Similar Disease Characteristics Research Articles

Disease Characteristics in Non-Erosive Reflux Disease with and without Endoscopically Minimal Change Esophagitis: Are They Different?

Background/Aims: The majority of patients with gastroesophageal reflux disease (GERD) appear to have non-erosive reflux disease (NERD). NERD may include minimal change esophagitis (MCE) and no endoscopic abnormalities (MCE–). We aimed to determine whether intraesophageal acid reflux as well as esophageal motility differed between patients with and without MCE. Methods: Consecutive patients with classic reflux symptoms were enrolled in the study. Patients without any mucosal injury were considered to be MCE–. Esophageal acid exposure as well as intragastric pH (<4) was determined by dual-channel ambulatory 24-hour pH monitoring. Results: A total of 100 patients (MCE–, 52 patients; MCE, 48 patients) were studied. The percentage of effective peristalsis was found similar between patients with and without MCE (p = NS). Esophageal acid contact as well as the DeMeester score did not differ between the groups (p = NS). The prevalence of positive symptom index was greater in MCE– patients than in MCE patients (p = 0.001). Intragastric acidity (pH <4) was similar between MCE– and MCE groups (p = NS). Conclusions: NERD, regardless of the presence of MCE, might exhibit similar disease characteristics in terms of esophageal acid exposure and motor dysfunction.

Differences between rheumatologists and other internists regarding diagnosis and treatment of systemic lupus erythematosus

To compare the diagnostics and treatment of SLE patients in the care of rheumatologists with patients in the care of other specialities within a geographically complete cohort. Nine different sources were used to identify SLE patients resident in Oslo between 1999 and 2008. Only SLE patients fulfilling four or more of the updated 1997 ACR criteria were included. Data were extracted from medical records. The patients were classified into three groups according to each patient's responsible doctor's speciality. A total of 325 SLE patients were included in the study. Of these, 227 had solely been in the care of rheumatologists (rheumatology group), 34 had solely been in the care of nephrologists, haematologists or infectious disease specialists (non-rheumatology group) and 64 had been in the care of both rheumatologists and other specialists (multidisciplinary group). Even though patients in the non-rheumatology group and multidisciplinary group showed similar disease characteristics, patients in the non-rheumatology group were less often tested for aPLs (68 vs 94%; P = 0.001) and less often treated with HCQ (12 vs 78%; P < 0.001). In contrast to rheumatologists, non-rheumatologists do not routinely test all SLE patients for aPLs, and rarely prescribe HCQ. These findings indicate that more communication between different specialists caring for SLE is needed, and highlights an area in need of agreement.

Usefulness of transnasal endoscopy where endoscopic submucosal dissection is difficult

Early gastric cancer located from the pyloric ring to inside the duodenal bulb (DB) is not easily treated by endoscopic submucosal dissection (ESD). The endoscope needs to be reversed inside the DB to set the resection line at a safe distance from the anal side. Because of the space limitations and limited flexibility of conventional endoscopy (CE), there have been increasing possibilities of complications. Here we report a new ESD technique using a transnasal endoscope (TN-E) that is reversed inside the DB. The subjects were 5 patients with early gastric cancer or adenoma, at locations ranging from the pyloric ring to inside the DB, who were all treated by ESD. We compared results in these patients (TN-E group) with results in five patients with similar disease characteristics who were treated by ESD before July 2008, when the TN-E treatment method was introduced (CE group). In the TN-E group, after marking by CE, we switched the endoscope to the TN-E, and performed the reversing procedure inside the DB, and cut the anal side of the lesion in a semicircle. We switched back to CE to dissect the remaining half on the oral side. We compared the average resection time, en-bloc resection rate, and safety margin between the TN-E and CE groups. Reversing inside the DB and the anal-side procedures proved easy and there were no complications. No bleeding or perforation occurred. The average resection times and en-bloc resection rates were not different between the two groups. All the resections by the TN-E were more than 5 mm away from the tumor margin, whereas a resection rate with a safety margin of more than 5 mm was 80% by CE. In conclusion, the TN-E was safe and effective for use inside the DB. ESD using the TN-E contributed to accurate pathological diagnosis, because the size of the resected specimen was sufficient to prevent the burning effect caused by the ESD.

Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II

Congenital dyserythropoietic anaemias (CDAs) are heterogeneous, hereditary disorders hallmarked by ineffective erythropoiesis and tissue iron overload. Growth differentiation factor 15 (GDF15) was suggested to mediate iron overload in iron-loading anaemias, such as the thalassaemias and CDAI by suppressing hepcidin, the key regulator of iron absorption. Here, we show that serum GDF15 concentrations are elevated in subjects with CDAI and CDAII. Despite similar disease characteristics, CDAI patients present with significantly higher GDF15 concentrations compared to CDAII patients. Hepcidin concentrations are inappropriately low in CDAII patients considering the severe hepatic iron overload associated with this disorder. GDF15 significantly correlates with the degree of anaemia (Hb), the response of erythropoiesis (reticulocyte index) as well as with iron availability in the serum (transferrin saturation). The observation that GDF15 is elevated in CDAII patients is consistent with the proposal that GDF15 is among the erythroid factors down-regulating hepcidin and contributing to iron overload in conditions of dyserythropoiesis.

Pregnancy-Associated Breast Cancer

ABSTRACT The incidence of pregnancy associated with breast cancer can be expected to increase as maternal age at the time of pregnancy continues to increase. Women diagnosed with breast cancer during pregnancy have similar disease characteristics to age-matched controls. Surgical treatment may be performed as for the nonpregnant women. Radiotherapy and endocrine or antibody treatment should be postponed until after delivery. A multidisciplinary approach is recommended for optimal clinical decision-making. But physicians should be aggressive in the work-up of breast symptoms in the pregnant population to expedite diagnosis. It is generally agreed that therapeutic radiation, if necessary, should be delayed until completion of pregnancy.

Disease Characteristics and Patterns of Care In Elderly Patients (80+ years) with Follicular Lymphoma (FL) In the United States (US); Are Older Patients Treated Differently? Report From the National LymphoCare Study (NLCS)

AbstractAbstract 4152 Background:While FL is the most common low-grade lymphoma in the US, median age was less than 60 in patients enrolled on pivotal studies that led to our understanding of disease biology and optimal therapy. It remains unclear whether similar disease characteristics, presentation, prognostic factors, treatment patterns, and outcomes pertain to older patients with FL. No clear guidelines exist on how older patients should be treated and data is lacking as to whether current practice patterns affect their survival and progression. Previous reports on FL in the elderly have been retrospective and single center-based. Methods:The NLCS is a prospective, longitudinal multicenter, observational study that enrolled consecutive newly diagnosed FL patients from 3/2004 through 3/2007 collecting data on disease and patients' characteristics, treatment patterns, and outcome. Using the NLCS data we analyzed information on disease stage, grade, FL International Prognostic Index (FLIPI), B symptoms, and treatment choice for patients <60 years, 60–69 years, 70–79 years, and 80+ years. Either Chi-square or Fisher's exact comparison was used to assess the correlations depending on the sample size of the test. Results:A total of 2,736 pts were enrolled, of which 1,215 (44%) were < 60, 708 (25%) were between 60–69, 549 (20%) were between 70–79, and 264 (9%) were >80. There was a significant difference in grade distribution across the different age groups (p < 0.0001), with 22% of pts 80+ having grade 3 FL vs 17% pts <60. No significant differences across age groups in B symptoms, extra nodal sites, or LDH values were observed. A significant difference in FLIPI score was seen across the age groups (p < 0.0001) where high-score FLIPI was present in 48% of pts 80+ as opposed to 16% of pts <60, although calculating FLIPI might be confounded by the fact that older patients were more likely to not have received a bone marrow (BM) exam with 66% of pts 80+ not having BM exam vs. only 40% of those <60 (p < 0.0001). The difference in FLIPI was mainly due to lower Hgb values as older patients were more likely to have had Hgb < 12 g/dL than younger patients (31% of pts 80+ vs. 15% of pts <60) and to age being a component of the FLIPI index. The difference in FLIPI score across age groups was also observed in patients with grade 3 FL where 53% of pts 80+ had poor FLIPI vs. 15% of pts <60 (p < 0.0001). A statistically significant difference in treatment patterns was found across age groups (p <0.0001). When treatment was implemented, older patients were more likely to have received rituximab (R) monotherapy (37% of 80+ vs. 12% of <60) and less likely to have received R+Chemotherapy (40% of pts 80+ vs. 64% of pts<60). In addition, more pts 80+ were observed compared to those <60 (23% vs. 16%). These differences persisted even in those with advanced stage (III/IV), grade 3 disease, region of diagnosis, and in poor-risk FLIPI. When chemotherapy was used, older patients were less likely than younger patients to receive anthracyclines (p < 0.0001) (31% of pts 80+ vs. 69% of pts<60). Anthracycline use remained significantly different regardless of disease stage, grade, or FLIPI score. Conclusions:To our knowledge, this is the largest prospective data collection available for FL pts 80+ years of age. We demonstrate that these pts have higher FLIPI score and grade 3 disease. When treatment is initiated, these patients receive R monotherapy more often than their younger counterpart. Anthracycline use in this population is also less common regardless of disease stage, grade, or risk profile. Whether these baseline differences translate into different outcomes remains to be seen. Disclosures:Nabhan:genentech: Research Funding, Speakers Bureau. Byrtek:Genentech: Employment. Taylor:Genentech: Employment. Hirata:Genentech: Employment. Flowers:Genentech/Biogen-Idec (unpaid): Consultancy; Celgene, Intellikine: Consultancy; Millennium: Research Funding.

