Background: Carfilzomib (K)-based combinations have been established as effective frontline and relapse regimens in pts with multiple myeloma (MM). Aims: In this randomized phase II trial we evaluated the impact of either Revlimid (R) or Thalidomide (T) as combination partner for K and dexamethasone (KRd or KTd) on outcome in pts with newly diagnosed MM (NDMM) not eligible for autologous transplantation (TNE). Further, we evaluated the role of one year K maintenance therapy compared to observation. Methods: One hundred twenty two pts have been enrolled (ITT population). Median age was 75 yrs, ISS stage I/II/III: 29 (23.8%)/48 (39.3%)/45 (36.9%), ECOG stage 0/1: 64 (52.5%) / 58 (47.5%). t(4;14) ± del17p was noted in 15 (16.3%) of 92 pts with results available. Pts were randomized to 9 cycles of KRd or KTd, and 107 pts received at least one full cycle. Carfilzomib (K) was started with 20mg/m2 at d 1 of cycle 1, and was continued with 27mg/m2 for the first 2 cycles (d 1 + 2, 8 + 9, 15 + 16 schedule); followed by K administration at 57mg/m2 once weekly for a 28 d cycle. Thalidomide 100mg/d (50mg in pts >75 yrs of age), d 1-28, or Revlimid 25mg/d (15mg in pts 375 yrs of age) d 1-21. Dexamethasone 40mg (20mg in pts 375 yrs of age) once/week. After induction, pts with 3SD were randomized to K maintenance (d 1 and 15) for 12 cycles or observation. MRD was assessed by NGF with a sensitivity of 10-6 in pts with ≥VGPR. Survival estimates were calculated according to Kaplan-Meier and survival curves were compared with the log-rank test. PFS and OS results presented are given for the ITT population. This trial is registered on clinicaltrials.gov (NCT02891811). Results: Median follow-up was 25.3 mos, 15 pts discontinued therapy within the first cycle due to patient (3) or investigator (1) decision, AE/toxicity (8), death or progressive disease (2) or other reason (1). Overall response rate was 91.3% in the entire group with available data (n=115). Results for sCR, CR, VGPR, PR, and ORR for KRd and KTd were similar between both groups (7.3%/10.0%, 27.3%/33.3%, 38.2%/35.0%, 14.5/16.7%, 87.3%/95.0%, respectively). Minor response was noted in 4 (3.5%), stable disease in 5 (4.3%) and progressive disease in 1 (0.8%) pts. PFS (median 26.9 and 23.5 mos, p=0.832) and OS (not reached vs 52.2 mos, p=0.398) were similar between the KRd and KTd group, respectively. The OS rate at 36 mos was 82% in both groups. MRD testing was performed in 57 pts at time of CR/VGPR. Of those, 43.9%, (20.5% of the ITT group) pts were found to be MRDneg. PFS was significantly longer in MRDneg vs. MRDpos pts (p=0.003). Seventy six pts were randomized to K maintenance therapy or observation. Median PFS was numerically higher in the pts with K maintenance treatment (median 33.0 vs 24.0, p=0.714), but the difference was not statistically significant. Data on OS are not mature yet (only 9 events). Grade 3/4 hematologic AEs were anemia (4.1%), leukopenia (0.8%), thrombocytopenia (7.4%), while non-hematologic grade 3/4 AEs were infection (20.5%), GI-disorders (7.4%), hypertension (7.4%), renal and cardiac impairment/failure (6.6% and 8.2% respectively). Image:Summary/Conclusion: Our data show similar high efficacy of KRd and KTd in elderly NTE NDMM pts, including no difference in ORR (KRd and KTd, 87.3% and 95%, respectively), PFS and OS. Overall survival rate at 3 yrs was 82%. Median PFS was significantly longer in MRDneg pts. PFS was numerically, but not statistically longer in pts on K maintenance vs observation. Treatment was associated with an acceptable tolerance profile.

