The implication of serum HLA-G in angiogenesis of multiple myeloma.

BACKGROUND: Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM. METHODS: We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells. RESULTS: We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN. CONCLUSION: These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.

PD-L1-positive circulating endothelial progenitor cells associated with immune response to PD-1 blockade in patients with head and neck squamous cell carcinoma.

A number of the inhibitors against programmed death protein 1 (PD-1) have been approved to treat recurrent or metastatic squamous cell carcinoma of head and neck (HNSCC). The interaction between PD-1 and its ligand (PD-L1) serves as an immune checkpoint that governs cytotoxic immune effectors against tumors. Numerous clinical trials of PD-1/PD-L1 inhibitors have so far been discordant about having sufficient PD-L1 expression in the tumor as a prerequisite for a successful anti-PD-1 treatment. On the other hand, vascular endothelial cells modulate immune activities through PD-L1 expression, and thus it is possible that the expressions of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CPCs) could affect antitumor immunity as well as neoangiogenesis. Here we investigated the potential involvement of PD-L1+ CECs and PD-L1+ CPCs in PD-1 blockade treatments for HNSCC patients. We measured CD8+ T cells, CECs, and CPCs in the peripheral blood of the HNSCC patients treated by anti-PD-1 therapies. We found that their PD-L1+ CPC expression before anti-PD1 therapies was strongly correlated with treatment responses and overall survival. Moreover, if the first infusion of PD-1 inhibitors reduced ≥ 50% PD-L1+ CPCs, a significantly better outcome could be predicted. In these patients as well as in an animal model of oral cancer, Pd-l1+ CPC expression was associated with limited CD8+ T-cell infiltration into the tumors, and anti-PD-1 treatments also targeted Pd-l1+ CPCs and increased CD8+ T-cell infiltration. Our results highlight PD-L1+ CPC as a potential regulator in the anti-PD-1 treatments for HNSCC.

Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations.

The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Combination of GT90001 and nivolumab in patients with advanced hepatocellular carcinoma: a multicenter, single-arm, phase 1b/2 study.

BACKGROUND: GT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to determine the recommended phase 2 dose (RP2D) of GT90001 plus nivolumab, and assess the safety and anti-tumor activity in patients with advanced HCC. METHODS: Patients with advanced HCC were recruited from 3 centers. Eligible patients in the dose de-escalation stage received the GT90001 on day 1 of a 14-day cycle in a rolling-six design with a fixed dose of nivolumab (3.0 mg/kg). Patients in dose-expansion stage received the RP2D of GT90001 plus nivolumab. Primary endpoint was safety. Key secondary endpoint was objective response rate (ORR) as per RECIST 1.1. RESULTS: Between July 9, 2019, and August 8, 2022, 20 patients were treated (6 in phase 1b; 14 in phase 2) and evaluable for analysis. In phase 1b, no dose-limiting toxicities were observed, and GT90001 7.0 mg/kg was confirmed as the RP2D. Common grade 3/4 adverse events (AEs) were platelet count decreased (15%). No deaths due to AEs were reported. Confirmed ORR and disease control rate were 30% (95% CI, 14.6%-51.9%) and 40% (95% CI, 21.9%-61.3%), respectively. Median duration of response was not calculated (95% CI, 7.39 months to not calculated). Median progression-free survival (PFS) was 2.81 months (95% CI, 1.71-9.33), with 6-month and 12-month PFS rates of 35% and 25%, respectively. One patient with multiple intra- and extra-hepatic metastases was diagnosed with pseudo-progression upon GT90001 plus nivolumab exposure. CONCLUSIONS: GT90001 plus nivolumab has a manageable safety profile and promising anti-tumor activity in patients with advanced HCC. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03893695.

Nicotine exhausts CD8+ T cells against tumor cells through increasing miR-629-5p to repress IL2RB-mediated granzyme B expression.

