival (RFS) between p53-positive and -negative tumors in chemotherapy, radiation or endocrine therapy alone and no treatment groups were estimated by Kaplan-Meier method. OS and RFS were further assessed by multivariable Cox model that incorporates p53, age, tumor size and grade, estrogen receptor, and HER2 in specific treatment group(s). Results: p53 expression was detected in 22.7% of breast cancer. Median follow-up time was 115.5 months, with a range of 5 to 282 months. Expression of p53 was associated with younger age at diagnosis, higher tumor grade, ER/PR negativity, and HER2 positivity ( P&lt; 0.001). Without any treatment including systemic and radiation therapy (n = 227), OS and RFS curves were overlapped from the beginning until the end of follow-up between p53-positive and -negative patients, respectively. In contrast, p53 was significantly associated with worse OS and RFS with univariate analysis and multivariate statistics of OS (HR 4.07, 95% CI 1.95-8.50; P&lt; 0.001) and risk of relapse (HR 2.23, 95% CI 1.11-4.48; P= 0.025) by endocrine therapy alone (n = 130). Moreover, apparent trends for p53 toward unfavorable OS and RFS were observed in those undergoing homogeneous radiation therapy and chemotherapy, only within 150 months of follow-up. Conclusions: p53 is not associated with clinical outcomes in the absence of conventional therapy, and independently predicts worse survival and increased risk of recurrence after endocrine therapy.

Effect of Primary Tumor Side on Survival Outcomes in Untreated Patients With Metastatic Colorectal Cancer When Selective Internal Radiation Therapy Is Added to Chemotherapy: Combined Analysis of Two Randomized Controlled Studies

BackgroundThe primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and MethodsSeparate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. ResultsIn the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). ConclusionThe addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain.

Transfer of stroke patients impairs eligibility for endovascular stroke treatment

BackgroundMany patients who are potentially eligible for endovascular stroke treatment (EST) receive intravenous rtPA in the closest stroke unit before being transferred to tertiary centres for EST. It has been shown that clinical outcome of transferred and EST-treated patients is comparable to that of patients with direct access to EST. We analysed clinical outcome of patients, who were transferred and eventually not treated due to clinical and/or radiological deterioration. MethodsWe retrospectively analysed our prospectively maintained stroke registry for patients who were transferred for stroke therapy. ResultsFour hundred twenty-two of 1208 patients (35.1%), who were admitted for acute reperfusion stroke therapy between 03/10 and 01/15 were eligible for EST. Ninety-one (7.5%) of these patients were admitted specifically for EST from remote hospitals. Favorable clinical outcome rates after 90 days (mRS≤2) were comparable between 63 transferred and 295 directly-admitted patients, who received EST (P=0.699). However, transferred patients, who were eligible for EST on initial admission, were less likely to receive EST after transfer (P<0.001): twenty-two of 91 patients (24.2%), who were transferred for EST, became ineligible during transfer due to infarct demarcation. Procedural times of treated and untreated transferred patients were comparable (P≥0.508). There was a trend towards worse clinical outcome in untreated patients, without reaching statistical significance (OR, 0.269; 95% CI, 0.55–1.324; P=0.119). ConclusionsEST should be provided directly whenever possible as one in four transferred stroke patients becomes ineligible for EST during transfer. If direct transfer is not possible, indication for EST should be re-assessed after transfer.

Clinical Impact of the Presence of a Diffuse Large B-Cell Lymphoma (DLBCL) Component in the Outcome of Untreated Patients with Follicular Lymphoma (FL)