BACKGROUND AND PURPOSE:Since the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several reports indicated neurological involvement in COVID-19 disease. Muscle involvement has also been reported as evidenced by creatine kinase (CK) elevations and reports of myalgia.METHODS:Creatine kinase, markers of inflammation, pre-existing diseases and statin use were extracted from records of Austrian hospitalised COVID-19 patients. Disease severity was classified as severe in case of intensive care unit (ICU) admission or mortality. COVID-19 patients were additionally compared to an historical group of hospitalised influenza patients.RESULTS:Three hundred fifty-one patients with SARS-CoV-2 and 258 with influenza were included in the final analysis. CK was elevated in 27% of COVID-19 and in 28% of influenza patients. CK was higher in severe COVID-19 as were markers of inflammation. CK correlated significantly with inflammation markers, which had an independent impact on CK when adjusted for demographic variables and disease severity. Compared to influenza patients, COVID-19 patients were older, more frequently male, had more comorbidities, and more frequently had a severe disease course. Nevertheless, influenza patients had higher baseline CK than COVID-19, and 35.7% of intensive care unit (ICU)-admitted patients had CK levels >1,000 U/L compared to only 4.7% of ICU-admitted COVID-19 patients.CONCLUSIONS:HyperCKemia occurs in a similar frequency in COVID-19 and influenza infection. CK levels were lower in COVID-19 than in influenza in mild and severe disease. CK levels strongly correlate with disease severity and markers of inflammation. To date, it remains unclear whether hyperCKemia is due to a virus-triggered inflammatory response or direct muscle toxicity.

Background: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. Methods: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. Results: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06–1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00–1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31–0.94, p = 0.020). Conclusions: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Rationale. Oncological treatment, applying chemotherapy or new targeted drugs has already shown to induce cardiotoxicity. Present knowledge is primarily based on patients, who were treated in prospective clinical trials and is focused on acute toxicities. In contrast, there is a lack of data concerning the long-term cardiotoxic effects of systemic cancer therapies. The present trial aims to prove the risk and the consequences of long-term cardiotoxicity experienced after different cancer treatments in an unselected cohort of patients.

Das Magenkarzinom ist nach wie vor eine Erkrankung mit ungünstiger Prognose. Aufgrund der unspezifischen Symptomatik und fehlender Vorsorgeprogramme wird die Diagnose häufig erst in fortgeschrittenen Stadien gestellt, sodass über 70 % der Patienten zum Zeitpunkt der Diagnose nicht mehr kurativ behandelbar sind. In der palliativen Therapie gewinnen – neben und in Kombination mit der Chemotherapie – weitere Therapieformen mit Biologika an Bedeutung. So ist beispielsweise bei HER2-positiven Patienten Trastuzumab in Kombination mit Chemotherapie Standard. Weitere vielversprechende Substanzen, wie z. B. Pertuzumab, T-DM1 und Ramucirumab, sind derzeit Teil klinischer Studien. Es eröffnen sich mehr Möglichkeiten, den Patienten eine Therapie anzubieten, die aufgrund häufig geringer Nebenwirkungen im Vergleich zur Chemotherapie eine Lebenszeitverlängerung unter Verbesserung der Lebensqualität darstellen.

Rationale: Medical treatment applying chemotherapy or new targeted drugs have already shown to induce cardiotoxicity. Present knowledge is primarily based on patients, who were treated in prospective clinical trials, and is focused on acute toxicities. In contrast, there is a lack of data concerning the long-term cardiotoxic effects of systemic cancer therapies. The present trial aims to prove the risk and the consequences of long-term cardiotoxicity experienced after different cancer treatments in an unselected cohort of patients.

ABSTRACT Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Treatment of gastrointestinal neoplasias has changed substantially during the last decade. Nihilism and poor response rates have been replaced by aggressive treatment strategies and even curative approaches in metastatic colorectal cancer for example. A major achievement is the multidisciplinary treatment – lead by tumour boards – enabling optimal treatment sequences and utilization of diff erent treatment modalities. Increase in response rates and prolongation of survival is also achieved by the use of novel cytostatic drugs and implementation of so called “targeted therapies” . In spite of these undoubtedly positive developments many questions still remain unanswered and implementation of novel treatment strategies is not uniformly successful. Furthermore predictive markers for targeted therapies are warranted but preclinical and clinical data however are not

Gastric cancer is still a devastating disease. Two thirds of the patients are diagnosed in a locally advanced or metastatic stage. Even if surgery is possible, long-term survival is low. Optimal therapy in a curative and a palliative setting is still not clear yet. ASCO 2010 could shed some light on optimal chemotherapy and the introduction of molecular targeted therapy. The aim of this article is to summarize the most important publications at this year's ASCO annual meeting and to put them into context of current therapeutic strategies.