The mechanism exhausting CD8+ T cells is not completely clear against tumors. Literature has demonstrated that cigarette smoking disables the immunological activity, so we propose nicotine is able to exhaust CD8+ T cells. The CD8+ T cells from healthy volunteers with and without cigarette smoking and the capacity of CD8+ T cells against tumor cells were investigated. RNAseq was used to investigate the gene profiling expression in CD8+ T cells. Meanwhile, small RNAseq was also used to search novel microRNAs involved in the exhaustion of CD8+ T cells. The effect of nicotine exhausting CD8+ T cells was investigated in vitro and in the humanized tumor xenografts in vivo. We found that CD8+ T cells were able to reduce cell viability in lung cancer HCC827 and A549 cells, that secreted granzyme B, but CD8+ T cells from the healthy cigarette smokers lost anti-HCC827 effect. Moreover, nicotine suppressed the anti-HCC827 effect of CD8+ T cells. RNAseq revealed lower levels of IL2RB and GZMB in the exhausted CD8+ T cells. We identified that miR-629-5p was increased by nicotine, that targeted IL2RB. Transfection of miR-629-5p mimic reduced IL2RB and GZMB levels. We further validated that nicotine reduced granzyme B levels using a nuclear imaging technique, and demonstrated that nicotine exhausted peripheral blood mononuclear cells against HCC827 growth in the humanized tumor xenografts. This study demonstrated that nicotine exhausted CD8+ T cells against HCC827 cells through increasing miR-629-5p to suppress IL2RB.

STAT3 induces G9a to exacerbate HER3 expression for the survival of epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancers.

BACKGROUND: HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers. METHODS: First, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer. RESULTS: BBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study. CONCLUSIONS: The present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.

Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers.

The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.

STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening.

BACKGROUND: Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes. METHODS: In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs. RESULTS: RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades. CONCLUSIONS: We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/ß-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.

Objective Sleep Measures in Inpatients With Subacute Stroke Associated With Levels and Improvements in Activities of Daily Living.

OBJECTIVE: To investigate whether objective polysomnographic measures of prevalent sleep problems such as sleep-disordered-breathing (SDB) and insomnia are associated with activities of daily living levels in inpatients at rehabilitation units. DESIGN: Retrospective and observational study. SETTING: Single rehabilitation center. PARTICIPANTS: Inpatients with subacute stroke (N=123) (61.6±13.1 years; 23.8±3.4 kg/m2; 33% women; 90.5±36.7 days post-stroke) underwent a 1-night polysomnographic study and a 1-month inpatient rehabilitation program. MAIN OUTCOME MEASURES: Admission and discharge Barthel Index (BI) scores and its change scores. RESULTS: One hundred three (92%) patients had moderate-to-severe SDB (46.7±25.1 events/h in the apnea-hypopnea index), and 24 (19.5%) patients had acceptable continuous positive airway pressure adherence. Diverse values were found for total sleep time (259±71 min), sleep efficiency (69.5%±19.3%), sleep latency (24.3±30.9 min), and wakefulness after sleep onset (93.1±74.2 min). Admission BI scores and the BI change scores were 33.8±23.2 and 10.1±9.2, respectively. The National Institutes of Health Stroke Scale (NIHSS, 10.2±5.6), available in 57 (46%) patients, was negatively associated with admission levels and gains in BI change scores (P<.001, =0.002, respectively) in a univariate analysis. In regression models with backward selection, excluding NIHSS score, both age (P=.025) and wakefulness after sleep onset (P<.001) were negatively associated (adjusted R2=0.260) with admission BI scores. Comorbidity of hypertension; sleep latency percentage of stage 1, non-rapid eye movement sleep; and desaturation events ≥4% (P<.001, 0.001, 0.021, and 0.043, respectively; adjusted R2=0.252) were negatively associated with BI score gains. CONCLUSIONS: Based on objective sleep measures, insomnia rather than SDB in inpatients with subacute stroke was associated negatively with admission levels of activity of daily living and its improvement after a 1-month rehabilitation course.

Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma.

PURPOSE: A phase II trial was conducted to evaluate the therapeutic efficacy and safety profiles of frontline concurrent chemoradiotherapy (CCRT) plus consolidation chemotherapy for patients with stage I/II nasal natural killer/T-cell lymphoma (NKTCL). PATIENTS AND METHODS: Patients with newly diagnosed, measurable stage I/II nasal NKTCL were eligible. The CCRT included two cycles of the DEP regimen (dexamethasone, etoposide, and cisplatin) every 4 wk with concurrent 5040 cGy radiation in 28 fractions for 5 wk. Patients without disease progression after CCRT were subjected to two cycles of DVIP consisted of dexamethasone, etoposide, ifosphamide, mesna, and cisplatin every 4 wk. The primary endpoint was tumor response rate, and secondary endpoints were survival and toxicities. This phase II study has been registered in the ClinicalTrials.gov (NCT00292695). RESULTS: Thirty-three patients received CCRT, and 29 patients received two cycles of consolidation DVIP after CCRT. Among the 32 evaluable patients, 20 achieved complete response and 6 achieved partial response. The overall and complete response rate was 81% (95% CI, 68-95%) and 63% (95% CI, 46-79%), respectively. The 2-yr and 5-yr progression-free survival rate for intention-to-treat population was 64% (95% CI, 47-80%) and 60% (95% CI, 39-73%), respectively; while the corresponding overall survival rate was 73% (95% CI, 57-88%) and 66% (95% CI, 50-83%), respectively. The most common treatment-related grade 3/4 adverse event was leukopenia (85%). CONCLUSION: Frontline CCRT plus consolidation chemotherapy is feasible and effective for treating localized nasal NKTCL.

Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective Phase II trial.

OBJECTIVE: This multicenter Phase II trial evaluated the toxicity/efficacy of gemcitabine plus cisplatin as first-line chemotherapy in patients with recurrent/metastatic nasopharyngeal carcinoma. METHODS: Gemcitabine 1250 mg/m(2) on Days 1 and 8 and cisplatin 75 mg/m(2) on Day 1 were administered at a 3-week interval. The primary endpoint was the response rate. Secondary endpoints included progression-free survival, overall survival, response duration and safety. RESULTS: Fifty-two patients were recruited between 2004 and 2008. The response rate was 51.9% (complete remission rate, 9.6%) in the intent-to-treat group. The median progression-free and overall survivals were 9.8 and 14.6 months, respectively. The major Grade III/IV adverse event was leucopenia (61.6%). The mean number of cycles was 6.63 ± 0.40. The regimen was well-tolerated, although one treatment-related death occurred after severe sepsis from aspiration pneumonia. CONCLUSIONS: Gemcitabine plus cisplatin is an effective, well-tolerated regimen as a first-line treatment for recurrent/metastatic nasopharyngeal carcinoma.

Posttraumatic growth and demoralization after cancer: The effects of patients' meaning-making.

OBJECTIVE: It is common for patients to experience positive and negative psychological changes (e.g., posttraumatic growth or demoralization) after being diagnosed with cancer. Although demoralization and posttraumatic growth are both related to meaning-making, little attention has been paid to the associations among these concepts. The current study investigated the relationship between demoralization, posttraumatic growth, and meaning-making (focusing on sense-making and benefit-finding during the experience of illness) in cancer patients. METHOD: Some 200 cancer patients (with lung cancer, lymphoma, or leukemia) at the MacKay Memorial Hospital in New Taipei completed the Demoralization Scale-Mandarin Version (DS-MV), the Chinese Posttraumatic Growth Inventory (CPTGI), and a self-designed questionnaire for assessing sense-making and benefit-finding. RESULTS: Demoralization was negatively correlated with posttraumatic growth, sense-making, benefit-finding, and time-since-diagnosis. Multiple regression analysis showed that meaning-making had different effects on demoralization and posttraumatic growth. The interactions of sense-making with either benefit-finding or time-since-diagnosis significantly predicted demoralization. Individuals with relatively higher sense-making and benefit-finding or shorter time-since-diagnosis experienced less demoralization. SIGNIFICANCE OF RESULTS: The suffering of cancer may turn on the psychological process of demoralization, posttraumatic growth, and meaning-making in patients. Cancer patients who evidenced higher posttraumatic growth experienced less demoralization. Trying to identify positive changes in the experience of cancer may be a powerful way to increase posttraumatic growth. As time goes by, patients experienced less demoralization. Facilitating sense-making can have similar effects. Cancer patients with less benefit-finding experience higher demoralization, but sense-making buffers this effect.

