Circulating metastasis associated in colon cancer 1 transcripts in gastric cancer patient plasma as diagnostic and prognostic biomarker

METHODS: We provide for the first time a blood-based assay for transcript quantification of the metastasis inducer MACC1 in a prospective study of gastric cancer patient plasma. MACC1 is a strong prognostic biomarker for tumor progression and metastasis in a variety of solid cancers. We conducted a study to define the diagnostic and prognostic power of MACC1 transcripts using 76 plasma samples from gastric cancer patients, either newly diagnosed with gastric cancer, newly diagnosed with metachronous metastasis of gastric cancer, as well as follow-up patients. Findings were controlled by using plasma samples from 54 tumor-free volunteers. Plasma was separated, RNA was isolated, and levels of MACC1 as well as S100A4 transcripts were determined by quantitative RT-PCR. RESULTS: Based on the levels of circulating MACC1 transcripts in plasma we significantly discriminated tumor-free volunteers and gastric cancer patients (P < 0.001). Levels of circulating MACC1 transcripts were increased in gastric cancer patients of each disease stage, compared to tumor-free volunteers: patients with tumors without metastasis (P = 0.005), with synchronous metastasis (P = 0.002), with metachronous metastasis (P = 0.005), and patients during follow-up (P = 0.021). Sensitivity was 0.68 (95%CI: 0.45-0.85) and specificity was 0.89 (95%CI: 0.77-0.95), respectively. Importantly, gastric cancer patients with high circulating MACC1 transcript levels in plasma demonstrated significantly shorter survival when compared with patients demonstrating low MACC1 levels (P = 0.0015). Furthermore, gastric cancer patients with high circulating transcript levels of MACC1 as well as of S100A4 in plasma demonstrated significantly shorter survival when compared with patients demonstrating low levels of both biomarkers or with only one biomarker elevated (P = 0.001). CONCLUSION: Levels of circulating MACC1 transcripts in plasma of gastric cancer patients are of diagnostic value and are prognostic for patient survival in a prospective study

Regional hyperthermia of the abdomen, a pilot study towards the treatment of peritoneal carcinomatosis

Background Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with a dismal prognosis. Some doubts remain whether the whole abdomen can be treated by regional hyperthermia, therefore we analyzed feasibility conducting a pilot study. Methods A simulation of the abdominopelvic heat distribution in 11 patients with peritoneal carcinomatosis was done using the HyperPlan software and the SIGMA-60 and SIGMA-Eye applicators. Tissue-specific region-related electrical and thermal parameters were used to solve the Maxwell’s equations and the bioheat-transfer equation. Three-dimensional specific absorption rate (SAR) distributions and, additionally, estimated region-related perfusion rates were used to solve the bioheat-transfer equation. The predicted SAR and temperature distributions were compared with minimally invasive measurements in pelvic reference points. Results In 11 patients (7 of them treated in the SIGMA-60 and 4 in the SIGMA- Eye applicator) the measured treatment variables (SAR, temperatures in the pelvic reference points) indicated that the heated volumes were higher for the SIGMA-Eye applicator. The mean computed abdominal SARs were less for the SIGMA-Eye (33 versus 44 W/kg). Nevertheless, the temperature distributions in the abdomen (peritoneal cavity) were more homogeneous in the SIGMA-Eye applicator as compared to the SIGMA-60 as indicated by higher values of T 90 (mean 40.2 versus 38.2 °C) and T 50 (mean 41.1 versus 40.2 °C), while the maximum temperatures were similar (in the range 41 to 43 °C). Even though the mean abdominal SAR was lower in the SIGMA-Eye, the heat distribution covered a larger volume of the abdomen (in particular the upper abdomen). For the SIGMA-60 applicator the achieved T 90 appeared to be limited between 41 and 42 °C, for the SIGMA Eye applicator more effective T 90 in the range 42 to 43 °C were obtained. Conclusion Our results suggest that an adequate heating of the abdomen and therefore abdominal regional hyperthermia in PC patients appears feasible. The SIGMA-Eye applicator appears to be superior compared to the SIGMA-60 applicator for abdominal hyperthermia