Summary Overall survival of patients suffering from gastric cancer is still poor. Two-thirds of patients are diagnosed in a locally advanced stage or with metastatic tumour. But even in patients with operable disease recurrence rate is high. To increase the prognosis of this devastating disease much effort has been put in the development of curative and palliative therapy concepts recently. The aim of this article is to summarize the most important publications at this year's ASCO meeting and to put them into context of current therapeutic strategies.

Gastric cancer is still one of the predominant causes of death on account of gastrointestinal neoplasias. In recent years, chemotherapy and radiotherapy have substantially improved the outcome in operable gastric cancer patients. A benefit in median overall survival is reported for perioperative chemotherapy as well as for postoperative adjuvant radio-chemotherapy. But there is still a controversy about the best treatment sequence. The aim of this paper is to critically review current literature, to discuss the pros and cons of neoadjuvant (preoperative) or postoperative adjuvant therapy and to give treatment recommendations based on large phase III trials.

Overall survival of patients suffering from gastric cancer is still poor. Two-thirds of patients are diagnosed in a locally advanced stage or with metastatic tumour. But even in patients with operable disease recurrence rate is high. To increase the prognosis of this devastating disease much effort has been put in the development of curative and palliative therapy concepts recently. The aim of this article is to summarize the most important publications at this year's ASCO meeting and to put them into context of current therapeutic strategies.

Although treatment of gastric cancer has improved substantially during the last decade there is still controversy about the best way and sequence of treatment. An early interdisciplinary treatment plan is mandatory before therapy is started. In this multidisciplinary expert statement we review current literature and give treatment recommendations for neoadjuvant, adjuvant, and palliative treatment of gastric cancer.

Fresh frozen bone marrow biopsies were evaluated immunohistochemically, applying monoclonal antibodies against CD31, CD34, VEGFR-2 and CD133, a novel marker identifying human endothelial progenitor cells (EPCs). Specimens of 51 patients diagnosed with MDS were compared with 16 AML and 18 controls. The percentage of CD34 expressing cells was increased and CD31 expression was decreased in advanced stages of MDS compared with normal BM. VEGFR-2 expression was also raised in MDS. Here we show for the first time that increased numbers of CD133 positive cells are present in the majority of MDS patients. Additionally, those cells occasionally seem to contribute to capillary forming units in bone marrow.

Aims: Recent results generated in a mouse model suggest that tumour angiogenesis/vasculogenesis can be initiated and maintained by bone marrow derived endothelial progenitor cells. This present study investigated the distribution and frequency of CD133 positive endothelial progenitor cells in patients with non-small cell lung cancer (NSCLC) (tumour tissue and tumour free lung regions) and healthy controls using fresh frozen specimens. The novel marker CD133 identifies human haemopoetic precursor cells, in addition to human endothelial progenitor cells. Methods: Seventy nine lung cancer specimens and 66 adjacent histologically tumour free tissues of the same patient cohort were analysed; 11 postmortem specimens from control patients who did not suffer from malignant disease served as controls. Cryostat sections were stained for CD133, CD31, vascular endothelial growth factor receptor 2 (VEGFR-2; KDR), p53, and the proliferation marker Ki-67, and the correlations were analysed. Results: Forty three of 63 evaluable tumour specimens had increased numbers of CD133 positive cells and in some cases capillary forming CD133 positive structures were detectable. In addition, 30 of 63 specimens had raised expression of KDR and 29 of 63 had increased MVD. Increased CD133 expression marginally correlated with raised KDR expression but not with p53 and Ki-67. Conclusion: A significant increase in CD133 positive cells was documented in patients with NSCLC, suggesting an involvement of endothelial progenitor cells in tumour vasculogenesis and tumour growth in these patients.

