Antibiotic prescription patterns during last days of hospitalized patients with advanced cancer: the role of palliative care consultation.

OBJECTIVES: Issues regarding antibiotic use in end-of-life patients with advanced cancer present a challenging ethical dilemma in academic referral centres. This study aimed to investigate the role of palliative care consultation on antibiotic prescription patterns among hospitalized patients with advanced cancer during their last days of life. METHODS: This retrospective cohort study included adult patients with metastatic solid cancer admitted to a tertiary referral hospital for at least 4 days and subsequently died and who were given antibiotics 4 days before death between January 2018 and December 2021. Patients were divided into palliative care consultation (PC) and non-consultation (non-PC) groups. The outcomes were the proportion of patients who received antibiotic combination treatment, antibiotic escalation and antibiotic de-escalation within 3 days of death. Propensity score analysis with the inverse probability of the treatment weighting method was used to compare the outcomes. RESULTS: Among the 1177 patients enrolled, 476 (40.4%) received palliative care consultation and 701 (59.6%) did not. The PC group received considerably less antibiotic combination treatment (49.0% versus 61.1%, adjusted OR: 0.69, 95% CI: 0.53-0.90, P = 0.006) and antibiotic escalation (15.8% versus 34.8%, adjusted OR: 0.41, 95% CI: 0.30-0.57, P < 0.001) than the non-PC group. Additionally, the PC group reported significantly higher antibiotic de-escalation (30.7% versus 17.4%, adjusted OR: 1.74, 95% CI: 1.28-2.36, P < 0.001). CONCLUSION: Receiving palliative care consultation may minimize aggressive antibiotic prescription patterns in the last days of patients with advanced cancer in an academic referral centre setting.

Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years' real-world experience in a single institute.

Although the current standard of care for diffuse large B-cell lymphoma (DLBCL) is six cycles of rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone combination chemotherapy (R-CHOP), a larger than expected number of patients cannot complete planned six cycles for various reasons in the real world. We aimed to evaluate the prognosis of patients with DLBCL after incomplete treatment by analyzing the chemotherapy response and survival according to the cause of discontinuation and the number of cycles. We analyzed a retrospective cohort of patients diagnosed with DLBCL who underwent incomplete cycles of R-CHOP at Seoul National University Hospital and Boramae Medical Center from January 2010 to April 2019. A total of 1183 patients were diagnosed with DLBCL, of which 260 (22%) did not complete six cycles of R-CHOP. The most common cause of discontinuation of chemotherapy was life-threatening infection, and the most common pathogen was Pneumocystis jirovecii. Overall survival (OS) and progression-free survival (PFS) were significantly better in patients who achieved complete response (CR) or partial response (PR) at the first response evaluation. Patients underwent three or more cycles of chemotherapy had a longer OS than those who did not. In patients with limited-stage disease, consolidative radiotherapy showed a significant improvement in OS and PFS. Advanced stage, high comorbidity score, and poor primary response to chemotherapy were poor prognostic factors in patients with unplanned treatment shortening. This study provides real-world outcomes for patients who could not complete the planned six cycles of R-CHOP.

The impact of palliative care consultation on reducing antibiotic overuse in hospitalized patients with terminal cancer at the end of life: a propensity score-weighting study.

OBJECTIVES: A substantial number of hospitalized patients with terminal cancer at the end-of-life phase receive antibiotics, even with imminent death. We evaluated the impact of palliative care consultation on antibiotic use in hospitalized patients with terminal cancer during the end-of-life phase. METHODS: We identified adult patients with metastatic solid cancer who died at a tertiary medical centre in Seoul, Republic of Korea, following at least 4 days of hospitalization (January 2018-December 2020). Patients were divided into palliative and non-palliative care consultation groups. Propensity score-weighted, multivariable logistic regression analysis was used to compare the proportion of patients receiving antibiotics within 3 days before death between the two groups. RESULTS: Among 1143 patients analysed, 940 (82.2%) received antibiotics within 3 days before death. The proportion of patients receiving antibiotics was significantly lower (propensity score-weighted P < 0.001) in the palliative care consultation group (344/468; 73.5%) than in the non-palliative care consultation group (596/675; 88.3%). The decrease in the proportion of patients receiving antibiotics in the palliative care consultation group was significant for a carbapenem (42.4% versus 22.4%; P < 0.001), a glycopeptide (23.3% versus 11.1%; P < 0.001) and a quinolone (30.5% versus 19.4%; P = 0.012). In the multivariable logistic regression analysis, receiving palliative care consultation (adjusted OR 0.46, 95% CI 0.33-0.65; P < 0.001) was independently associated with reduced antibiotic use during the end-of-life phase. CONCLUSIONS: Palliative care consultation may reduce aggressive antibiotic use in hospitalized patients with terminal cancer during the end-of-life phase.