High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients

BACKGROUND: The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III. FINDINGS: We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis. CONCLUSION: According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the “Traditional pathway” with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-015-0316-2) contains supplementary material, which is available to authorized users

Protocol of a phase II trial

Background Current studies on salvage radiotherapy (sRT) investigate timing, dose-escalation and anti-hormonal treatment (ADT) for recurrent prostate cancer. These approaches could either be limited by radiation-related susceptibility of the anastomosis or by suspected side-effects of long-term ADT. A phase II protocol was developed to investigate the benefit and tolerability of regional hyperthermia with moderately dose-escalated radiotherapy. Methods The study hypothesis is that radio-thermotherapy is a safe and feasible salvage treatment modality. The primary endpoint is safety measured by frequency of grade 3+ genitourinary (GU) and gastrointestinal (GI) adverse events (AE) according to Common Toxicity Criteria (CTC) version 4. Feasibility is defined by number of hyperthermia treatments (n ≥ 7) and feasibility of radiotherapy according to protocol. Target volume delineation is performed according to the EORTC guidelines. Radiation treatment is administered with single doses of 2 Gy 5×/week to a total dose of 70 Gy. Regional hyperthermia is given 2×/week to a total of 10 treatments. Results European centres participate in the phase II trial using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The initiating centres were participants of the SAKK 09/10 study, where the same patient criteria and target volume definition (mandatory successful performed dummy run) were applied insuring a high standardisation of the study procedures. Conclusions The introduced phase II study implements highly precise image-guided radiotherapy and regional hyperthermia. If the phase II study is found to be safe and feasible, a multicenter phase III study is planned to test whether the addition of regional hyperthermia to dose-intensified sRT improves biochemical control

SARS-CoV-2 Variant of Concern B.1.1.7: Diagnostic Sensitivity of Three Antigen-Detecting Rapid Tests.

Funder: Foundation for Innovative New DiagnosticsFunder: World Health OrganizationFunder: Ministry of Science, Research and Culture, State of Baden Wuerttemberg, German

Diagnostic accuracy and feasibility of patient self-testing with a SARS-CoV-2 antigen-detecting rapid test.

BACKGROUND: Considering the possibility of nasal self-sampling and the ease of use in performing SARS-CoV-2 antigen-detecting rapid diagnostic tests (Ag-RDTs), self-testing is a feasible option. OBJECTIVE: The goal of this study was a head-to-head comparison of diagnostic accuracy of patient self-testing with professional testing using a SARS-CoV-2 Ag-RDT. STUDY DESIGN: We performed a manufacturer-independent, prospective diagnostic accuracy study of nasal mid-turbinate self-sampling and self-testing with symptomatic adults using a WHO-listed SARS-CoV-2 Ag-RDT. Procedures were observed without intervention. For comparison, Ag-RDTs with nasopharyngeal sampling were professionally performed. Estimates of agreement, sensitivity, and specificity relative to RT-PCR on a combined oro-/nasopharyngeal sample were calculated. Feasibility was evaluated by observer and participant questionnaires. RESULTS: Among 146 symptomatic adults, 40 (27.4%) were RT-PCR-positive for SARS-CoV-2. Sensitivity with self-testing was 82.5% (33/40; 95% CI 68.1-91.3), and 85.0% (34/40; 95% CI 70.9-92.9) with professional testing. At high viral load (≥7.0 log10 SARS-CoV-2 RNA copies/ml), sensitivity was 96.6% (28/29; 95% CI 82.8-99.8) for both self- and professional testing. Deviations in sampling and testing were observed in 25 out of the 40 PCR-positives. Most participants (80.9%) considered the Ag-RDT as easy to perform. CONCLUSION: Laypersons suspected for SARS-CoV-2 infection were able to reliably perform the Ag-RDT and test themselves. Procedural errors might be reduced by refinement of the instructions for use or the product design/procedures. Self-testing allows more wide-spread and frequent testing. Paired with the appropriate information of the public about the benefits and risks, self-testing may have significant impact on the pandemic

Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society

BACKGROUND: The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control. METHODS: Patients with histological proven rectal cancer staged T2N+ or T3 are randomized to receive either SCRT (25 Gy in five fractions of 5 Gy) plus TME-surgery within 5 days or RCT (50.4 Gy in 28 fractions of 1.8 Gy, continuous infusion 5-fluorouracil) plus TME-surgery 4-6 weeks later. All patients receive adjuvant chemotherapy (12 weeks continuous infusional 5-FU) and are followed up for 5 years. TME-quality is independently documented by the surgeon and the pathologist. Hypothesis of the study is that RCT is superior to SCRT in terms of local recurrence after five years. Secondary endpoints are overall survival, disease-free survival, complete resection rate (R0 resection), rate of sphincter saving resection, acute and late toxicity (radiation related side effects), and quality of life (including long term bowel function). DISCUSSION: Similar long-term survival, local control and late morbidity have been reported for both concepts of preoperative therapy in non-comparative studies. In addition to other ongoing (and recently published) comparative trials we include a larger number of patients for adequate power, apply quality-controlled TME and try to avoid the adjuvant treatment bias by mandatory adjuvant chemotherapy in both groups. Further more, stratification of the initially planned surgical procedure and sphincter-preservation will generate valid evidence whether RCT will allow a less aggressive (sphincter saving) surgical approach