Identification of biomarkers is one of the most promising approaches for the detection of early malignant or even premalignant lesions with the chance of diagnosing early stages of non-small cell lung cancer that could be treated curatively. Alterations of chromosomes (3p, 5q 9p), genes (Rb, C-myc, C-mos, hTERT), proteins (p16, p53, K-ras, hnRNP A2/B1, MCM2, EGFR, erbB-2, erbB-3, erbB-4) and others can be found in lung cancer. Some of these occur at early stages of the disease and few could serve as potential screening markers. The actual literature is reviewed and the relevance of the different biomarkers for early lung cancer detection is discussed. (C) 2004 Lippincott Williams Wilkins.

The frequency of increased EGFR-mRNA expression was determined in 57 patients suffering from NSCLC by applying quantitative real-time PCR. The findings were correlated with clinical parameters and the immunohistochemical (IHC) markers EGFR, c-erbB-2, c-erbB-3, Ki-67 and p53 on cryostat sections. Of the patients 46% showed increased EGFR-mRNA, 35% revealed an increased IHC-EGFR expression; 16% of the patients showed a combined positivity and 35% a combined negativity when applying both methods, and 17 (30%) of the cases revealed increased EGFR-mRNA without IHC-EGFR expression. This subgroup was characterised by p53 coexpression and the highest frequency of deaths (35% vs. 20%) indicating a more aggressive tumour type. In contrast to IHC - where positivity was seen predominantly in squamous cell carcinomas (48% vs. 27%) - EGFR-mRNA expression was observed equally in both histological subtypes (48% vs. 43%). PCR-EGFR and IHC-EGFR tumour typing identifies different tumour characteristics with different clinical courses. Whether this combined typing could help to identify patients who respond to anti-EGFR therapies is worth further testing.

AIMS:To investigate the immunohistochemical expression of a panel of biologically relevant markers in patients with non-small cell lung cancer using fresh frozen specimens and to test their prognostic relevance for identification of patients at risk.METHODS:Seventy nine tumour infiltrated lung cancer specimens and 66 adjacent histologically tumour free tissues were analysed; 11 postmortem specimens from patients who did not suffer from a malignant disease served as a control group. Cryostat sections were stained with monoclonal antibodies against epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, CD82, Ki-67, p120, p53, bcl-2, and CD31.RESULTS:At least one of the tested markers was raised above the defined cut off point in 75 of the tumours. In 55, three to six factors were increased. EGFR was raised in 32, c-erbB-2 in 29, c-erbB-3 in 46, p53 in 29, bcl-2 in 26, Ki-67 in 36, p120 in 46, and CD31 in 29. None of the tested parameters was significant in univariate survival analysis. In a second step, three variables were combined (c-erbB3, p53, and microvessel density), and cases with increased expression of two or three parameters proved to have a significantly lower survival probability than those expressing none or only one factor. In the tumour free group only 10 showed raised marker expression.CONCLUSION:Characterisation of tumour cells in surgical specimens with immunohistological markers could help identify those patients at risk for early cancer death who could possibly profit from adjuvant treatment after curative tumour resection.

A real-time PCR technique with automated computerized analysis (TaqMan ) was tested to detect K-ras mutations in 66 patients suffering from NSCLC. This technology is characterized by high reproducibility of data and a time-saving analysis procedure. In 11% (7/66) of the tumour specimens and 2% (1/58) of adjacent tumour-free lung specimens a K-ras codon 12 mutation was detected. In adenocarcinomas containing > or =40% tumour cells, however, K-ras mutations were seen in 25% of the cases. The point mutations detected in tumours were GGT right curved arrow TGT in five cases and GGT right curved arrow GTT in two cases. As compared with immunohistochemical parameters, the K-ras mutated group was characterized by a c-erbB-2 negativity (p=0.04) and a smaller number of c-erbB-3 (p=0.02) positive cases. EGFR, bcl-2, p53, Ki-67 and p120 expression did not differ significantly. Determination of the K-ras point mutations by automated TaqMan PCR in NSCLC tumour specimens is feasable and highly specific. Due to its high throughput capacity this method represents a valuable tool for routine screening.