Cancer Research and Clinical Oncology

Stuttering as the first sign of CAR-T-cell-related encephalopathy syndrome (CRES)

Combined loss of TFF3 and PTEN is associated with lethal outcome and overall survival in men with prostate cancer Abstract Background Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease. Design 228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort. Results TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15–16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67–3.18, p < 0.0001) and (HR 3.99, CI: 2.43–6.56; p < 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49–3.62; p < 0.0001) and PCSM (HR = 3.44, CI: 1.75–6.78, p < 0.0001). Conclusion The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease.

Patient-reported outcomes and health-related quality of life for cetuximab versus bevacizumab in metastatic colorectal cancer: a prospective cohort study Abstract Purpose Uncertainty exists regarding Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab or bevacizumab. We conducted a prospective cohort study comparing PROs and HRQoL from both therapies. Methods We assessed PROs and HRQoL from patients treated with cetuximab or bevacizumab using QLQ-C30 and QLQ-CR29 questionnaires at three sequential time points, including baseline. Global Health Status (GHS), functional and symptom scales, and Overall Treatment Utility (derived from clinical and patient-reported outcomes) were compared for the two treatment strategies. Results Between January 2017 and April 2018, 44 patients were allocated to cetuximab (n = 19) or bevacizumab (n = 25). Except for RAS mutation status, patient baseline characteristics were generally well balanced across treatment groups. A higher proportion of patients experienced a deterioration in GHS (≥ 10%) in cetuximab arm − 53.8% (95% CI 25.1–80.8%) at 6 weeks and 66.7% (95% CI 29.9–92.5%) at 12 weeks—comparing to bevacizumab cohort: 18.2% (95% CI 5.2–40.3%) at 6 weeks and 12.5% (95% CI:1.6–38.3%) at 12 weeks. Treatment utility rates at 6 and 12 weeks were, respectively, 88.6% and 69.8% for bevacizumab, compared to 49% and 19.1% for cetuximab (p = 0.004), a difference confirmed in subset analyses. Conclusions In patients with mCRC, cetuximab-containing regimens led to a progressive negative impact on PROs and global HRQoL, when compared to baseline and bevacizumab. Future research is needed to confirm these results. Our findings demonstrate the value of PROs when assessing comparative effectiveness of different treatment regimens.

HALFMOON TomoTherapy (Helical ALtered Fractionation for iMplant partial OmissiON): implant-sparing post-mastectomy radiotherapy reshaping the clinical target volume in the reconstructed breast Abstract Purpose To report the dosimetric feasibility of the radiation technique HALFMOON (Helical ALtered Fractionation for iMplant partial OmissiON) for post-mastectomy radiation therapy (PMRT) in intermediate–high-risk breast cancer patients with implant-based immediate breast reconstruction, where the clinical target volume (CTV) does not include the whole implant (implant-sparing approach). Methods In the HALFMOON technique, the CTV consisted of skin, subcutaneous tissues, and pectoralis major muscle, excluding the implant, chest wall muscles, and rib plane. The HALFMOON plans were compared with conventionally contoured CTV plans, in which the whole implant, chest wall muscles, and ribs plane were included in the CTV, in a ratio 1:3. All patients underwent hypofractionated treatment of 40.05 Gy/15 fractions, using helical Tomotherapy®. Results Eighteen patients undergoing HALFMOON technique were compared to 54 subjects treated with conventionally contoured CTV plans. No difference was found in the planning target volume coverage between the two groups. Conversely, a statistically relevant dose reduction in HALFMOON patients was observed for ipsilateral lung (D15%, p < 0.0001; D20%, p < 0.0001; D35%, p = 0.003), contralateral lung (D20%, p = 0.048), contralateral breast (D15%, p = 0.031; D20%, p = 0.047), and stomach (Dmean, p = 0.011). Regarding the implant, V90% and D50% decreased by 46% and 8%, respectively, in the HALFMOON plans (p < 0.0001). Conclusion The HALFMOON approach is technically feasible and resulted in high-dose conformity of the target with a significant reduction of radiation dose delivered to implant and other organs. A clinical study is needed to assess the impact on reconstruction cosmetic outcome and local control.

Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia Abstract Purpose Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics. Methods The anti-leukemic effects of IFNα and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFNα-2b and human IFNα-Le in MOLM-13 cells by IMAC/2D DIGE/MS analysis and phospho-flow cytometry, and in primary healthy and AML patient-derived PBMCs by CyTOF. In vivo, IFNα-Le and VPA efficacy were investigated in the immunodeficient NOD/Scid IL2γ−/− MOLM-13Luc+ mouse model and the syngeneic immunocompetent BNML rat model. Results IFNα-2b and IFNα-Le differed in the modulation of phospho-proteins involved in protein folding, cell stress, cell death and p-STAT6 Y641, whereas VPA and IFNα-Le shared signaling pathways involving phosphorylation of Akt (T308), ERK1/2 (T202/T204), p38 (T180/Y182), and p53 (S15). Both IFNα compounds induced apoptosis synergistically with VPA in vitro. However, in vivo, VPA monotherapy increased survival, but no benefit was observed by IFNα-Le treatment. CyTOF analysis of primary human PBMCs indicated that lack of immune-cell activation could be a reason for the absence of response to IFNα in the animal models investigated. Conclusions IFNα-2b and IFNα-Le showed potent and synergistic anti-leukemic effects with VPA in vitro but not in leukemic mouse and rat models in vivo. The absence of IFNα immune activation in lymphocyte subsets may potentially explain the limited in vivo anti-leukemic effect of IFNα-monotherapy in AML.

Assessment of tumor-associated immune cells in laryngeal squamous cell carcinoma Abstract Purpose This study investigated the characteristics of tumor-associated immune cells (TAICs) in laryngeal squamous cell carcinoma (LSCC) and their correlation with clinicopathological variables. Methods The immune cell infiltrates of 71 specimens of stages I–IV LSCC were examined. The density of TAICs expressing CD3, CD4, CD8, CD68, and CD163 was assessed using immunohistochemical staining and image analysis in peritumoral and intratumoral regions. Results Higher densities of CD3+ and CD8+ cell and lower densities of CD68+ and CD163+ cell infiltrations were found in early tumor stages than in late tumor stages. A higher percentage of patients with strong CD3+ and CD8+ immune cell infiltration and weak CD68+ cell infiltration in both tumor regions presented with T1 stage tumors compared with T4 stage tumors. Further, strong CD68+ cells infiltration in both regions was observed in a greater number of patients who had a relapse, while a weak CD3+ cells infiltration in both regions was found in a greater number of patients with nodal lymphatic metastasis. The univariate analysis showed that a high density of peritumoral CD3+ and CD8+ immune cells in both regions was significantly associated with a favorable overall survival (OS) (P = 0.004; P = 0.006; P = 0.042). In contrast, a high density of intratumoral CD68+ cells and peritumoral CD163+ cells was significantly associated with poor OS durations (P = 0.026; P = 0.030). The multivariate analysis demonstrated that a high density of peritumoral CD163+ cells correlated with poor OS after adjusting for tumor stage, recurrence, and nodal lymphatic metastasis (P = 0.034). This study found different patterns of TAIC infiltration in LSCC. The density and location of TAICs infiltration correlated with the clinicopathological characteristics of LSCC. Conclusion A combined analysis of the density of TAICs and their location may help predict patient survival and response to checkpoint inhibitors.

Safety and efficacy of 125 I brachytherapy for bilateral lung recurrences from hepatocellular carcinoma after resection or ablation Abstract Purpose To evaluate the safety and efficacy of 125I brachytherapy to treat bilateral lung recurrences from hepatocellular carcinoma (HCC) after resection or ablation. Materials and methods We retrospectively recruited 95 patients with bilateral lung recurrences from hepatocellular carcinoma (HCC) after resection or ablation who had received 3–6-month sorafenib with or without stereotactic body radiotherapy (SBRT), from October 2011 to January 2015; patients were then randomly divided into two groups, 44 patients received computed tomography (CT)-guided 125I brachytherapy (group A), and 51 patients were treated with supportive and symptomatic treatments (group B). Results The median survival time was 19 months (range of 3–36 months). The local response rate (LRR) at 3, 6, 12, 18, 24, 30 and 36 months in group A was 81.8%, 65.9%, 59.1%, 45.0%, 38.6%, 22.7%, 11.4%, respectively, and 64.7%, 47.1%, 33.3%, 25.4%, 15.7%, 11.7%, 7.8%, respectively, in group B (P < 0.05). The mean progression-free survival time (PFST) and overall survival (OS) of group A were significantly longer than those of group B. Alpha fetoprotein (AFP) and tumor size were independent factors that affected the PFST and OS, normal AFP levels and less than 1-cm tumor diameter had better PFST and OS (P < 0.05). No massive bleeding or serious complications occurred. Conclusion CT-guided 125I brachytherapy is safe and effective for the treatment of bilateral lung recurrences from HCC after resection or ablation.