Adjuvant oral etoposide plus cisplatin (EoP) following sequential doxorubicin/cyclophosphamide (AC) and docetaxel (T) in early breast cancer patients with 4 or more positive lymph nodes (10 years follow-up)

Background and objectives Previous reports suggest that including cisplatin plus etoposide in the adjuvant treatment may improve the outcomes in patients with early breast cancer. Patients and Methods Forty-one patients with early breast cancer and 4 or more positive lymph nodes were treated with 3 cycles of EoP (oral etoposide plus cisplatin) in addition to 3 cycles of AC (doxorubicin plus cyclophosphamide) and 3 cycles of T (docetaxel) (Group 1). Toxicity and survival results were compared to those with similar disease characteristics who were treated with 4 cycles of AC plus 4 cycles of T (Group 2) during the same period. Results There were no long-term side effects related to EoP. While median disease-free and overall survivals were not reached in Group 1, they were 107 ± 13 ( p = 0.387) months and 123 ± 5 months ( p = 0.618) in Group 2. Likewise 10-year disease-free survivals (DFS) were 59.3% and 44.7% respectively. Conclusions The trend towards improvement in survival with adjuvant AC + T + EoP when compared to AC + T needs to be studied in randomized trial.

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

The prognostic value of c‐Kit, K‐ras codon 12, and p53 codon 72 mutations in Egyptian patients with stage II colorectal cancer

The prognosis for patients with colorectal cancer (CRC) depends mainly on standard clinicopathologic factors. However, patients with similar disease characteristics exhibit various outcomes, especially in stage II. Therefore, the identification of molecular prognostic markers is needed to predict patient outcomes. The authors assessed the prognostic value of c-Kit (also called cluster of differentiation 117 [CD117] or KIT), cyclooxygenase-2 (COX-2), tumor protein 53 (p53), and Kirsten rat sarcoma viral oncogene homolog (K-ras) aberrations in 90 patients with stage II CRC using immunohistochemistry and molecular techniques. The results were correlated with standard clinicopathologic prognostic factors, overall survival (OS), and disease-free survival (DFS). COX2 and c-Kit overexpression was detected in 54.6% and 59.3% of patients, respectively. Overexpression of p53 was detected in 47 patients, including 29 who had mutations, and a unique mutation pattern was detected with 3 hotspots at codons 72, 245, and 273. Overexpression of ras was detected in 44 patients, including 37 who had mutations. On multivariate analysis, c-Kit overexpression, p53 codon 72 mutations, perforation, and performance status were independent prognostic factors for DFS (P=.054, P=.015, P<.0001, and P=.043, respectively); whereas codon 12 K-ras mutation, performance status, and perforation were independent prognostic factors for OS (P=.033, P=.006, and P<.0001, respectively). The current results provide evidence for the prognostic value of c-Kit overexpression in patients with stage II CRC. The high p53 mutation rate and the unique hotspot in codon 72 have not been reported previously in CRC. This may be related to environmental or racial features that are unique to the studied population.

Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients

Background Infliximab (IFX) can be immunogenic for humans and lead to the formation of antibodies against IFX (anti-IFX Ab), which could induce acquired IFX resistance. Objective To test whether the presence of anti-IFX Ab and residual circulating IFX levels are associated with acquired IFX resistance in RA. Methods A multivariate logistic regression was used to analyze the relationship between anti-IFX Ab, residual IFX concentrations, and acquired IFX resistance in a nested cohort within the Swiss RA registry (SCQM-RA). Results Sixty-four RA patients on longstanding IFX therapy were included; 24 with an acquired therapeutic resistance to IFX and 40 with continuous good response to IFX. The two groups had similar disease characteristics, but patients with acquired IFX resistance required significantly higher dosage of IFX (5.4 mg/kg versus 4.3 mg/kg, p = 0.02) and shorter infusion intervals (7.1 versus 8.7 weeks, p = 0.01) than long-term good responders. The presence of residual IFX tended to be associated with a decreased risk of acquired therapeutic resistance (OR 0.4 [95% CI: 0.1–1.5]), while the presence of anti-IFX Ab tended to be associated with an increased risk of acquired therapeutic resistance (OR: 1.8 [95% CI: 0.4 – 9.0]). The presence of either high anti-IFX Ab levels or low residual IFX concentrations was strongly associated with acquired therapeutic resistance to IFX (OR 5.9, 95% CI 1.3 – 26.6). However, just 42% of patients with acquired IFX resistance had either low IFX or high anti-IFX Ab levels. Conclusion These results suggest that the assessment of anti-IFX Ab and residual IFX levels is of limited value for individual patients in routine clinical care.

Validation of a nomogram to predict disease progression following salvage radiotherapy after radical prostatectomy: results from the SEARCH database

To externally validate the nomogram published by Stephenson et al. (termed the 'Stephenson nomogram') to predict disease progression after salvage radiotherapy (SRT) among patients with prostate cancer from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. We analysed data from 102 men treated with SRT for prostate-specific antigen (PSA) failure after prostatectomy, of whom 30 (29%) developed disease progression after SRT during a median follow-up of 50 months. The predicted 6-year progression-free survival (PFS) was compared to the actuarial PFS using calibration plots. The accuracy of the nomogram to risk-stratify men for progression was assessed by the concordance index. The median PSA and PSA doubling time before SRT was 0.6 ng/mL and 10.3 months, respectively. The 6-year actuarial disease-free progression after SRT was 57% (95% confidence interval 42-69%). The overall concordance index of the Stephenson nomogram was 0.65. The nomogram predicted failure more accurately at the extremes of risk (lowest and highest) but in intermediate groups, the accuracy was less precise. Of the 11 variables used in the nomogram, only negative margins and high PSA level before SRT were significantly associated with increased disease progression. The Stephenson nomogram is an important tool to predict disease progression after SRT following radical prostatectomy. It adequately predicted progression in SEARCH with reasonable accuracy. Also, in SEARCH, disease progression was predicted by similar disease characteristics. However, the overall modest performance of the model in our validation cohort indicates there is still room for improvement in predictive models for disease progression after SRT.

A randomized, double-blind study comparing corticorelin acetate with dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptoms of peritumoral brain edema

2080 Background: Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor, undergoing clinical trials as a treatment for peritumoral edema in patients with cerebral tumors. This study compared CrA therapy vs an increase in dexamethasone (dex) dose (+4 mg) for controlling symptoms in primary glioma patients with a subacute exacerbation. Methods: In addition to their prestudy dex dose, patients were randomized to receive CrA 1 mg bid SC or control (+4 mg dex PO) for 8 weeks. Patients were evaluated at baseline and during weeks 1 and 2 for their neurologic status, Karnofsky Performance Score (KPS), and continuing dex requirements. The primary endpoint was response, defined as no post-baseline increase in dex dose &gt;4 mg for &gt;1 day; stable or improved KPS; and ≥25% improvement in 10-item Neurological Examination Score during weeks 1 and 2. Dex therapy requirements were also evaluated. The study aimed to enroll 120 patients, but was terminated with only 37 patients (20 CrA, 17 control) due to slow recruitment. Results: Formal statistical analyses were not undertaken due to the small sample size. The treatment groups had similar demographic and baseline disease characteristics. Despite the small numbers, the data suggest that CrA treatment had similar efficacy to increased dex: (1) The proportions of responders were similar (CrA 3/20; control 3/17); (2) Comparable proportions of patients completed 8 weeks’ treatment (CrA 16/20; control 12/17); (3) After randomization of blinded study drug (CrA or dex 4 mg), dex dosing remained stable for most patients in each arm (CrA 12/20; control 11/17); (4) The mean daily dex dose was 3 mg in the CrA arm and 7 mg in the control arm. There was a lower incidence of cushingoid symptoms in the CrA arm (CrA 1/20, control 3/17). Patients in the CrA arm reported more injection site erythema and flushing vs. the control arm. CrA was well tolerated and no patient withdrew from the trial because of CrA side effects. Conclusions: CrA may be of value in managing patients with cerebral tumors who have subacute exacerbations of their symptoms, without needing to increase their dex dose. [Table: see text]