A correlational study of suicidal ideation with psychological distress, depression, and demoralization in patients with cancer.

PURPOSE: This study aims to study the effects of depression and demoralization on suicidal ideation and to determine the feasibility of the Distress Thermometer as a screening tool for patients with cancer who experience depression and demoralization, and thus to establish a model screening process for suicide prevention. METHODS: Purposive sampling was used to invite inpatients and outpatients with lung cancer, leukemia, and lymphoma. Two hundred participants completed the questionnaire, which included the Distress Thermometer (DT), Patient Health Questionnaire-9 (PHQ-9), Demoralization Scale-Mandarin Version (DS-MV), and Beck Scale for Suicide Ideation. All data obtained were analyzed using SPSS 18.0 and SAS 9.3. RESULTS: Tobit regression analysis showed that demoralization influenced suicidal ideation more than depression did (t = 2.84, p < 0.01). When PHQ-9 ≥ 10 and DS-MV ≥42 were used as criteria for the DT, receiver operating characteristic analysis revealed that the AUC values were 0.77-0.79, with optimal cutoff points for both of DT ≥5; sensitivity 76.9 and 80.6 %, respectively; and specificity of 73.9 and 72.2 %, respectively. CONCLUSIONS: Demoralization had more influence on suicidal ideation than depression did. Therefore, attention should be paid to highly demoralized patients with cancer or high demoralization comorbid with depression for the purposes of suicide evaluation and prevention. The DT scale (with a cutoff of ≥5 points) has discriminative ability as a screening tool for demoralization or depression and can also be used in clinical settings for the preliminary screening of patients with cancer and high suicide risk.

Clinical outcomes of cetuximab-based treatment for distant metastatic head and neck squamous cell carcinoma: A real-world study using Taiwan Head Neck Society registry database.

BACKGROUND: For R/M HNSCC, the differences in prognosis and treatment options between distant metastasis (DM) and locoregional recurrence, especially in the DM group, remain unclear. METHODS: From the Taiwan Head Neck Society registry database, patients who were diagnosed with R/M HNSCC and received cetuximab-based frontline therapy were collected for analysis. RESULTS: Among the enrolled patients, 59.3% (491/827) belonged to the DM group. The DM group had less primary site of oral cavity, less betel nut chewing, higher lactate dehydrogenase (LDH) levels, and higher LDH/albumin ratio compared with the non-DM group. For the patients with primary site of oral cavity and current smokers, DM coexisted with poorer outcomes. In the DM group, EXTREME-like regimen was more suitable for older patients, those with elevated LDH, and those with higher LDH/albumin ratio than TPExtreme-like regimen. CONCLUSION: DM coexisted with poorer prognosis in certain groups. LDH-associated biomarkers may aid treatment options for DM patients.

Higher complication risk of totally implantable venous access port systems in patients with advanced cancer - a single institution retrospective analysis.

