Large Number Of Unselected Patients Research Articles

Prognostic value of systemic inflammatory response in early-stage triple-negative breast cancer.

e14562 Background: Among breast cancer (BC) triple-negative (TN) subtype is the most immunogenic. Host and systemic immune response characterised by tumor-infiltrating lymphocytes (TILs) and immune cells in peripheral blood shape the net anti-tumor immune status. The systemic immune-inflammation index (SII) represents an effective indicator of the peripheral immune status. To date, TILs and SII have been largely examined separately. Therefore, in the present study, we investigated the prognostic value and relationship between pretreatment TILs and SII in a large number of unselected patients (pts) with early (e) stage TNBC. Methods: A total of 301 consecutive eTNBC pts treated with curative intent at Oncology Institute Ljubljana from January 2000 till August 2007 were investigated. Histopathological and clinical data were obtained retrospectively from the medical records. TILs were scored as intensive vs others. SII was determined by platelet × neutrophil/lymphocyte. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The optimal cut-off value of SII was 675 and was evaluated using the receiver operating characteristic (ROC) curve. Results: The median follow-up period was 17,6 years (16.9-18.3), and the entire cohort`s 10-year DFS was 67.5% and 10-year OS 72.1%. The median age was 54 (53-57) years. Most pts were diagnosed node negative (40.7%), with larger tumors (≥ 2 cm, 57.1%), grade 3 (83.5%) and underwent perioperative chemotherapy (cht) (81%). Patients with positive lymph nodes (LN) had higher SII (r=0.21, p=0.003), no correlation between LN and TILs was found. Patients with higher TILs had significantly better OS (HR: 0.40, 95% CI 0.37-0.97, p=00.004), and lower SII predicted significantly better DFS and OS (HR for DFS: 1.65 95% CI 1,03-2.67, p=0.038, HR for OS: 1.72, 95% CI 1.11-2.65, p=0,015). In multivariate analysis, positive LN status retained its independent prognostic value for worse DFS and positive LN and higher SII for worse OS. Conclusions: Our data confirms important role of systemic immune response in the prognosis of eTNBC. The survival of these pts is significantly influenced by the pretreatment SII and TILs, the prognostic value of SII seems to be stronger in our cohort. However, positive lymph node status remains the strongest predictor for worse survival in eTNBC. [Table: see text]

The evolution of fracture clinic design : the activity and safety of the Edinburgh Trauma Triage Clinic, with one-year follow-up.

Fracture clinics are often characterised by the referral of large numbers of unselected patients with minor injuries not requiring investigation or intervention, long waiting times and recurrent unnecessary reviews. Our experience had been of an unsustainable system and we implemented a 'Trauma Triage Clinic' (TTC) in order to rationalise and regulate access to our fracture service. The British Orthopaedic Association's guidelines have required a prospective evaluation of this change of practice, and we report our experience and results. We review the management of all 12 069 patients referred to our service in the calendar year 2014, with a minimum of one year follow-up during the calendar year 2015. Following the successful introduction of the TTC, only 2836 patients (23.5%) who would previously have been reviewed in the general fracture clinic were brought back to such a clinic to be seen by a surgeon. An additional 2366 patients (19.6%) were brought back to a sub-specialist injury-specific clinic. Another 2776 patients (23%) with relatively predictable injuries were reviewed by a nurse practitioner according to an established protocol or specific consultant instructions. A further 3222 patients (26.7%) were discharged from the service without attending the clinic. No significant errors or omissions occurred with the introduction of the TTC. We have found that our TTC allows large numbers of referrals to be reviewed and triaged safely and effectively, to the benefit and satisfaction of patients, consultants, trainees, staff and the organisation. This paper provides the first large-scale review of the instigation of a TTC, and its effect, acceptability and safety. Cite this article: Bone Joint J 2017;99-B:503-7.

Introduction to special issue on biomarker-based clinical trial designs in oncology.

