Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high ...mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
This study assessed the activity of the mAb cetuximab in combination with cisplatin and 5-fluorouracil (5-FU) in advanced esophageal squamous cell carcinoma.
For a maximum of six 29-day cycles, ...patients received cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 1–5 (CF), either alone or in combination with cetuximab (CET–CF; 400 mg/m2 initial dose followed by 250 mg/m2 weekly thereafter). The primary end point was tumor response. Tumor material was obtained for analysis of KRAS mutation status.
Sixty-two eligible patients were included, 32 receiving CET–CF and 30 CF. Cetuximab did not exacerbate grade 3/4 toxicity, except for rash (6% versus 0%) and diarrhea (16% versus 0%). The overall response rate according to RECIST criteria was 19% and 13% and the disease control rate 75% and 57% for the CET–CF and CF arms, respectively. With a median follow-up of 21.5 months, the median progression-free survival was 5.9 and 3.6 months and median overall survival 9.5 and 5.5 months for CET–CF and CF, respectively. No KRAS codon 12/13 tumor mutations were identified in 37 evaluated samples.
Cetuximab can be safely combined with CF chemotherapy and may increase the efficacy of standard CF chemotherapy.
Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.
Patients with previously untreated, ...metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.
Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.
Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.
Background: Although all first-generation 5-HT3 receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has ...not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT3 receptor antagonist, with ondansetron. Patients and methods: In this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg or ondansetron 32 mg, each administered 30 min before initiation of moderately emetogenic chemotherapy. The primary end point was the proportion of patients with no emetic episodes and no rescue medication complete response (CR) during the 24 h after chemotherapy administration (acute period). Secondary end points included efficacy in treatment of delayed CINV (≤5 days post-chemotherapy) and overall tolerability. Results: 563 patients were evaluable for efficacy. CR rates were significantly higher (P <0.01) for palonosetron 0.25 mg than ondansetron during the acute (0–24 h) (81.0% versus 68.6%, respectively), delayed (24–120 h) (74.1% versus 55.1%) and overall (0–120 h) (69.3% versus 50.3%) periods. CR rates achieved with palonosetron 0.75 mg were numerically higher but not statistically different from ondansetron during all three time intervals. Both treatments were well tolerated. Conclusions: A single i.v. dose of palonosetron 0.25 mg was significantly superior to i.v. ondansetron 32 mg in the prevention of acute and delayed CINV.
Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS ...correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.
We aimed to establish the superiority (or noninferiority if superiority was not achieved) in terms of time to progression (TTP) of irinotecan/5-fluorouracil (IF) over cisplatin/5-fluorouracil (CF) in ...chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction.
Patients received either IF: i.v. irinotecan 80 mg/m2 30 min, folinic acid 500 mg/m2 2 h, 5-fluorouracil (5-FU) 2000 mg/m2 22 h, for 6/7 weeks or CF: cisplatin 100 mg/m2 1–3 h, with 5-FU 1000 mg/m2/day 24 h, days 1–5, every 4 weeks.
In all, 333 patients were randomized and treated (IF 170, CF 163). Patient characteristics were balanced except more IF patients had Karnofsky performance status 100%. TTP for IF was 5.0 months 95% confidence interval (CI) 3.8–5.8 and 4.2 months (95% CI 3.7–5.5) for CF (P = 0.088). Overall survival (OS) was 9.0 versus 8.7 months, response rate 31.8% versus 25.8%, time to treatment failure (TTF) 4.0 versus 3.4 months for IF and CF, respectively. The difference in TTF was statistically significant (P = 0.018). IF was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10.0% versus 21.5%), severe neutropenia, thrombocytopenia and stomatitis, but not diarrhea.
IF did not yield a significant TTP or OS superiority over CF, and the results of noninferiority of IF were borderline. However, IF may provide a viable, platinum-free front-line treatment alternative for metastatic gastric cancer.
Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in ...vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.
Background: Phase II and III trials of docetaxel, cisplatin and fluorouracil (DCF) have shown superior efficacy versus cisplatin and fluorouracil alone but high rates of hematologic toxicity in ...advanced gastric cancer. To reduce toxicity while maintaining the efficacy of DCF, we investigated split doses of docetaxel (T), cisplatin (P), leucovorin (L) and fluorouracil (F). Patients and methods: Chemotherapy-naive patients with advanced gastric-/esophageal adenocarcinomas received T 50 mg/m2 and P 50 mg/m2 on days 1, 15 and 29 and L 500 mg/m2 plus F 2000 mg/m2 weekly, every 8 weeks. Because significant dose reductions to <80% became necessary in 80% of patients, the regimen was amended after the first 15 patients to T 40 mg/m2, P 40 mg/m2, L 200 mg/m2 and F 2000 mg/m2. The primary endpoint was response rate. Results: Sixty patients were enrolled: 24 had locally advanced (LA) tumors and 36 had metastatic disease. Grade 3/4 toxicities included neutropenia (22%), febrile neutropenia (5%), diarrhea (20%) and lethargy (18%). The overall response rate was 47%. Twenty-three LA patients underwent secondary surgical resection (96%); complete resection was achieved in 87%. Overall, median time to progression and overall survival were 9.4 and 17.9 months, respectively (8.1 and 15.1 months, respectively, for patients with metastatic disease). Conclusion: T-PLF regimen is highly active and has a favorable toxicity profile.
Purpose
To evaluate efficacy and safety of vaccination with StroVac compared to placebo in patients with recurrent urinary tract infections (rUTI).
Material and methods
We performed a prospective, ...double-blinded, placebo-controlled study in patients with uncomplicated rUTI. Patients received three single intramuscular injections with StroVac every two weeks. Primary endpoint was the number of bacterial urinary tract infections (UTI) over 13.5 months after randomization and adjusted by the respective “baseline” value when comparing verum and placebo group. Secondary endpoints were the number of patients with non-recurrence, time to first recurrence, frequency of recurrences, and patients' self-assessment of quality of life using a validated questionnaire.
Results
376 patients were randomized to both groups between January 2012 and March 2015. Mean age was 44.4 years. Patients were mainly female (98.4%). In the StroVac group (
n
= 188), the number of UTIs was reduced from 5.5 to 1.2, in the placebo group (
n
= 188) from 5.4 to 1.3 (
p
= 0.63). In patients with ≥ 7 UTIs prior to study inclusion, StroVac was statistically significantly superior to placebo (
p
= 0.048). However, in all other secondary endpoints, no statistical differences between the two groups could be seen (all
p
> 0.3).
Conclusion
StroVac reduced the number of clinically relevant UTIs like in former studies but did not show statistically significant better results than the chosen placebo. Most likely, that was due to a, since confirmed, prophylactic effect of the chosen placebo itself. Therefore, placebo-controlled and double-blinded studies using a different ineffective placebo preparation are needed to determine the importance of StroVac in prophylaxis of rUTI.
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