Age as independent prognostic factor for survival of cancer patients

Einleitung Krebs ist eine altersabhängige Erkrankung. Ursächlich für die insgesamt ansteigende Inzidenz im höheren Lebensalter sind eine verlängerte Expositionsdauer mit oxidativen Stressfaktoren wie z.B. Strahlung, Giftstoffen und karzinogenen Stoffen sowie eine altersbedingte nachlassende Funktionsfähigkeit des Immunsystems. Patienten in verschiedenen Altersgruppen weisen relevante Unterschiede in Hinblick auf altersphysiologische Veränderungen und Komorbiditäten auf. Dies hat Einfluss auf das Gesamtüberleben, das krankheitsfreie Überleben und die Durchführung einer tumorspezifischen Therapie. Allerdings unklar, inwieweit Alter ein unabhängiger prognostischer Faktor ist und ob es generell altersspezifische Unterschiede in der Tumorbiologie gibt. Methodik Zunächst wurde während eines zweijährigen Forschungsaufenthaltes die Studiendatenbank der European Organisation for Research and Treatment of Cancer (EORTC), welche qualitativ hochwertige Studien mit langer Nachbeobachtungszeit enthält, auf geeignete Studien für eine Auswertung gescreent. 7 Studien (4 Studien zum Mammakarzinom und 3 Studien zum kolorektalen Karzinom) wurden in die finale Analyse eingeschlossen. Anschließend erfolgte ein Pooling der Daten der jeweiligen Entität und eine Auswertung des Gesamtüberlebens (OS), des krankheitsfreien Überlebens (DFS), des lokoregional-rezidivfreien Überlebens (LRFS) sowie des fernmetastasenfreien Überlebens (DMFS) innerhalb verschiedener Altersgruppen. Weiterhin erfolgte eine Analyse in Hinblick auf Kofaktoren wie z.B. Tumorstadium oder Performance Status (PS). Um die Unabhängigkeit und Wertigkeit der Faktoren zu vergleichen wurde weiterhin eine multivariate Regressionsanalyse nach Cox durchgeführt. Ergebnisse Beim Mammakarzinom zeigte sich, dass die Gruppen der 40-49-Jjährigen, der 50-59-Jährigen und der 60-69-Jährigen ein ähnliches OS und DFS aufwiesen, wohingegen ein großer Unterschied zu der Gruppe der unter 40-Jährigen bestand. Das Risiko, ein Lokalrezidiv oder Fernmetastasen zu entwickeln, war in der jüngeren Patientengruppe deutlich erhöht (10-Jahres-DFS-Rate: Altersgruppe unter 30: 60%, Altersgruppe 30- 39: 74,2%, Altersgruppe 40-49: 80,5%, Altersgruppe 50-59: 82,7%, Altersgruppe 60-69: 82,7%, Altersgruppe ab 70: 86,3%). Beim kolorektalen Karzinom zeigte sich, dass die Altersgruppe ab 60 Jahre im Vergleich mit den jüngeren Altersgruppen ein signifikant schlechteres OS aufwies (10-Jahres-OS-Rate: Altersgruppe unter 40: 67%, Altersgruppe 40-49: 73,6%, Altersgruppe 50-59: 69,1%, Altersgruppe 60-69: 56,5%, Altersgruppe ab 70: 49,4%). Bezüglich des DFS zeigte sich beim kolorektalen Karzinom nur für das DMFS ein signifikanter Unterschied, wobei die Altersgruppe ab 70 seltener Fernmetastasen entwickelte als die Altersgruppe 60-69. Insgesamt zeigt die Analyse, dass der Faktor „Alter“ je nach Tumorentität ein positiv oder ein negativ prognostischer Faktor sein kann. Der Einfluss des Alters lässt sich v. a. beim Mammakarzinom zum Teil durch die unterschiedliche Tumorbiologie in den verschiedenen Altersgruppen erklären. Es ist zu vermuten, dass auch bei anderen Entitäten dieser Einfluss über eine altersabhängige unterschiedliche Tumorbiologie vermittelt wird.Introduction Cancer is an age-related disease. Reasons for increasing incidence with old age are prolonged exposure to oxidative stress factors like radiation, toxic agents and carcinogens as well as a diminished immune system. Patients in different age cohorts have relevant differences with respect to age-related physiological transformations and comorbidities. This has an impact on overall survival (OS), disease-free survival (DFS) and anticancer therapy. However, it is not yet know whether age is an independent prognostic factor and to what extent general age-related differences in tumor biology exist. Methodology The clinical trial database of the European Organisation for Research and Treatment of Cancer (EORTC), which contains high quality data of clinical trials with long-term follow-up, was screened for this analyses during a 2-year research fellowship. 7 trials (4 trials for breast cancer (BC) and 3 trials for colorectal cancer (CRC)) were included in the final analysis. Data were pooled for the respective entity, and analysis for OS, DFS, locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were conducted within different age cohorts. Furthermore, analyses for cofactors like e.g. tumor stage or performance status were performed. To investigate the independence and the role of these factors multivariate regression analysis after Cox was performed. Results For BC, the age cohorts of 40-49, 50-59 and 60-69 years showed similar OS and DFS, but there was a large difference compared to the cohort of patients younger than 40 years. The risk of developing local recurrence or distant metastases was increased for the younger cohort (10-year-DFS-rate < 30 years: 60%, 30-39 years: 74.2%, 40-49 years: 80.5%, 50-59 years: 82.7%, 60-69 years: 82.7%, > 70 years: 86.3%). In contrary , the cohort of patients the CRC group older than 59 years had a significantly worse OS compared to younger patients (10-year- OS-rate: < 40 years: 67%, 40-49 years: 73.6%, 50-59 years: 69.1%, 60-69 years: 56.5%, >70 years: 49.4%). With respect to DFS, the only difference seen was for DMFS, the cohort aged > 70 years did develop less often distant metastases than the cohort aged 60-69 years. Altogether, the analysis showed that, depending on tumour entity, age can be a positive or negative prognostic factor. The impact of age for BC can be partially explained by differences in tumour biology of different age cohorts. It could be hypothesised that this impact mediated by age-related differences in tumour biology might be present in other tumour entities as well