Information needs, communication and usage of social media by cancer patients and their relatives Abstract Purpose The aim of this study was to evaluate cancer patients' need for information, their communication and usage of social media. Methods We developed a standardized questionnaire comprising sections on information needs, communication behavior and usage of social media with respect to cancer and combined this with a validated instrument on eHealth literacy for patients. This questionnaire was provided online and with the help of bloggers and leaders of social media groups, distributed in their networks. Results The Internet was the most important information source (n = 308; 77.4%). Yet, most of the participants wanted to get information from their doctor (n = 342; 85.9%). With respect to trust in a source of information, oncologists were named most often (n = 285; 71.6%). On the one hand, many participants got in contact with others, especially peers, via social media (n = 319; 80.3%) with a growing bond to their family members on the other hand (n = 324; 81.6%). The cancer diagnosis was an impulse for starting with active participation in social media for some participants (n = 196; 49.2%). Conclusions With social media gaining importance as source of information for patients, improving the quality of information in these networks is an important task in health care systems.

Neutrophil extracellular traps enhance procoagulant activity in patients with oral squamous cell carcinoma Abstract Background Hypercoagulability is a major cancer-associated complication linked to poor patient prognosis. The production of neutrophil extracellular traps (NETs) is increasingly found to be linked with the development and metastasis of cancer, as well as with thrombi formation in cancer patients. We hypothesized that the neutrophil NET release may be triggered by specific cytokines in oral squamous cell carcinoma (OSCC) patients, thereby predisposing them to a hypercoagulable state. Moreover, we have evaluated the interaction between NETs and endothelial cells (ECs). Methods NET procoagulant activity was assessed based on fibrin and purified coagulation complex production assays, as well as by measuring coagulation time (CT). We further used confocal microscopy to quantify the exposure of phosphatidylserine (PS), fibrin strands, and cell FVa/Xa binding. Results OSCC patients with stage III/IV exhibited elevated plasma NET levels compared to stage I/II or CTR (all P < 0.05). Neutrophils from OSCC patients are predisposed to amplified NET release compared to those from CTR. Furthermore, depleting IL-8, IL-6, and TNF-α led to a reduction in NET release in the plasma. OSCC NETs increased thrombin and fibrin generation and decreased CT significantly (P < 0.05). When NETs were isolated and used to treat ECs, these cells exhibited disrupted morphology by retracting from their cell–cell junctions and convert to a procoagulant phenotype. These effects could be attenuated by approximately 70% using DNase I. Conclusions Our findings are consistent with a model wherein OSCC drives a systemic inflammatory state, which, in turn, drives neutrophils to prime and release NETs, which drive the development of a hypercoagulable state. Intervening in this process may be a viable means of disrupting these undesirable coagulation dynamics in stage III/IV OSCC patients.

Accuracy of Raman spectroscopy in discrimination of nasopharyngeal carcinoma from normal samples: a systematic review and meta-analysis Abstract Objectives The aim of this review was to systematically evaluate the diagnostic accuracy of Raman spectroscopy (RS) in the identification of nasopharyngeal carcinomas from normal nasopharyngeal tissue. Methods We searched six databases (PubMed, Embase, Cochrane Library, Web of Science, Scopus and CNKI) up to September 2018 for all published studies that assessed the diagnostic accuracy of RS in the detection of nasopharyngeal carcinomas. Non-qualifying studies were screened out in accordance with the specified exclusion criteria and relevant information about the diagnostic performance of RS extracted. A random effects model was adopted to calculate the pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic threshold and diagnostic odds ratio (DOR). Additionally, we conducted a summary receiver-operating characteristic (SROC) curve analysis and threshold analysis, reporting area under the curve (AUC) to evaluate the overall performance of RS. Results Three studies examined RS analysis in vivo, the pooled sensitivity and specificity of RS of which were 0.90 and 0.91, respectively, with an AUC of 0.9617. Eighteen studies assessed ex vivo samples, for which RS exhibited particularly high accuracy for the analysis of blood plasma. Conclusions RS was demonstrated to be a reliable technique for the detection of nasopharyngeal carcinoma with high accuracy, but additional studies are required to improve its performance and expand its application in ex vivo detection.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com