Aggressiveness of care in the last days of life in the emergency department of a tertiary hospital in Korea.

BACKGROUND: High-quality end-of-life (EOL) care requires both comfort care and the maintenance of dignity. However, delivering EOL in the emergency department (ED) is often challenging. Therefore, we aimed to investigate characteristics of EOL care for dying patients in the ED. METHODS: We conducted a retrospective cohort study of patients who died of disease in the ED at a tertiary hospital in Korea between January 2018 and December 2020. We examined medical care within the last 24 h of life and advance care planning (ACP) status. RESULTS: Of all 222 disease-related mortalities, 140 (63.1%) were men, while 141 (63.5%) had cancer. The median age was 74 years. As for critical care, 61 (27.5%) patients received cardiopulmonary resuscitation, while 80 (36.0%) received mechanical ventilation. The absence of serious illness (p = 0.011) and the lack of an advance statement (p < 0.001) were both independently associated with the receipt of more critical care. Only 70 (31.5%) patients received comfort care through opioids. Younger patients (< 75 years) (p = 0.002) and those who completed life-sustaining treatment legal forms (p = 0.001) received more comfort care. While EOL discussions were initiated in 150 (67.6%) cases, the palliative care team was involved only in 29 (13.1%). CONCLUSIONS: Patients in the ED underwent more aggressive care and less comfort care in a state of imminent death. To ensure better EOL care, physicians should minimize redundant evaluations and promptly introduce ACP.

Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues.

BACKGROUND: Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR. METHODS: Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples. RESULTS: The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8+ tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8+ T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient. CONCLUSIONS: Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.

Severe late dysphagia after multimodal treatment of stage III/IV laryngeal and hypopharyngeal cancer.

BACKGROUND: Long-term side effects after radiotherapy for organ preservation 'could deteriorate' the laryngeal function. This study intended to identify the incidence of severe late dysphagia following the multimodal treatment for stage III/IV laryngeal and hypopharyngeal cancer 'to evaluate the function of larynx'. METHODS: The medical records of patients successfully treated for laryngeal and hypopharyngeal cancer with a multimodal approach, including radiotherapy, were retrospectively analyzed. 'Functional larynx was defined as tolerable oral diet without severe late dysphagia or tracheostoma'. RESULTS: The study included 99 patients with a median follow-up period of 72 months. 'Tracheostomy during the follow-up period was required in only one patient due to aspiration pneumonia, and dysphagia is the main determinant for functional larynx'. The probability of maintaining functional larynx was 63% for 10 years, when the treatment was started with radiotherapy or concurrent chemoradiotherapy. In upfront surgery (operation first and adjuvant radiotherapy/concurrent chemoradiotherapy) group, 37% of patients required total laryngectomy as primary treatment and 43% of patients could maintain laryngeal function for 10 years. And severe late dysphagia in the latter group developed mainly after laryngeal preservation surgery. The patients aged ≥65 years showed significantly higher incidence of dysphagia. Severe late dysphagia was very rare in laryngeal cancer successfully cured with radiotherapy/concurrent chemoradiotherapy (1/25, 4%); however, it gradually increased over time in hypopharyngeal cancer patients showing a statistically significant difference from laryngeal cancer patients (P = 0.040). CONCLUSION: Severe late dysphagia occurred in 19.2% of patients treated for laryngeal and hypopharyngeal cancers, regardless of whether treatment started with radiotherapy/concurrent chemoradiotherapy or surgery.