Cancer du sein et grossesse

As maternal age at the time of pregnancy continues to increase and the incidence of breast cancer is raising, the incidence of pregnancy associated with breast cancer can be expected to increase. A review of the literature was performed to help identify optimal treatment strategies. Methods: a search of electronic databases between 1967 and the present identifies studies reporting breast cancer associated with pregnancy. There is a paucity of prospective studies regarding diagnosis and treatment of breast cancer during pregnancy. Women diagnosed with breast cancer during pregnancy have similar disease characteristics to age-matched controls. Current evidence suggests that diagnosis may be carried out with limitations regarding staging. Surgical treatment may be performed as for the non-pregnant women. Radiotherapy and endocrine or antibody treatment should be postponed until after delivery. Chemotherapy is allowed after the first trimester. Breast cancer in pregnancy is an uncommon phenomenon but one which poses dilemmas for patients and their physicians. A multidisciplinary approach is recommended for optimal clinical decision making. But physicians should be aggressive in the workup of breast symptoms in the pregnant population to expedite diagnosis.

Long-term survival of chronic dialysis patients following survival from an episode of multiple-organ failure

IntroductionThis study aimed to examine the long-term outcome for patients with end-stage renal failure (ESRF) who survived multiple-organ failure.MethodsWe performed a review of databases from the renal medicine service and intensive care units (ICU) of the participating hospitals within Imperial College Healthcare NHS Trust, London, UK. Patients with ESRF admitted to ICU who required support of two or more organ systems or were ventilated for more than 36 hours were included. To provide a comparison we examined the survival of a comparator group of ESRF patients in the general population with similar demographic and disease characteristics to our study group. We also examined the outcome for ESRF patients admitted to ICU who died prior to discharge.ResultsSurvival data for two years following discharge from ICU were examined for the impact of age, prior dialysis history, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and medical or surgical status. Of the 199 patients who met the inclusion criteria, 111 (56%) survived their ICU stay. Sixty-two (56%) of the survivors remained alive two years following discharge. There was no group difference in survival with regards to age, dialysis history or APACHE II scores. Those admitted with a medical rather than surgical diagnosis were less likely to survive two years (P < 0.01). Patients who died in ICU had higher APACHE II scores (P < 0.0001) and were more likely to have a medical diagnosis. By log rank analysis two-year mortality was significantly higher (P = 0.003) in the ICU survivors than the comparator group with ESRF. This difference was lost when patients who died within a month of discharge were excluded.ConclusionsESRF patients with multiple-organ failure have a high mortality, with the increased risk of death continuing into the early post-ICU period. Those with non-surgical diagnoses have the highest risk. Survival within the group who live beyond the early post-ICU period appears similar to the background population of ESRF patients.

Long Term Follow-up and Matched Pair Analysis of Adjuvant Donor Lymphocyte Transfusions Following Allogeneic Stem Cell Transplantation after Reduced Intensity Conditioning for High-Risk AML.