Recent years have seen an explosion in knowledge of the biologic drivers of cancer. Many (and likely soon most) tumors are now sub-classified by a molecular profile, with different treatment options and strategies for patients based on their tumor biomarker status. Therapeutic development is similarly now mostly targeted to subsets of patients within any given tumor type based on specific molecular and biologic characteristics. With the so-called basket trials, early phase therapeutic development of targeted agents is focused only on specific molecular aberrations, ignoring tumor type. Umbrella trials on the other hand focus on drug development targeting distinct molecular alterations in one tumor entity. These novel approaches to clinical drug development have resulted in a rapid evolution of methodologies to perform clinical trials in the setting of biomarkers and targeted therapies, where the paradigm of treating very large number of unselected patients is increasingly non-viable.

LiverTox: An online information resource and a site for case report submission on drug-induced liver injury.

Drug-induced liver injury (DILI) is an infrequent cause of liver disease in the general population and accounts for< 1% of hospitalized patients presenting with jaundice. 1,2 Nonetheless, DILI is a leading reason for regulatory actions involving investigational and approved medications and is also a leading cause of acute liver failure in the United States. 3,4 Implicated drugs include not only prescription medications but also herbal products and over-the-counter dietary supplements and medications. It is noteworthy that since inception of the Drug-Induced Liver Injury Network (DILIN) by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2003, the number of enrolled cases of herbal and dietary supplements-induced liver injury have steadily increased, representing the second most commonly recorded class of hepatotoxicity-causing products in DILIN. The low incidence of DILI, coupled with the limited knowledge of the biochemical mechanism(s) or pathways responsible for this ‘‘idiosyncratic’’ adverse event, make it difficult to identify high-risk patients. 5 Furthermore, preclinical testing does not always provide a reliable assessment of the hepatotoxic risk of new medications; and because DILI is a rare event, premarketing clinical studies usually conducted in highly selected populations over a relatively short period of time also may not detect a potential for liver injury. Therefore, the hepatotoxicity of a specific medication often becomes apparent only after regulatory approval—and when the drug is used by large numbers of unselected patients in the general population. Finally, because the biochemical, clinical, and histological features of DILI mimic most other known forms of acute and chronic liver injury, and there is no objective gold standard for diagnosing DILI, its identification largely relies on excluding other more common causes of liver injury and having a ‘‘compatible’’ time of onset and evolution.

Molecular analysis of adrenocortical carcinoma (ACC) tumors.

e21174 Background: Personalized medicine has become increasingly important in the management of oncology patients. Traditional approaches require a large numbers of unselected patients to enroll on clinical studies with empirically derived therapies. Newer approaches include analysis of tumor specimens to determine potential predictive and prognostic clinical biomarkers. Recently, a study by Von Hoff and colleagues utilized a molecular analysis of freshly biopsied tumors to determine gene array profile along with immunohistochemical staining in effort to generate potential targets for therapeutic intervention. This approach led to 28% of the study patients achieving a 33% increase in progression free survival. Adrenocortical carcinomas (ACC) occur in only one out of one million people and many patients have metastatic disease at the time of diagnosis (1). The rarity of this disease makes it difficult to study and with few treatment options the prognosis is poor (5). The standard management of this disease is largely surgical, with a role for adjuvant mitotane post-operatively, and palliative chemotherapy in the case of metastatic disease (9). Methods: Six consecutive unselected patients at UCLA Medical Center were chosen for this study. The patients had surgery at UCLA and had a portion of their tumors fresh frozen and sent CARIS MPI where molecular analysis was performed. A gene microarray profile that focused on 81 genes, potentially important in oncogenesis and oncomaintenance, was run as well as immunohistochemistry staining of 50 proteins important in cell growth and division. Genetic data were categorized, qualitatively reviewed, and attempts at correlations were made. Results: The microarray data provided some consistencies across the patients. All the patients were found to overexpress DNA associated molecules such as; TOP2A, RRM2, TK1, and TYMS also found to be underexpressed were molecules involved in signaling pathways such as; PDGFRA and ECGF1. Conclusions: While many cancers have known genetic defects contributing to their molecular phenotype ACC has yet to have any clearly defined molecular defect. This brief molecular study and clinical description of six ACC patients illustrates the heterogeneity of this disease.