A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

LESSONS LEARNED: Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results. BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of ASPSCR1 to the TFE3 transcription factor. Because this results in the upregulation of angiogenesis-related transcripts, antiangiogenic drugs have been used in ASPS patients. METHODS: This open-label, single-arm, multicenter, investigator-initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator-assessed overall response rate (ORR), and secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). 68Ga-RGD (Arg-Gly-Asp) positron emission tomography (PET) scan and gene expression profiling using NanoString platform were performed for biomarker analysis. RESULTS: Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow-up of 33 months (range 18.7-39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4-7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea. CONCLUSION: Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS.

A Phase II Study of Genexol-PM and Cisplatin as Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma.

LESSONS LEARNED: Induction chemotherapy with Genexol-PM and cisplatin demonstrated modest tumor response in locally advanced head and neck squamous cell carcinoma.Considering favorable toxicity profiles and promising survival data, further studies on this regimen are warranted in patients with head and neck squamous cell carcinoma. BACKGROUND: Genexol-PM is a polymeric micellar formulation of paclitaxel without Cremophor EL. We investigated the efficacy and safety of Genexol-PM plus cisplatin as induction chemotherapy (IC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). METHODS: Patients received Genexol-PM (230 mg/m2) and cisplatin (60 mg/m2) every 3 weeks as IC. After three cycles of IC, definitive treatment of either concurrent chemoradiotherapy (CCRT) with weekly cisplatin (30 mg/m2) or surgery was performed. The primary endpoint was overall response rate (ORR) after IC. RESULTS: Of 52 patients enrolled, 47 completed three cycles of IC, and the ORR was 55.8% (95% confidence interval, 42.3-69.3). Although there was one treatment-related death, toxicity profiles to Genexol-PM and cisplatin were generally favorable, and the most common grade 3 or 4 toxicities were neutropenia (15.4%), anorexia (7.7%), and general weakness (7.7%). Fifty-one patients received definitive treatment (CCRT [n = 44] or radical surgery [n = 7]). The rate of complete response following CCRT was 81.8% (36/44). After a median follow-up of 39 months, estimates of progression-free survival (PFS) and overall survival (OS) at 3 years were 54.3% and 71.3%, respectively. CONCLUSION: IC with Genexol-PM and cisplatin demonstrated modest tumor response with well-tolerated toxicity profiles for patients with LA-HNSCC.

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

BACKGROUND: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines. MATERIALS AND METHODS: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907). RESULTS: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies. CONCLUSION: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment. IMPLICATIONS FOR PRACTICE: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.

NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors.

BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells. MATERIALS AND METHODS: TKI-resistant NSCLC cells (H3122CR1, H3122LR1, H3122CR1LR1, PC-9GR, PC-9ER, EBC-CR1 and EBC-CR2) were established from NCI-H3122 (EML4-ALK fusion), PC-9 (EGFR exon19 deletion) and EBC-1 (MET amplification) after continuous exposure to crizotinib, ceritinib, gefitinib, erlotinib and capmatinib. Expression of ligands for natural killer (NK) cell receptors and total EGFR were analyzed using flow cytometry. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) using anti-EGFR monoclonal antibody (mAb) cetuximab were measured using NK92-CD16 as effectors and detected using the 51Chromium-release assay. RESULTS: We found that NK92-CD16 cells preferentially killed TKI-resistant NSCLC cells when compared with their parental NSCLC cells. Mechanistically, intracellular adhesion molecule 1 (ICAM-1) was up-regulated in the TKI-resistant NSCLC cells and patients' tumors, and the ICAM-1 up-regulated cancer cells lines were less susceptible to NK cytotoxicity by blocking ICAM-1. Moreover, NK92-CD16 cell-induced cytotoxicity toward TKI-resistant NSCLC cells was enhanced in the presence of cetuximab, an EGFR-targeting mAb. CONCLUSION: These data suggest that combinational treatment with NK cell-based immunotherapy and cetuximab may be promising for patients with TKI-resistant NSCLC.

Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.

BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells. RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.

Correction to: The impact of caregiver's role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver's disclosure of terminal disease status.

In the original publication of the article, the incorrect grant number HC13C1391 was published in the acknowledgement section. The correct grant number is HC15C1391.

Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody.

