A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency.

Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples.

Socio-demographic predictors of high support needs in newly diagnosed breast cancer patients.

GRIESSER A.-C., VLASTOS G., MOREL L., BEAUME C., SAPPINO A.-P. & HALLER G. (2010) European Journal of Cancer Care Socio-demographic predictors of high support needs in newly diagnosed breast cancer patients This study aimed to identify high support needs and their socio-demographic predictors to improve supportive care for newly diagnosed breast cancer patients. A cross-sectional study measured patients' needs and unsatisfied support needs by the supportive care needs survey (SCNS-34), administered after surgery, chemotherapy or radiotherapy. Socio-demographic, disease and treatment characteristics completed data collection. A total of 308 questionnaires were completed with a response rate of 88%. The most frequent support needs (73.3% of patients) related to information and the highest unsatisfied support needs to the management of emotions and daily life (36.3-39.6% of patients). Younger age predicted high and dissatisfied support needs (P < 0.05). Patients born outside Switzerland or with a lower level of education had more needs in daily living and psychological domains (P < 0.05). Being born outside Switzerland also predicted dissatisfaction with information provided. Being parent was a predictor of significant needs in the daily living domain after adjusting for disease and treatment characteristics (P= 0.01). Therefore, information, psychological and daily living support for newly diagnosed breast cancer patients should be strongly reinforced, particularly in patients being born outside Switzerland, those with children or being younger. For the latter, support in sexuality domain should also be emphasised.

Alexithymia in cancer patients: review of the literature.

Objective: To summarize the literature on alexithymia in cancer patients. Methods: The empirical literature published between 1972 and January 2010 was searched through MEDLINE, PSYINFO, EMBASE and the Cochrane Library. Key words were: alexithymia, affective symptoms, cancer, neoplasms. Results: The search identified 16 relevant studies which are methodologically problematic and show conflicting results. However, several interesting hypotheses emerge such as a possible link between alexithymia and the immune system, between alexithymia and quality of life, or between alexithymia, anxiety and depression. The question to what degree alexithymia in cancer patients is a trait or a state cannot be answered by these studies. Conclusions: A lack of methodologically sound studies and the large variations of results among studies suggest that the role of alexithymia in patients with cancer deserves more systematic research. Consequently, studies are needed which investigate the nature (state or trait) of alexithymia, its impact on cancer development and progression, as well as its influence on compliance and on the underestimation of psychological distress and psychiatric outcome in cancer patients.

MMP-9 as predictive factor for response and progression free survival in breast cancer patients treated with bevacizumab and pegylated liposomal doxorubicin. A multicenter, single-arm phase II trial (SAKK24/06). On behalf of the Swiss Group for Clinical Cancer Research (SAKK).

The benefit of bevacizumab (Bv) has been shown in different tumors including colorectal cancer, renal cancer, pulmonary non-small cell cancer and also breast cancer. However to date, there is no established test evaluating the angiogenic status of a patient and monitoring the effects of anti-angiogenic treatments. Tumor angiogenesis is the result of a balance between multiple pro- and anti¬angiogenic molecules. There is very little published clinical data exploring the impact of the anti-angiogenic therapy on the different angiogenesis-related molecules and the potential role of these molecules as prognostic or predictive factors.

Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy.

OBJECTIVE: To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). DESIGN: Retrospective study. SETTING: University of Lausanne, Lausanne, Switzerland. PATIENTS: Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). INTERVENTIONS: Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. RESULTS: All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections (P = .15). CONCLUSIONS: Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).

Coronary heart disease in primary care: accuracy of medical history and physical findings in patients with chest pain - a study protocol for a systematic review with individual patient data.