Introduction: Histological transformation into an aggressive lymphoma, usually DLBCL, may occur during the follow-up of FL patients and determines a poor outcome. The presence of a DLBCL component in a FL (FL/DLBCL) is observed in some cases at diagnosis, usually being considered a transformation of a FL with a previously undetected indolent course. The clinical implications of this situation in terms of prognosis and treatment remain unclear. The aim of the present study was to analyze the clinicobiological characteristics and outcome of patients diagnosed with FL/DLBCL in the rituximab era, in comparison with patients diagnosed with pure FL or de novo DLBCL at the same period in a single institution.Patients and Methods: Eight hundred seventy eight patients sequentially diagnosed with either FL, DLBCL or FL/DLBCL between 2002 and 2015 ina single institution were included in the study. The histological distribution was as follows: FL grade 1, 2, 3a, 320 cases (140M/180F; median age, 58 years), FL 3b, 8 cases (4M/4F; median age, 66 years), DLBCL, 510 cases (275M/235F; median age, 65 years) and FL/DLBCL, 40 (16M/24F; median age, 65 years).According to institutional guidelines, the latter were treated as aggressive lymphomas, with no maintenance or further intensification. All FL/DLBCL biopsies were reviewed and the DLBCL component semiquantified. Cell of origin (COO) assessment by gene expression-based assay was determined in 127 cases and NOTCH1-2 mutational status in 216.Results: Main clinicobiological characteristics of the patients according to the histology are listed in the table. Compared to DLBCL cases, FL/DLBCL patients showed more frequently ambulatory performance status, primary nodal origin and advanced stage, with these features being closer to those of FL patients. On the contrary, FL/DLBCL patients had an intermediate position between FL and DLBCL cases regarding B-symptoms, bone marrow infiltration, hemoglobin and serum LDH levels. The proportion of DLBCL component in FL/DLBCL cases ranged from 5 to 95%, with no significant differences in the initial characteristics according to the proportion of DLBCL component. COO was determined in 11 FL/DLBCL, with 8 (73%) being GCB, 2 (18%) ABC, and 1 unclassified. Such distribution in 116 DLBCL with COO available was: 50 (43%) GCB, 50 (43%) ABC and 16 unclassified. NOTCH 1-2 was mutated in 4/39 (10%) FL/DLBCL, whereas this proportion was 1/41 (2%) FL and 11/136 (8%) DLBCL. All FL/DLBCL patients were treated as aggressive lymphoma with no intensification after front-line therapy. The proportion of primary refractoriness in FL/DLBCL patients was significantly higher than in FL and similar to that of DLBCL. Progression free survival (PFS) and overall survival (OS) are showed in the table and figure. Among the 40 FL/DLBCL cases, the amount of DLBCL component did not show prognostic impact, whereas the histological grade did (5-year OS FL grades 1-2-3a/DLBCL, 92% vs. FL grade 3b/DLBCL, 38%; p=0.001). In the different cohorts analyzed (FL+FL/DLBCL, FL+FL/DLBCL+DLBCL, and FL/DLBCL+DLBCL), FL/DLBCL histology did not show independent value for OS in multivariate analyses that included standard prognostic variables, namely, serum β2m and FLIPI or IPI scores. Sequential biopsies were available in 120 cases, with the following distribution according to the primary diagnosis: FL, 60 cases (at relapse: 37 FL and 23 DLBCL), FL/DLBCL, 6 cases (at relapse: 3 FL, 2 FL/DLBCL and 1 DLBCL), and DLBCL, 54 cases (at relapse: 4 FL and 50 DLBCL).Conclusion: Patients with FL/DLBCL, although infrequent, exists and have clinicobiological differentiated features compared to pure FL and DLBCL. When treated with standard immunochemotherapy their outcome is not worse than that of de novo DLBCL. Some clinicobiological characteristics suggest FL/DLBCL to be a specific category rather than a transformation from a FL; however, this warrants further biological studies. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Applicability, basic techniques and current status—‘the essential ABCs’—of transcatheter aortic valve replacement (TAVR)

Aortic stenosis is the most common valvular heart disease in the elderly which warrants immediate intervention due to the poor outcomes in untreated patients. Even though the procedure of choice is surgical aortic valve replacement (SAVR) in good risk patients, transcatheter aortic valve replacement (TAVR) is evolving as a standard of care in extreme high-risk patients. Encouraging results are obtained by proper patient selection by a heart team. Transoesophageal echocardiogram and TAVR CT scan-based sizing and deployment strategies have yielded good results. Though transfemoral is the preferred route of deployment, alternate access route like trans apical, transcaval and transaortic routes has resulted in extending this modality of treatment to patients with aortoiliac occlusive disease. Self expanding and balloon expandable valves have been licenced for human use in indicated patients in the USA and in Europe. Increasing expertise, recapturement ability, and reduction is the sheath size has resulted in fewer complications. Durability of transcatheter valves need further evaluation. Trials like PARTNER 2 and SURTAVI are currently being undertaken to improve the existing technology and to expand the indications of TAVR.

Therapeutic approach to IgG4-related disease: A systematic review.

To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice.A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed.The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used.Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological, and clinical factors, especially with respect to the predominant organ affected. The frequency of glucocorticoid failure to induce sustained remissions both during and after treatment and the assessment of glucocorticoid toxicity in IgG4-RD require further study.

Effect of alvimopan on return of bowel function after robot-assisted radical cystectomy.