Adjuvant transfusion of donor lymphocytes (aDLT) may reduce the risk of relapse after allogeneic stem cell transplantation. We report our data on aDLT in high-risk AML. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and aDLT. For aDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression and free of GvHD. 30% of patients (n=46) alive at day +120 fulfilled the criteria for aDLT. They had been transplanted for refractory (n=11) or relapsed leukemia (n=24) or in CR1 because of unfavourable cytogenetics (n=7) or other unfavourable criteria (n=2) or in CR2 with unfavourable cytogenetics (n=2). 24 patients had an unfavourable karyotype, 10 with complex aberrations. Thirty-one patients with similar disease characteristics and fulfilling similar selection criteria (being alive in CR at d +120, no cGVHD and no history of aGVHD> II°) transplanted during the same time period served as control. Of these, 10 pts. were transplanted at a different center not using aDLT and 21 at the center in Wiesbaden during 2000 and 2002 prior to the introduction of the protocol at this center. The median time from transplant to first aDLT was 160 days (range 71–303). Median follow up of the surviving transfused patients is 3.6 years (range 1.8–7.8). Seven patients received 1, 15 patients received 2, and 24 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at aDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or patient's refusal. Induction of GvHD was the main complication; grade II/III acute GvHD developed in 4, and chronic GvHD in 8 patients. So far, 9 (19.6%) patients have relapsed despite aDLT, as compared to 52.9% in the control group (Fisher-exact: p=0.004). Of these, 8 pts. finally died despite adoptive immunotherapy and only one patient is now surviving more than 3 years after relapse was treated by a second transplantation. Non relapse mortality post DLT was low with patients dying from infection, severe cGvHD, and secondary solid tumour one each. At the time of analysis, 35/46 patients are alive and all are in CR at a median of 3.2 years post first DLT. The actuarial overall survival four years after transplant is 79% as compared to 34% in the control group and at six years 63% vs. 31%, respectively (p=0.000). In conclusion, aDLT is safe, when given in escalating doses and to a selected group of patients. Results are encouraging, and improved long term leukemia-free survival can be achieved.

Comparison of Pulsatile Perfusion and Cold Storage for Paired Kidney Allografts

Use of pulsatile perfusion to optimize outcomes in deceased donor kidney transplantation remains controversial. This study is a retrospective analysis of all cadaveric renal allografts procured locally by our center over a 3-year period. Kidney pairs were identified in which one kidney underwent pulsatile perfusion and transplantation at our center, whereas the contra-lateral kidney underwent cold storage and transplantation at another center. Eighty-eight percent of the exported kidneys were six-antigen matches. Study outcomes included 1-year graft and patient survival, delayed graft function, and need for posttransplant dialysis. Recipients had similar demographic and disease characteristics. Survival for pulsatile perfusion and cold storage were 95% and 88% (graft, P=0.43) and 98% and 90% (patient, P=0.36), respectively. The incidence of delayed graft function was 5% and 35% (P<0.01), whereas posttransplant dialysis was 5% and 30% (P<0.01), for pulsatile perfusion and cold storage, respectively. These data support routine use of pulsatile perfusion.

Response to Dr Gilman

We thank Drs Gilman and Oesterheld for their comments on our paper.1 The aim of our study was to identify risk factors associated with progression-free survival in patients with Ewing's sarcoma undergoing autologous stem cell transplantation (ASCT). We identified three risks factors: metastatic disease at diagnosis, recurrence prior to transplantation and patients with poor performance score were associated with higher rates of treatment failure and consequently lower progression-free survival rates. We acknowledge data analyzed are subject to the limitations of using an observational database and described in our manuscript. Contrary to the suggestion, the sites of metastases are provided in our paper; lung metastasis was the most frequent. Site of metastases was not associated with progression-free survival in our analysis. We did not intend this paper to serve as a formal comparison of progression-free survival rates after conventional therapy for Ewing sarcoma and this is stated in our paper. We agree that the role of ASCT can only be addressed satisfactorily when patients with similar disease characteristics are randomized to receive one of the two treatment options. The data presented in our report are sobering, considering that patients enrolled on clinical trials are subject to an intent-to-treat analysis, whereas our cohort of patients was analyzed from the time of ASCT. It is our intent this report will serve as a reminder to clinicians to enroll their patients on prospective clinical trials such as the Euro EWING 99 so that optimal treatment recommendations are available at the completion of that study.

Degeneration, inflammation, regeneration, and pain/disability in dogs following destabilization or articular cartilage grooving of the stifle joint