BACKGROUND: Chest pain is a common complaint in primary care, with coronary heart disease (CHD) being the most concerning of many potential causes. Systematic reviews on the sensitivity and specificity of symptoms and signs summarize the evidence about which of them are most useful in making a diagnosis. Previous meta-analyses are dominated by studies of patients referred to specialists. Moreover, as the analysis is typically based on study-level data, the statistical analyses in these reviews are limited while meta-analyses based on individual patient data can provide additional information. Our patient-level meta-analysis has three unique aims. First, we strive to determine the diagnostic accuracy of symptoms and signs for myocardial ischemia in primary care. Second, we investigate associations between study- or patient-level characteristics and measures of diagnostic accuracy. Third, we aim to validate existing clinical prediction rules for diagnosing myocardial ischemia in primary care. This article describes the methods of our study and six prospective studies of primary care patients with chest pain. Later articles will describe the main results. METHODS/DESIGN: We will conduct a systematic review and IPD meta-analysis of studies evaluating the diagnostic accuracy of symptoms and signs for diagnosing coronary heart disease in primary care. We will perform bivariate analyses to determine the sensitivity, specificity and likelihood ratios of individual symptoms and signs and multivariate analyses to explore the diagnostic value of an optimal combination of all symptoms and signs based on all data of all studies. We will validate existing clinical prediction rules from each of the included studies by calculating measures of diagnostic accuracy separately by study. DISCUSSION: Our study will face several methodological challenges. First, the number of studies will be limited. Second, the investigators of original studies defined some outcomes and predictors differently. Third, the studies did not collect the same standard clinical data set. Fourth, missing data, varying from partly missing to fully missing, will have to be dealt with.Despite these limitations, we aim to summarize the available evidence regarding the diagnostic accuracy of symptoms and signs for diagnosing CHD in patients presenting with chest pain in primary care. REVIEW REGISTRATION: Centre for Reviews and Dissemination (University of York): CRD42011001170.

Minimal clinically meaningful differences for the eortc QLQ-C30 and eortc QLQ-Bn20 scales in brain cancer patients

Objective: The aim of this study was to determine the smallest changes in health-related quality of life (HRQOL) scores in the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the EORTC Brain Cancer Module (QLQ-BN20), which could be considered as clinically meaningful in brain cancer patients. Methods: World Health Organization (WHO) performance status (PS) and the Mini Mental State Examination (MMSE) were used as clinical anchors to determine minimal clinically important differences (MCID) in HRQOL change scores (range 0 - 100) in the EORTC QLQ-C30 and QLQ-BN20. Anchor-based MCID estimates less than 0.2SD (small effect) were not recommended for interpretation. Other selected distribution-based methods were also used for comparison purposes. Results: Based on WHO PS, our findings support the following whole number estimates of the MCID for improvement and deterioration respectively: physical functioning (6, 9), role functioning (14, 12), cognitive functioning (8, 8), global health status (7, 4*), fatigue (12, 9) and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and those for communication deficit were (9, 7). The estimates with asterisks were less that the set 0.2 SD threshold and are therefore not recommended for interpretation. Our MCID estimates therefore range from 5-14. Conclusion: These estimates can help clinicians to evaluate changes in HRQOL over time and, in conjunction with other measures of efficacy, help to assess the value of a health care intervention or to compare treatments. Furthermore, the estimates can be useful in determining sample sizes in the design of future clinical trials.

VeriStrat(®) has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: Pooled analysis of SAKK19/05 and NTR528.

BACKGROUND: VeriStrat(®) is a serum proteomic test used to determine whether patients with advanced non-small cell lung cancer (NSCLC) who have already received chemotherapy are likely to have good or poor outcomes from treatment with gefitinib or erlotinib. The main objective of our retrospective study was to evaluate the role of VS as a marker of overall survival (OS) in patients treated with erlotinib and bevacizumab in the first line. PATIENTS AND METHODS: Patients were pooled from two phase II trials (SAKK19/05 and NTR528). For survival analyses, a log-rank test was used to determine if there was a statistically significant difference between groups. The hazard ratio (HR) of any separation was assessed using Cox proportional hazards models. RESULTS: 117 patients were analyzed. VeriStrat classified patients into two groups which had a statistically significant difference in duration of OS (p=0.0027, HR=0.480, 95% confidence interval: 0.294-0.784). CONCLUSION: VeriStrat has a prognostic role in patients with advanced, nonsquamous NSCLC treated with erlotinib and bevacizumab in the first line. Further work is needed to study the predictive role of VeriStrat for erlotinib and bevacizumab in chemotherapy-untreated patients.