The relationship between etiology, symptom severity and indications of surgery in cases of anal incontinence: a 25-year analysis of 1,046 patients at a tertiary coloproctology practice

The etiology of anal incontinence (AI) is often multifactorial. There is little data on the relationship between the etiology of AI, symptom severity, and the need for surgery. The aim of our study was to investigate this association in a large number of unselected patients with AI referred to a tertiary specialist coloproctological practice. Patients with AI seen at our unit between 1983 and 2008 were analyzed. The main etiologies were categorized as congenital, traumatic, neurologic, idiopathic, post-operative, post-obstetric, secondary to rectal prolapse, or inflammatory bowel disease. The severity of AI was graded using the validated Pescatori incontinence scale. Overall, 1,046 patients were studied. The AI score was higher in patients with congenital (4.7 ± 1.1), traumatic (4.6 ± 1.4), and neurological (4.4 ± 1.2) incontinence. Surgical treatment was indicated in 214 cases (20.5%). Patients with AI related to trauma and congenital anomalies required surgery in 43.5 and 31.4% of cases, respectively, a percentage significantly higher than that for patients with other etiologies (P = 0.002). Prolapse-related AI usually responded to correction of the prolapse. Patients with congenital, traumatic, and neurological AI tend to have greater symptom severity. Traumatic, rectal prolapse-related, and congenital AI cases more often require surgery.

No Significant Improvement In the Outcome of Patients with Waldenström's Macroglobulinemia Treated Over the Last 25 Years

AbstractAbstract 3032The treatment of Waldenström's Macroglobulinemia (WM) has changed over the last decades, mainly since the introduction of nucleoside analogues and of rituximab in the management of this disease. Furthermore, novel agents such as bortezomib have been recently introduced. Several analyses in multiple myeloma indicated that the outcome of these patients has significantly improved over the last decade as a result of the introduction of novel agents. However, such data are not available for patients with WM. Thus, we performed an analysis in order to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs, such as rituximab became widely available, especially as part of the frontline treatment. We analyzed the database of the Greek Myeloma Study Group which includes 345 patients, who started treatment after January 1985: 130 patients initiated treatment before 1/1/2000 (Group A) and 215 patients started treatment after 1/1/2000 (Group B). More patients were males in both groups (54% in group A vs. 63% in group B, p=0.084), but patients in group B were older (median age 70 years vs. 65 years in group A, p=0.001). Patients in both groups started treatment mainly due to anemia (40% and 43% in groups A and B, respectively). Similar percentages of patients in groups A and B had hemoglobin ≤11.5 g/dl (74% vs. 77%, p=0.57), platelets ≤100,000/ml (12% vs. 14%, p=0.643), albumin ≤3.5 g/dl (44% vs. 50%, p=0.306) and elevated LDH (≥250 IU/L) (21% vs. 17%, p=0.422). The median serum M-peak levels were also similar (3.95 g/dl vs. 3.75 g/dl, p=0.485) while 5% and 7% of patients in groups A and B had a serum M-peak >7 g/dl (p=0.491). However, more patients in group B had serum beta2-microglobulin above 3 mg/dl (62% vs. 42%, p=0.004). Thus, according to the International Prognostic Scoring System (IPSS) for WM, 30%, 48%, and 22% had low, intermediate and high risk disease in group A and 15%, 42% and 43% in group B, respectively (p<0.001). Most patients (92%) who started treatment before 1/1/2000 were treated upfront with alkylating agent-based regimens without nucleoside analogues and only 4% of patients received frontline treatment with rituximab-based regimens. In contrast, in group B, most patients (78%) received rituximab-based regimens as initial treatment (p<0.001). A similar proportion of patients achieved at least partial response (63% in group A and 59% in group B, p=0.438) after initial treatment. The median overall survival (OS) for groups A and B was 106.5 and 94 months, respectively (p=0.327). In patients older than 70 years, the median OS in group A was 77 months and in group B was 62 months (p=0.982). There was no difference in the median OS in patients ≤70 years (120 vs. 121 months for groups A and B, respectively, p=0.897). When we evaluated cause specific survival, there was no difference in the outcome of patients who were older than 70 years and who started treatment before 1/1/2000 (median survival 98 months) compared to those who started treatment after 1/1/2000 (median survival 89 months, p=0.815). Similar data were obtained for cause specific survival of patients who were ≤70 years. There was no difference regarding OS or cause specific survival in each risk group of IPSSWM between patients who were treated before or after 1/1/2000. In order to adjust for differences in the baseline characteristics between patients of groups A and B, we performed a multivariate analysis using a Cox regression model. Again, we did not to find any significant difference between groups A and B for both OS (p=0.842) and cause specific survival (p=0.834). We conclude that our analysis of a large number of unselected patients with WM who initiated treatment over the last twenty five years, did not show any significant improvement in patients' survival, despite the fact that nucleoside analogues and rituximab were introduced in the management of this disease. This observation needs to be confirmed in other databases and may be explained by the indolent course of WM and by the lack of profound cytoreduction (i.e. low rate of complete response) in patients with high-risk disease. However, possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients. Disclosures:No relevant conflicts of interest to declare.