Alvimopan has been shown to improve time to return of bowel function in patients undergoing bowel resection. The objective of this study is to determine if alvimopan has similar benefits for patients undergoing robot-assisted radical cystectomy (RARC). All RARC cases were reviewed from January 2008 to March 2012. All patients during this time were administered alvimopan unless they had been receiving narcotics preoperatively. Patients receiving alvimopan received a preoperative dose of 12 mg perorally and then were dosed twice daily for 7 days or until first bowel movement. Clinicopathologic outcomes were summarized and compared, and functional outcomes of treated patients were compared with outcomes of untreated patients. One hundred seventeen RARCs meeting study criteria were performed. All urinary diversions used an extracorporeal approach. Urinary diversions consisted of 50 Studer neobladders, 22 Indiana pouches, and 45 ileal conduits. Fifty-four patients received alvimopan, and 63 did not. The median time to first bowel movement was 5 days in the alvimopan group and 6 days in the untreated group (P=.03). Median time to solid diet was 6 days in the treated group and 7 days in the untreated group (P=.03). There was a trend toward fewer hospital days in the alvimopan group (alvimopan, 8 days; untreated, 9 days; P=.1). Alvimopan administration appears to reduce the time to return of bowel function and initiation of diet following RARC. This was a trend toward shorter hospitalization in the alvimopan group. Alvimopan should be considered in ongoing research into protocols to aid in shorter convalescence following RARC.

Upfront Autologous Stem Cell Transplantation for Untreated High-Risk Diffuse Large B-Cell Lymphoma in Patients Up to 60 Years of Age

Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n=14 (64%)] or high [n=8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n= 15 (68%)) or a partial response (PR; n= 7 (32%)). The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n=9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P= .002). These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.

PCN109 Progressive Worsening of Patient-Reported Outcomes in Untreated Patients With Myelofibrosis

PCN109 Progressive Worsening of Patient-Reported Outcomes in Untreated Patients With Myelofibrosis

Mild hyperphenylalaninemia: to treat or not to treat.

One of the issues to be resolved in phenylketonuria is whether patients with mild hyperphenylalaninemia need treatment, or in other words, in what patients treatment needs to be started. Do patients need treatment when phenylalanine concentrations in blood are >360 μmol/L or >600 μmol/L? This paper reviews the literature on the outcome of untreated patients with mild hyperphenylalaninemia to try to determine whether outcome is normal. The paper concludes that there is, in fact, only one paper that can be used to answer this question. Therefore, the question is whether we may rely on one paper to draw conclusions or whether more research is necessary to determine whether all patients with phenylalanine concentrations >360 μmol/L or all patients with phenylalanine concentrations >600 μmol/L require treatment.

Pro: Intravenous Tissue Plasminogen Activator in Stroke Patients With Rapid, Complete Recovery During Evaluation (Transient Ischemic Attack) and Evidence of Middle Cerebral Artery Occlusion

Carlos A. Molina MD, PhD Magdy H. Selim MD, PhD Section Editors: The Case: A patient presents within 3 hours of acute onset of left-sided weakness. Symptoms rapidly resolve spontaneously. Vascular imaging reveals evidence of right middle cerebral artery (MCA) occlusion. The Questions: (1) Should treatment decision be based on clinical or vascular status? (2) Would treatment with t-PA prevent clinical worsening or early stroke recurrence in this patient? (3) Is increased collateral flow good enough to maintain perfusion? The Controversy: Role of Thrombolysis in Patients with Rapid Recovery during Evaluation and Evidence of Arterial Occlusion on Vascular Imaging. There are some points on which to agree at the beginning of this controversy. The middle cerebral artery (MCA) supplies a large and important proportion of the brain, which is not meant to be perfused through small collaterals. Acute occlusion of the MCA in most cases leads to devastating strokes. Thus, a patent MCA is probably better than an occluded one. Would we really consider a spontaneously recovering stroke patient with a proven, persistent occlusion of the MCA to have a “transient ischemic attack” (TIA) not necessitating thrombolysis? The …