Persistence of EBV Antigen-Specific CD8 T Cell Clonotypes during Homeostatic Immune Reconstitution in Cancer Patients.

Persistent viruses are kept in check by specific lymphocytes. The clonal T cell receptor (TCR) repertoire against Epstein-Barr virus (EBV), once established following primary infection, exhibits a robust stability over time. However, the determinants contributing to this long-term persistence are still poorly characterized. Taking advantage of an in vivo clinical setting where lymphocyte homeostasis was transiently perturbed, we studied EBV antigen-specific CD8 T cells before and after non-myeloablative lympho-depleting chemotherapy of melanoma patients. Despite more advanced T cell differentiation, patients T cells showed clonal composition comparable to healthy individuals, sharing a preference for TRBV20 and TRBV29 gene segment usage and several co-dominant public TCR clonotypes. Moreover, our data revealed the presence of relatively few dominant EBV antigen-specific T cell clonotypes, which mostly persisted following transient lympho-depletion (TLD) and lymphocyte recovery, likely related to absence of EBV reactivation and de novo T cell priming in these patients. Interestingly, persisting clonotypes frequently co-expressed memory/homing-associated genes (CD27, IL7R, EOMES, CD62L/SELL and CCR5) supporting the notion that they are particularly important for long-lasting CD8 T cell responses. Nevertheless, the clonal composition of EBV-specific CD8 T cells was preserved over time with the presence of the same dominant clonotypes after non-myeloablative chemotherapy. The observed clonotype persistence demonstrates high robustness of CD8 T cell homeostasis and reconstitution.

Influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism.

BACKGROUND: The influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism (VTE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to compare the 3-month mortality rate in cancer patients with VTE, with patients categorized according to the presence of recent immobilization, surgery or neither. The major outcomes were fatal pulmonary embolism (PE) and fatal bleeding within the first 3 months. RESULTS: Of 6,746 patients with active cancer and acute VTE, 1,224 (18%) had recent immobilization, 1,055 (16%) recent surgery, and 4,467 (66%) had neither. The all-cause mortality was 23.4% (95% CI: 22.4-24.5), and the PE-related mortality: 2.5% (95% CI: 2.1-2.9). Four in every ten patients dying of PE had recent immobilization (37%) or surgery (5.4%). Only 28% of patients with immobilization had received prophylaxis, as compared with 67% of the surgical. Fatal PE was more common in patients with recent immobilization (5.0%; 95% CI: 3.9-6.3) than in those with surgery (0.8%; 95% CI: 0.4-1.6) or neither (2.2%; 95% CI: 1.8-2.6). On multivariate analysis, patients with immobilization were at an increased risk for fatal PE (odds ratio: 1.8; 95% CI: 1.2-2.5). CONCLUSIONS: One in every three cancer patients dying of PE had recent immobilization for ≥ 4 days. Many of these deaths could have been prevented with adequate thromboprophylaxis.

Alexithymie et psychopathologie de patients atteints de cancer = Alexithymia and psychopathology of patients with cancer

Résumé Objectif : Décrire l'alexithymie chez des patientsnouvellement diagnostiqués de cancer.Méthode : Les données sociodémographiques, médicales etpsychométriques (HADS, SCL-90, EORTC-QLQ-C30 etTAS-20) ont été enregistrées chez des patients récemment(< 4 mois) pris en charge pour un cancer.Résultats : Chez 70% des 419 patients inclus dans l'étude, unscore qualifiant pour un diagnostic d'alexithymie (TAS > 56)a été observé avec une corrélation négative avec les symptômespsychiatriques, qui par ailleurs ne dépassaient pas lesseuils d'anxiété et de dépression mesurés avec le HADS,et une corrélation positive avec la qualité de vie.Conclusion : La haute prévalence de l'alexithymie, considéréecomme une protection, questionne la nécessité et letype d'éventuelles interventions psycho-oncologiques.Pour citer cette revue : Psycho-Oncol. 5 (2011).