Effectiveness and Safety of Carotid Artery Stenting for Significant Carotid Stenosis in Patients With Contralateral Occlusion (from the German ALKK-CAS Registry Experience)

Data on the safety of carotid artery stenting (CAS) in a large number of unselected patients with contralateral occlusion and significant ipsilateral stenosis are less known. Accordingly, we evaluated 3,137 patients undergoing CAS who were enrolled in a German Registry from 2000 to 2008 and compared the clinical features and in-hospital outcomes of those with and without contralateral carotid occlusion. Contralateral carotid occlusion was present in 191 patients (6.1%) undergoing CAS. Despite the similar age of the patients with and without contralateral carotid occlusion, those with contralateral occlusion had a greater prevalence of co-morbidities, complex carotid stenosis, and greater number of focal neurologic lesions on the contralateral side. The incidence of in-hospital events, including death (1.0% vs 0.5%), ipsilateral major stroke (1.1% vs 1.1%), death or major ipsilateral stroke (1.6% vs 1.4%), ipsilateral transient ischemic attack (2.7% vs 2.5%), myocardial infarction (0.0% vs 0.1%), and reintervention (0.5% vs 1.1%), was low and was not significantly different between those with and without contralateral occlusion (p >0.05 for all comparisons). Among patients with carotid occlusion, major ipsilateral stroke (2.2%), death (2.2%), and a combination of these 2 events (3.3%) were observed exclusively in symptomatic patients with no event in asymptomatic patients. In conclusion, our data from a large number of patients undergoing CAS in a recent contemporary community-based practice attests to the low risk of periprocedural events among patients with contralateral carotid occlusion supporting CAS as an attractive option for the treatment of these patients.

Improved Survival of Patients with Multiple Myeloma after the Introduction of Novel Agents and the Applicability of the International Staging System (ISS) An Analysis of the Greek Myeloma Study Group (GMSG)