BACKGROUND: Totally implantable port systems are generally recommended for prolonged central venous access in diverse settings, but their risk of complications remains unclear for patients with advanced cancer. AIM: The aim of this study was to assess the risk of port system failure in patients with advanced cancer. DESIGN: We conducted a retrospective cohort study in a comprehensive cancer centre. SETTING/PARTICIPANTS: A detailed chart review was conducted among 566 patients with 573 ports inserted during January-June, 2009 (average 345.3 catheter-days). Cox regression analysis was applied to evaluate factors during insertion and early maintenance that could lead to premature removal of the port systems due to infection or occlusion. RESULTS: Port system-related infection was significantly associated with receiving palliative care immediately after implantation (hazard ratio, HR = 7.3, 95% confidence interval, 95% CI = 1.2-46.0), after adjusting for probable confounders. Primary cancer site also impacted the occurrence of device-related infection. Receiving oncologic/palliative care (HR = 3.0, P = 0.064), advanced cancer stage (HR = 6.5, P = 0.077) and body surface area above 1.71 m(2) (HR = 3.4, P = 0.029) increased the risk of port system occlusion. CONCLUSIONS: Our study indicates that totally implantable port systems yield a higher risk of complications in terminally ill patients. Further investigation should be carefully conducted to compare outcomes of various central venous access devices in patients with advanced cancer and to develop preventive strategies against catheter failure.

Demoralization syndrome among cancer outpatients in Taiwan.

GOALS: This paper aims to explore characteristics of demoralization syndrome as well as the relationship between demoralization syndrome and psychosocial issues as seen through examinations of cancer outpatients in Taiwan. MATERIALS AND METHODS: Outpatients with different cancer types were enrolled in this study. The Demoralization Scale Mandarin Version (DS-MV), Patient Health Questionnaire, Beck Hopelessness Scale, and McGill Quality of Life Questionnaire-Taiwan Version were used as instruments. All data were analyzed using SPSS 18.0. RESULTS: Among the 234 patients studied (97 men and 223 women), the majority had cervical cancer (29.1%), followed by breast cancer (26.5%) and head and neck cancer (24.3%). The mean score of DS-MV was 31.05 (SD 14.87). The results of ANOVA analysis showed a significant effect of occupation F(4.209) = 7.145 (p < 0.001), cancer diagnosis F(7.206) = 3.795 (p < 0.001), and treatment F(8.206) = 3.553 (p < 0.001) on DS-MV. CONCLUSIONS: Demoralization syndrome was found to be related to psychosocial issues, different cancer types, and treatments. Further studies are recommended to better understand causes and impacts of demoralization in the quality of life and care of cancer patients.

Delta-volume radiomics of induction chemotherapy to predict outcome of subsequent chemoradiotherapy for locally advanced hypopharyngeal cancer.

INTRODUCTION: Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) is recommended for larynx-preserving treatment of locally advanced hypopharyngeal cancer (LAHC). However, the conventional evaluation of response is not robust enough to predict the outcome of subsequent treatments. This study aimed to develop an imaging biomarker using changes in radiomic features in invasive tumor front (ITF) by IC to predict treatment outcome of subsequent CCRT in LAHC. METHODS: From 2006 to 2018, 59 computed tomography (CT) scan images before and after IC in patients with LAHC were used to contour the gross tumor volumes (GTVs). A total of 48 delta-volume radiomics features were acquired from the absolute spatial difference of GTVs (delta-GTV) before and after IC, conceptually representing a consistent portion of ITF. Least absolute shrinkage and selection operator regression (LASSO) was used to select features for establishing the model generating radiomic score (R score). RESULTS: A model including 5 radiomic features from delta-GTV to predict better progression-free survival (PFS) of patients receiving subsequent CCRT was established. The R score was validated with all datasets (area under the curve 0.77). Low R score (<-0.16) was associated with improved PFS (p < 0.05). CONCLUSIONS: The established radiomic model for ITF from radiomic features of delta-GTV after IC might be a potential imaging biomarker for predicting clinical outcome of subsequent CCRT in LAHC.