TLE3 as a candidate biomarker of response to taxane therapy

IntroductionThe addition of taxanes (Ts) to chemotherapeutic regimens has not demonstrated a consistent benefit in early-stage breast cancer. To date, no clinically relevant biomarkers that predict T response have been identified.MethodsA dataset of immunohistochemistry stains in 411 patients was mined to identify potential markers of response. TLE3 emerged as a candidate marker for T response. To test the association with T sensitivity, an independent 'triple-negative' (TN) validation cohort was stained with anti-TLE3 antibody.ResultsTLE3 staining was associated with improved 5-year disease-free interval (DFI) in the overall cohort (n = 441, P < 0.004), in patients treated with cyclophosphamide (C), methotrexate, and 5-fluorouracil (n = 72, P < 0.02), and in those treated with regimens containing doxorubicin (A) and a T (n = 65, P < 0.04). However, no association was shown with outcome in untreated patients (n = 203, P = 0.49) or those treated with a regimen containing A only (n = 66, P = 0.97). In the TN cohort, TLE3 staining was significantly associated with improved 5-year DFI in all patients (n = 81, P < 0.015), in patients treated with AC + T (n = 45, P < 0.02), but not in patients treated with AC (n = 17, P = 0.81). TLE3 was independent of tumor size, nodal status, and grade by bivariable analysis in both cohorts.ConclusionsTLE3 staining is associated with improved DFI in T-treated patients in two independent cohorts. Since the validation study was performed in a TN cohort, TLE3 is not serving as a surrogate for estrogen receptor or HER2 expression. TLE3 should be studied in large clinical trial cohorts to establish its role in T chemotherapy selection.

TLE3 as a biomarker for taxane sensitivity in breast cancer

573 Background: The addition of taxanes (T) to chemotherapeutic regimens has not demonstrated a consistent therapeutic benefit in early stage breast cancer (Ward, HTA 2007). A recent study by Hayes, et al. suggested that HER2+ breast tumors may gain increased clinical benefit from treatment with T. The toxicity associated with T therapy compels a search for additional and or refined biomarkers of response. Methods: A dataset of IHC stains in 411 patients from Clearview Cancer Center (CCI) was mined to identify biomarkers of T response (Ring, JCO 2006). TLE3 staining with a polyclonal antibody was nominated as a candidate T-response predictor. The association with T sensitivity was tested by staining with anti-TLE3 antibody on an independent triple-negative (TN) validation cohort assembled at the Roswell Park Cancer Institute (RPCI). Results: TLE3 was identified as a candidate T sensitivity marker in the CCI cohort by identifying patients with improved five-year disease-free interval (DFI) in overall cohort (n=441, p<0.004), patients treated with CMF (n=72 p<0.02), or those treated with a AC+T regimen (n=65 p<0.04) but no association of staining with outcome in untreated patients (n=203 p=0.49) or those treated with a AC without T (n=66 p=0.97). In the RPCI TN validation cohort, TLE3 staining was significantly associated with improved five-year DFI in T treated patients (n=45 p<0.02) and all patients (n=81 p<0.015) but not AC treated patients (n=17 p=0.81). These associations were independent of grade, tumor size and nodal status in both cohorts. Conclusions: TLE3 staining is associated with improved DFI in taxane-treated patients in two independent cohorts. Given that the validation cohort was triple negative, it is unlikely that TLE3 is serving as a surrogate for ER or HER2 expression. TLE3 should be studied in large clinical trial cohorts to establish its role in taxane chemotherapy selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Applied Genomics Applied Genomics Applied Genomics Applied Genomics

Suspected pulmonary embolism and deep venous thrombosis: A comprehensive MDCT diagnosis in the acute clinical setting

Both pulmonary arterial and peripheral venous sides of venous thromboembolism (VTE) can now be efficiently and safely investigated by multi-detector CT (MDCT) at the same time by a combined CT angiography/CT venography protocol. In the emergency setting, the use of such a single test for patients suspected of suffering from VTE on a clinical grounds may considerably shorten and simplify diagnostic algorithms. The selection of patients to be submitted to MDCT must follow well-established clinical prediction rules in order to avoid generalized referral to CT on a generic clinical suspicion basis and excessive population exposure to increased ionizing radiation dose, especially in young patients. Clinical and anatomical wide-panoramic capabilities of MDCT allow identification of underlying disease that may explain patients’ symptoms in a large number of cases in which VTE is not manifest. The analysis of MDCT additional findings on cardiopulmonary status and total thrombus burden can lead to better prognostic stratification of patients and influence therapeutic options. Some controversial points such as optimal examination parameters, clinical significance of subsegmentary emboli, CT pitfalls and/or possible falsely positive diagnoses, and outcome of untreated patients in which VTE has been excluded by MDCT without additional testing, must of course be taken into careful consideration before the definite role of comprehensive MDCT VTE “one-stop-shop” diagnosis in everyday clinical practice can be ascertained.