Since the 1960s the survival of patients with MM had remained rather stable, until the introduction of high-dose melphalan with autologous stem cell transplant (ASCT) in the early 90s which improved the survival of younger patients. In 1999, thalidomide was introduced in the treatment of relapsed/refractory MM, followed by two other novel drugs: bortezomib and lenalidomide. Clinical trials have indicated that novel agent-based treatment are associated with improvement of response and survival in both relapsed/refractory and newly diagnosed patients. A recent report from Mayo Clinic (Kumar et al Blood 2008, 111, 1516–20) has indicated that the survival of patients with MM treated at this major referral center, has improved significantly over the last decade. The purpose of our analysis was to confirm this observation in a large number of unselected patients who were treated in several hospitals throughout Greece and to assess the current applicability of ISS, a staging system that has been developed from a large database of patients who were treated with conventional or high-dose therapy before the introduction of novel drugs. Therefore we compared the outcome of two patient cohorts who started treatment before or after the introduction of the first novel drug, thalidomide: since January 1985, 1376 patients were entered in to the database of GMSG: 859 patients started treatment before 31/12/1999 (Group A) and 517 patients after 1/1/2000 (Group B), when thalidomide became available in Greece. Patients in group A were younger (p<0.001), had less often hypercalcemia (p=0.039), less often anemia (p=0.095), lower levels of urine Bence Jones protein (p=0.027) and less bone marrow plasma cell infiltration (p=0.030). One hundred and sixty seven patients (32%) patients in Group B were treated upfront with novel-drug based regimens compared to only 2 (0.2%) in Group A (p<0.0001). At least partial response to first line treatment was significantly higher in Group B compared to Group A (67% vs 56%, p<0.001). Despite more favorable characteristics of patients in Group A, the median overall survival for patients in group A was 36 months and for patients in Group B 48 months (p<0.001). For patients ≤70 years of age, median survival has improved almost two-fold in group B (74 months vs 39 months in group A, p<0.001). For patients >70 years of age, median survival for groups A and B was 26 and 33 months respectively (p=0.27). Early death rates were similar among patients in Group A and B: 8% and 9% (p=0.65) of patients survived less than 3 months in each group respectively. We then validated the applicability of the International Staging System (ISS) in patients of Group B which included patients who could receive either upfront or at a later stage of their disease novel-drug based regimens: 34.5% of patients were rated as ISS stage I, 22.2% as ISS stage II and 43.3% as stage III. The 5-year survival rate was 66% for ISS stage I patients, 45% for ISS stage II patients and 18% for ISS III patients (p<0.001). When only the 169 patients who were actually treated upfront with novel agent-based were analyzed, the 4-year survival rate was 85%, 61% and 26% for ISS stage I, II and III patients respectively (p=0.001). In conclusion, we confirmed that the introduction of novel drugs in the treatment of a large number of unselected patients with MM has significantly improved the outcome of this disease. Our data indicate that the survival benefit was more pronounced in patients ≤70 years of age. The widely available and reproducible ISS is applicable in patients treated with novel agent-based regimens and can be used for the staging of such patients. Despite the improvement of the survival of myeloma patients over the last decade, the outcome of older patients and of those with ISS stage III remains unsatisfactory.

Initial safety results of an open-label phase II trial of erlotinib in non-small cell lung carcinoma (NSCLC)

18038 Background: Erlotinib is an orally selective and reversible inhibitor of HER1/EGFR tyrosine kinase. Erlotinib has demonstrated to be effective in the treatment of advanced non-small-cell lung cancer, in terms of longer survival, better quality of life and delayed symptom progression. The TargeT trial is a large open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Methods: Eligibility criteria included stage IIIB-IV previously treated patients (p) with confirmed NSCLC. Patients harboring mutations in EGFR gene or p unsuitable for chemotherapy were also allowed to enter the study and received erlotinib as first line treatment. Subjects were treated with 150 mg/day po until disease progression or unacceptable toxicity. Dose reductions were allowed. Primary end-point was time to progression. Results: By the time of this analysis, data from 1,522 p were available. Median age: 65 y (range 26–95); most p were male (71.9%); active/former a smoker (78.3%). Around half of the p had adenocarcinoma histology, including bronchioloalveolar carcinoma (53%) and 81.8% exhibited stage IV. ECOG PS 0/1/2 were (%) 21/54/25. The % p receiving erlotinib as 1st/2nd/3rd-line treatment were 29/38/33. Safety data were available for 1,255 p. 6.9% p did not experience any adverse event. As expected most common adverse events were rash (any grade: 61%; gr. 3/4: 11%), and diarrhea (any gr.: 31%; gr. 3/4: 4%) 5.6% p withdrew prematurely the trial due to AE. Erlotinib-related AEs leading to treatment discontinuation were cutaneous toxicity in 21 p (17 gr. 3/4), diarrhea in 6 p (4 gr. 3/4), hepatic toxicity in 1 p, cholestasis in 1 p, and interstitial pneumonitis in 1 p. No unexpected toxicities were reported. 10% of p had dose reductions mainly due to rash and diarrhea. Response rate in these p was 18.7%; time to progression 3.8 months (95% CI: 3.5–4.2); and overall survival 6.0 months (95% CI: 5.5–6.4). Conclusions: These initial interim safety results of erlotinib in real-life clinical setting in a large number of unselected patients with advanced non-small-cell lung cancer confirm the favorable toxicity profile and good tolerability of erlotinib. No significant financial relationships to disclose.