Axillary Lymph Node Dissection for Sentinel Lymph Node Micrometastases May Be Safely Omitted in Early-Stage Breast Cancer Patients: Long-Term Outcomes of a Prospective Study.

OBJECTIVES: To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted. BACKGROUND: The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate. METHODS: In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 </= 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >.2 mm to </=2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests. RESULTS: The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median follow-up of 77 months (range, 24-106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = .656), locoregional (P = .174), and axillary and distant disease-free survival (P = .15) between patients with negative SLN and SLN micrometastases. CONCLUSIONS: This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early-stage breast cancer patients with SLN micrometastases.

Bisphosphonate-related osteonecrosis of the jaws: how to manage cancer patients.

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is defined as exposed necrotic bone appearing in the jaws of patients treated by systemic IV or oral BPs never irradiated in the head and neck area and that has persisted for more than 8 weeks. More than 90% of cases of osteonecrosis of the jaw have been in patients with cancer who received IV-BPs. The estimate of cumulative incidence of BRONJ in cancer patients with IV-BPs ranges from 0.8% to 18.6%. The pathogenesis of BRONJ appeared related to the potent osteoblast-inhibiting properties of BPs which act by blocking osteoclast recruitment, decreasing osteoclast activity and promoting osteoclast apoptosis. Dental extractions are the most potent local risk factor. Cancer patients wearing a denture could also be at increased risk of BRONJ. Non-healing mucosal breaches caused by dentures could be a portal for the oral flora to access bone, while the oral mucosa of patients on IV-BPs could also be defective. Whether periodontal disease is a risk factor for BRONJ remains controversial. Preventive measures are fundamental. Nevertheless, some teams have questioned its cost-effectiveness. The perceived limitations of surgical therapy of BRONJ led to the restriction of aggressive surgery to symptomatic patients with stage 3 BRONJ. The evidence-based literature on BRONJ is growing but there are still many controversial aspects.

Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(ab')2 in patients with non-resectable liver metastases from colorectal cancer.

Experimental studies in nude mice with human colon-carcinoma grafts demonstrated the therapeutic efficiency of F(ab')2 fragments to carcinoembryonic antigen (CEA) labeled with a high dose of 131Iodine. A phase I/II study was designed to determine the maximum tolerated dose of 131I-labeled F(ab')2 fragments (131I-F(ab')2) from anti-CEA monoclonal antibody F6, its limiting organ toxicity and tumor uptake. Ten patients with non-resectable liver metastases from colorectal cancer (9 detected by CT scan and 1 by laparotomy) were treated with 131I-F(ab')2, doses ranging from 87 mCi to 300 mCi for the first 5 patients, with a constant 300-mCi dose for the last 5 patients. For all the patients, autologous bone marrow was harvested and stored before treatment. Circulating CEA ranged from 2 to 126 ng/ml. No severe adverse events were observed during or immediately following infusion of therapeutic doses. The 9 patients with radiologic evidence of liver metastases showed uptake of 131I-F(ab')2 in the metastases, as observed by single-photon-emission tomography. The only toxicity was hematologic, and no severe aplasia was observed when up to 250 mCi was infused. At the 300-mCi dose, 5 out of 6 patients presented grade-3 or -4 hematologic toxicity, with a nadir for neutrophils and thrombocytes ranging from 25 to 35 days after infusion. In these 5 cases, bone marrow was re-infused. No clinical complications were observed during aplasia. The tumor response could be evaluated in 9 out of 10 patients. One patient showed a partial response of one small liver metastasis (2 cm in diameter) and a stable evolution of the other metastases, 2 patients had stable disease, and 6 showed tumor progression at the time of evaluation (2 or 3 months after injection) by CT scan. This phase-I/II study demonstrated that a dose of 300 mCi of 131I-F(ab')2 from the anti-CEA Mab F6 is well tolerated with bone-marrow rescue, whereas a dose of 200 mCi can be infused without severe bone-marrow toxicity.