Irradiation Mediates IFNα and CXCL9 Expression in Non-Small Cell Lung Cancer to Stimulate CD8+ T Cells Activity and Migration toward Tumors.

Irradiation-broken DNA fragments increase type I interferon and chemokines secretion in tumor cells. Since radiotherapy may augment tumor immunotherapy, we hypothesize that the chemokines increased by irradiation could recruit CD8+ T cells to suppress tumor proliferation. This study intended to unveil the secreted factors activating and recruiting CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive A549 was selected and treated by X-irradiation (IR) to identify the overexpression of chemokines associated to CD8+ T cell cytotoxicity and recruitment. A transwell assay with Alexa 488-labeled CD8+ T cells was used to evaluate CD8+ T cell motility in vitro. A nuclear imaging platform by In111-labeled nivolumab was used to track CD8+ T cells homing to tumors in vivo. The activation markers GZMB, PRF-1, and IFNγ, migration marker CD183 (CXCR3), and inhibitory marker CD274 (PD-1), were measured and compared in CD8+ T cells with A549 co-cultured, chemokines treated, and patients with late-stage lung cancer. We found that IR not only suppressed A549 proliferation but also induced IFNα and CXCL9 expression (p < 0.05). IFNα majorly increased IFNγ levels in CD8+ T cells (p < 0.05) and synergistically with CXCL9 enhanced CD8+ T cell migration in vitro (p < 0.05). We found that CXCR3 and PD-1 were down-regulated and up-regulated, respectively, in the peripheral blood CD8+ T cells in patients with lung cancer (n = 4 vs. healthy n = 3, both p < 0.05), which exhibited reduction of cell motility (p < 0.05). The in vivo nuclear imaging data indicated highly CD8+ T cells migrated to A549-induced tumors. In addition, we demonstrated that healthy PBMCs significantly suppressed the parallel tumor growth (p < 0.05) and the radioresistant tumor growth in the tumor xenograft mice (p < 0.05), but PBMCs from patients with lung cancer had lost the anti-tumor capacity. We demonstrated that IR induced IFNα and CXCL9 expression in A549 cells, leading to CD8+ T cell migration. This study unveiled a potential mechanism for radiotherapy to activate and recruit CD8+ T cells to suppress lung tumors.

Irradiation Suppresses IFNγ-Mediated PD-L1 and MCL1 Expression in EGFR-Positive Lung Cancer to Augment CD8+ T Cells Cytotoxicity.

Tumor cells express immune checkpoints to exhaust CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical applications. However, the radiotherapy-mediated molecular mechanism affecting CD8+ T cell activity remains elusive. We aimed to uncover the mechanism of radiotherapy augmenting cytotoxic CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive NSCLC cell lines were co-cultured with CD8+ T cells from healthy volunteers. Tumor cell viability and apoptosis were consequently measured. IFNγ was identified secreted by CD8+ T cells and PBMCs. Therefore, RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. The irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and western blots. We found that the co-culture of tumor cells stimulated the increase of granzyme B and IFNγ in CD8+ T, but A549 exhibited resistance against CD8+ T cytotoxicity compared to HCC827. Irradiation inhibited A549 proliferation and enhanced apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. We found that IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1 (p < 0.05). In RNAseq analysis, MCL1 was identified and increased by the IFNγ-STAT3 axis (p < 0.05). We demonstrated that irradiation specifically inhibited phosphorylation on STAT1 and STAT3 in IFNγ-treated A549, resulting in reductions of PD-L1 and MCL1 (both p < 0.05). Moreover, knockdowns of STAT3 and MCL1 increased the PBMCs-mediated anti-A549 effect. This study demonstrated that A549 expressed MCL1 to resist CD8+ T cell-mediated tumor apoptosis. In addition, we found that irradiation suppressed IFNγ-mediated STAT3 phosphorylation and PD-L1 and MCL1 expression, revealing a potential mechanism of radiotherapy augmenting immune surveillance.