The most used model for joint instability is the canine anterior cruciate ligament transection (ACLT)-model. The ACLT-model can be extended with a medial meniscectomy (MX) (i.e., ACLT-MX-model) to avoid unintentional, and with that variable, meniscal damage. The present study compares the ACLT-MX-model with the more recently introduced Groove-model on longitudinal measurements of osteophyte formation and gait as a surrogate marker of pain and disability, in addition to structural endpoint parameters. Degenerative joint damage was induced Labrador dogs according to the ACLT-MX-model (n=7) or Groove-model (n=7). Every 4 weeks radiographs were taken to analyze osteophyte formation. Every 2 weeks gait was recorded using force-plate analysis. Joints were analyzed for features of degeneration 12 weeks after surgery. Both models showed similar osteophyte formation and gait changes for both experimental and contra-lateral control joints, although more pronounced for the ACLT-MX-model. This was supported by the structural endpoint measurements. Cartilage integrity, chondrocyte activity and synovial inflammation revealed similar characteristics of degenerative joint disease in both groups, again more pronounced in the ACLT-MX-model. The ACLT-MX-model demonstrates characteristics of joint degeneration that are related to moderate to severe osteoarthritis with clear synovial inflammatory activity. The Groove-model is a less painful and a significantly milder model of joint degeneration. The latter model might be more suitable to study subtle changes as a result of intervention than the more robust ACLT-MX-model.

Use of Gene Signatures to Improve Risk Estimation in Cancer

BREAST CANCER IS ONE OF THE MOST PREVALENT HUman cancers and ranks second as a cause of cancer death in women. In 2006, approximately 212 000 new cases of invasive breast cancer were diagnosed in the United States, and each year more than 40 000 women die of the disease. To date, therapeutic decisions for locally advanced breast cancer are mainly guided by clinicopathological parameters, such as patient age and functional status, comorbidities, estrogen receptor status, tumor grade, tumor size, and lymph node status. This results in inaccurate risk estimation in which some patients in the early stage of disease are overtreated and experience undeserved adverse effects. In addition, there is substantial variation in outcome among patients with similar clinicopathological disease characteristics. This medical challenge calls for better understanding of this disease and refined risk estimation to improve treatment efficacy and patient quality of life. The advent of microarrays allows for a simultaneous screen of gene expression patterns on a genome-wide scale and has become one of the most widely used technologies to study the molecular biology of human disease. The application of this methodology to cancer research has demonstrated its potential for refining cancer diagnosis and outcome prognostication at large. Breast cancer is one of the cancers for which gene expression profiling has identified distinct molecular entities associated with differential prognosis and response to cytotoxic agents. In this issue of JAMA, Acharya and colleagues report on the use of gene expression signatures to refine risk estimation and therapeutic decision making in a multiinstitutional panel of 964 breast cancer cases. This is one of the largest studies in human cancer showing the ability of gene expression profiles to improve risk stratification beyond established risk assessment algorithms that take into account clinicopathological variables. Distinct from other breast cancer microarray studies, the study by Acharya et al did not develop another novel gene signature. Instead, by combining gene expression data for a set of oncogenic and tumor microenvironment–related genes previously identified to be associated with poor prognosis in breast cancer, the investigators showed that molecular profiles can be useful to refine risk estimation in 3 risk subgroups (low, intermediate, and high), which they have defined deliberately based on established clinicopathological variables, by using the Adjuvant! Online scoring tool in an initial training set of 573 patients. Subsets of patients with comparably poor and good prognosis were identified for each clinicopathological subgroup. The prognostic power of the gene signature was subsequently validated in an independent test set of 391 patients. Close examination of expression patterns for each individual gene does not reveal a clear distinction between the various prognostic subgroups. However, as stated by the authors, it is the aggregation of the gene signature that provides the prognostic power. This observation is consistent with most other cancer microarray studies, which have commonly used so-called metagenes—patterns of gene expression—for risk classification. Although such metagenes lend support to the notion that in a complex human disease, it is not a single gene but rather multiple genes that account for the disease process, the risk associations of metagenes must be considered purely correlative and thus only of predictive value. Metagenes identify gene subsets without considering underlying mechanisms; therefore, there is low potential to aid biological interpretation. Molecular predictor models that place genes into pathways and networks allow moving from association to mechanism. The mechanistic insights that are gained are crucial for novel molecularly targeted therapies. In contrast with other microarray studies, Acharya et al have chosen to build on previous knowledge and to select a parsimonious multigene predictor that has been well characterized in breast cancer in terms of its oncogenic mechanisms. This gene set should thus represent an attractive target of future therapeutic modulation. Although the findings are encouraging, several factors may confound the interpretation of this study. One issue is why the authors chose to apply clinicopathological risk group-

TNF-Based Isolated Limb Perfusion Followed by Consolidation Biotherapy with Systemic Low-dose Interferon Alpha 2b in Patients with In-transit Melanoma Metastases: A Pilot Trial

Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP. A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B). In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP. These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.