Journal of Cancer Research and Clinical Oncology

Purpose: Some limitations of effective therapy in multiple myeloma include the low growth fraction of the malignant plasma cells, multi-drug resistance, and the presence of other concurrent diseases in this patient population. A phase I study was conducted to evaluate the toxicity of granulocyte macrophage colony stimulating factor (GM-CSF) in myeloma patients as well as the potential effect on the plasma cell labeling index (PCLI). Relapsed patients with multiple myeloma were eligible. Methods: The first phase of this trial assessed the toxicity (including the effect on disease progression) of escalating doses (125–500 μg/m2 SC, days 1–5) of GM-CSF, and the effects of this cytokine on PCLI. Patients whose PCLI doubled and increased to ≥1.7% were treated with chemotherapy including cyclophosphamide, vincristine, prednisone, and GM-CSF. Twenty-two patients were enrolled. Results: The toxicity of GM-CSF was mild, and no dose-limiting side effects were seen. Twenty-five percent of patients (5/20) achieved the target PCLI, and 4/5 proceeded to receive chemotherapy. No relationship of GM-CSF dose to increases of the PCLI was noted. All patients who received chemotherapy responded. Conclusions: GM-CSF has acceptable toxicity in patients with multiple myeloma and produced increases of PCLI in selected individuals. Further studies of GM-CSF alone or in combination with chemotherapy are indicated.

The emerging use of direct oral anticoagulants (DOAC) in the management of cancer-associated venous thromboembolism (CAT) is significantly improving therapeutic adherence and quality of life. Despite this, many conditions can restrict the therapeutic index of these drugs. For all these reasons the latest guidelines recommend the use of heparins in the treatment of CAT as the preferred treatment in some clinical settings. We evaluated the efficacy and the safety of DOAC, in terms of recurrent venous thromboembolism (VTE) and major bleeding (MB), as a composite primary outcome. Mortality and clinically relevant non-major bleeding (CRNMB) were evaluated as secondary outcomes. We performed a retrospective study on 209 patients to compare the effects of DOAC versus heparins for the treatment of CAT. 127 patients with a high bleeding risk neoplasia were enrolled. A primary-outcome event occurred in 11.3% of patients treated with heparins and in 10.5% treated with DOAC (Relative Risk 0.92; 95% CI 0.42–2.01, p = 0.84). Recurrent VTE occurred in 6.1% in the heparins group and in 8.4% in the DOAC group (RR 1.37; 95% CI 0.51–3.64, p = 0.52). MB occurred in 5.2% in the heparins group and in 2.1% in the DOAC group (RR 0.40; 95% CI 0.08–1.93, p = 0.25). DOAC seem to be as effective and safe as heparins in the treatment of CAT. Most bleeding events occurred in patients with high-risk bleeding neoplasms regardless of the type of anticoagulant. Considering the characteristics and satisfaction of patients using DOAC in this setting, this approach should be considered as a first choice.

Women with breast cancer that initially involves local lymph nodes have a higher risk for local recurrence or developing metastases. Recent data suggest that germline polymorphism is a significant, previously unrecognized factor in breast cancer progression and metastasis. We assessed the influence of 16 selected common germline polymorphisms in disease-free survival and overall survival among 216 women diagnosed with lymph node-positive breast cancer. The rare allele of FAS 1377G>A was significantly associated with prolonged disease-free survival (P = 0.012, risk ratio of recurrence (RR) = 0.557, 95% confidence interval (CI) = 0.353–0.878) in univariate analysis. After adjusting for known breast cancer prognostic factors the association remained significant (P = 0.050, RR = 0.500, CI = 0.309–0.809). In overall survival analysis we found a significant association of the FAS 1377G>A (P = 0.040, RR = 0.451, CI = 0.496–1.188) and IL10 592C>A polymorphisms (P = 0.020, RR = 1.707, CI = 1.087–2.680) in the univariate Cox regression. The effect remained statistically significant in the multivariate analysis for the IL10 592C>A polymorphism (P = 0.013, RR 1.841, CI 1.140–2.973). No association was found for MTHFR 677C>T, VEGF 936C>T, CCND1 870G>A, TGFB1 29T>C, FASLG 844C>T, FAS 670A>G, GPB3 825C>T, ITGA2 807C>T, ITGA2 1648G>A, ITGB3 176T>C, MMP1 -1607 1G/2G, MMP3 5A/6A, PTGS2 8473T>C, IL10 592C>A and SULT1A1 638G>A polymorphisms and disease-free survival or overall survival. Our data suggest that the FAS 1377G>A and IL10 592C>A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer.

With the advent of large collections of adaptive immune receptor recombination reads representing cancer, there is the opportunity to further investigate the adaptive immune response to viruses in the cancer setting. This is a particularly important goal due to longstanding but still not well-resolved questions about viral etiologies in cancer and viral infections as comorbidities. In this report, we assessed the T cell receptor complementarity determining region-3 (CDR3) amino acid (AA) sequences, for blood-sourced TCRs from neuroblastoma (NBL) cases, for exact AA sequence matches to previously identified anti-viral TCR CDR3 AA sequences. Results indicated the presence of anti-viral TCR CDR3 AA sequences in the NBL blood samples highly significantly correlated with worse overall survival. Furthermore, the TCR CDR3 AA sequences demonstrating chemical complementarity to many cytomegalovirus antigens represented cases with a worse outcome, including cases where such CDR3s were obtained from tumor samples. Overall, these results indicate a significant need for, and provide a novel strategy for assessing viral infection complications in NBL patients.

Malignant hematological diseases represent the most common pediatric cancer. As they cannot always be cured by chemotherapy alone, leukemia and myelodysplastic syndrome (MDS) are frequent medical indications for hematopoietic stem cell transplantation, yet even this treatment is not capable of preventing relapse for certain. Therefore, molecular markers are used to monitor minimal residual disease (MRD) to be enabled to react early to an impeding relapse. As specific markers are not always available, Wilms’ tumor gene 1 (WT1) has been suggested as a universal marker, but has not yet been established clinically. We determined the level of WT1 gene expression in 130 children, adolescents and young adults with malignant hematological diseases prior to transplantation and evaluated its impact on patients’ outcome. A real-time quantitative RT-PCR was used for this purpose. The relationship between a high level of WT1 and the cumulative incidence of relapse, event-free survival and overall survival proved to be highly significant in univariate and multivariate analyses. Forty-eight percent of all patients with high WT1 levels suffered from a relapse, whereas only eight percent showing normal WT1 levels before transplantation relapsed. The most convincing result was found for acute myeloid leukemia (AML) and MDS. We conclude that WT1 expression prior to transplantation qualifies as an independent prognostic factor and should be further evaluated for MRD monitoring. It might especially be useful for patients with AML or MDS missing specific markers.