Comparison of Inhospital Outcomes of Patients With Versus Without Previous Carotid Endarterectomy Undergoing Carotid Stenting (from the German ALKK CAS Registry)

Repeat carotid endarterectomy (CEA) for recurrent stenosis remains a challenging treatment option associated with high morbidity and mortality. Carotid artery stenting (CAS) is an attractive alternative management option for these patients. However, data about the effectiveness and safety of CAS in a large number of unselected patients are less known. We evaluated 3,070 patients who underwent CAS enrolled in a German registry from 1996 to 2006 at 31 sites. We compared clinical and angiographic features and in-hospital outcomes of patients with and without previous CEA who underwent CAS. Of 3,070 patients in the registry, 223 (7.3%) underwent CAS for restenosis after previous CEA. Median age was similar in patients with and without previous CEA (70 years, interquartile range 64 to 76 vs 71 years, interquartile range 65 to 76). Ipsilateral neurologic symptoms occurred in approximately 1/2 the patients in both groups. Other co-morbid conditions and angiographic or procedural factors did not differ between the 2 groups. In-hospital events including death (0% vs 0.4%), ipsilateral major stroke (1.4% vs 1.5%), death or major ipsilateral stroke (1.4% vs 1.7%), ipsilateral transient ischemic attack (1.9% vs 2.8%), myocardial infarction (0.4% vs 0.1%), and reintervention (0.7% vs 0.4%) were all low and not significantly different between those with and without previous CEA (p >0.05 for all comparisons). In conclusion, our data for a large number of patients who underwent CAS in a recent contemporary community-based practice attests to the low risk of periprocedural events in patients with recurrent stenosis after previous CEA. This low risk along with the less invasive nature of the procedure should make CAS an attractive and perhaps preferred option for the treatment of these patients.

Efficacy of treatment with letrazole in patient with unexplained infertility − prospective observational data on 432 treatment cycles

We and other groups have previously shown the potential of the aromataze inhibitor, letrazole, in the treatment of patients with unexplained infertility. In this prospective study we observed the response to medication, pregnancy, miscarriage and multiple pregnancy rates when letrazole was given to a large number of unselected patients with unexplained infertility.

Clinical value of T-wave alternans assessment.

Microvolt-level T-wave alternans (TWA) is a new arrhythmia risk marker to assess subtle changes in repolarization that has been introduced for arrhythmia risk stratification. Recent experimental studies have demonstrated that it reflects a heartrate dependent increased spatial dispersion of repolarization associated with unidirectional conduction block, and reentry that may result in the occurrence of ventricular fibrillation. Clinical studies have convincingly demonstrated that TWA is closely related to arrhythmia induction in the electrophysiology (EP) laboratory as well as to the occurrence of spontaneous ventricular tachyarrhythmias in patients undergoing EP study. Subsequent studies showed that TWA-assessed noninvasively-is predictive of future arrhythmic events in patients with implanted ICDs as well as for ventricular tachyarrhythmias in patients with congestive heart failure without a prior history of arrhythmias. There is still controversy, however, about the predictive value of TWA in patients following acute myocardial infarction (MI). Several studies which differ in patient selection, pharmacologic treatment of the patients, and endpoint definitions, have reported conflicting results. Therefore, studies with a large number of unselected patients after acute MI on optimal treatment according to contemporary therapeutic guidelines as well as of patients with reduced left ventricular ejection fraction following MI are needed to define its role with regard to identifying patients who may benefit from primary preventive ICD therapy. Future research should also focus on evaluation of alternative methods to increase heart rate (i.e., pharmacological stimulation) in an attempt to reduce the proportion of incomplete tests in patients with insufficient increase in heart rate during exercise testing.

Specific IgG subclass antibody pattern toAspergillus fumigatus in patients with cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA)

BACKGROUNDIgG and IgG subclass antibodies to Aspergillus fumigatus (A fumigatus) were measured in a large population of patients with cystic fibrosis to elucidate a putative antibody pattern specific for allergic...