We investigated inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) that may predict the response to anti-PD-1 (programmed cell death protein 1) antibody therapy. Data from 54 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibodies were retrospectively analyzed. The NLR was assessed at baseline and 6 weeks after the start of treatment (post-treatment). Eighteen of 54 patients (33.3%) had objective responses to treatment. Older age, absence of brain metastasis, low post-treatment NLR (< 5), and immune-related adverse events were significantly associated with response. Patients with a high post-treatment NLR (≥ 5) had significantly shorter progression-free survival (PFS) than those with a low post-treatment NLR (median, 1.3 vs. 6.1 months, p < 0.001). Multivariate analysis demonstrated that high post-treatment NLR [hazard ratio (HR) 15.1, 95% confidence interval (CI) 1.5-50.1, p < 0.001], liver metastasis (HR 4.9, 95% CI 1.9-12.4, p = 0.001), and brain metastasis (HR 3.2, 95% CI 1.3-8.2, p = 0.013) were independent prognostic factors of shorter PFS. Overall survival (OS) was significantly different in patients with high and low post-treatment NLRs (median, 2.1 vs. 14.0 months, p < 0.001). A high post-treatment NLR remained an independent prognostic factor for OS in multivariate analysis (HR 3.9, 95% CI 1.6-9.2, p = 0.003). The NLR at 6 weeks after treatment initiation was a prognostic marker in patients with advanced NSCLC treated with anti-PD-1 antibody. Further studies are warranted to evaluate the role of the 6-week NLR as a predictor in anti-PD-1 antibody treatment.

CD21-independent Epstein-Barr virus entry into NK cells.

Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignant disease that is associated with Epstein-Barr viral (EBV) infection. To date, the mechanism of viral entry into NK cells remains uncertain. Here, we investigated this mechanism using human NK cells in vitro. CD21 mRNA expression, an EBV-entry receptor, was transiently detected in NK cells after exosome treatment, and levels decreased after further culture. CD21 protein expression was also transiently transferred to NK cells after co-culture with an EBV-positive Burkitt lymphoma cell line (Raji) via trogocytosis. However, EBV did not infect NK cells through CD21-mediated trogocytosis. Unexpectedly, when NK cell leukemia cells, as well as primary NK cells, were treated with viral supernatant, EBV genes, but not RNA, were detected in the NK cells, at latency stage 0. Therefore, these results suggest that EBV-NK cell infection results from the direct transfer of viral episomes, independent of EBV-positive B cells.

Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal Type.

Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3A573V, two JAK3H583Y, and one JAK3G589D mutation. Proliferation of Ba/F3 cells transduced with novel JAK3 mutations (JAK3H583Y and JAK3G589D) was independent of IL-3 and was inhibited by the JAK3 inhibitor tofacitinib (means ± SD drug concentration causing a 50% inhibition of the desired activity, 85 ± 10 nmol/L and 54 ± 9 nmol/L). Ribbon diagrams revealed that these JAK3 pseudokinase domain mutations were located at the pseudokinase-kinase domain interface. Although phosphorylated STAT3 was overexpressed in 35 of 68 patients with NTCL (51.4%), a STAT3 mutation (p.Tyr640Phe; STAT3Y640F) at the SRC homology 2 domain was detected in 1 of the 63 patients (1.5%). A STAT3 inhibitor was active against STAT3-mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3- or STAT3-mutant NTCL.

The impact of caregiver's role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver's disclosure of terminal disease status.

PURPOSE: The objective of this study was to investigate the impact of caregivers' role preference in decision making on conflicts and psychiatric distresses. METHODS: The responses of 406 caregivers of terminal cancer patients enrolled in a trial determining the efficacy of a decision aid focused on the disclosure of terminal disease status were included in this secondary analysis. The outcomes include the change scores of the Decision Conflict Scale (DCS) and depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS) at the 1 and 3 months from baseline. The linear mixed model was employed to discover the impact of caregivers' decisional role preference on the outcomes. FINDINGS: Of the 406, 137 (33.7%) showed an active role preference and 269 (66.3%) showed a passive role preference. In the post hoc analysis of the adjusted differences of change scores between passive caregivers who received decision aid (passive-decision aid) and active caregivers with decision aid (active-decision aid), non-significant differences were observed in the DCS. However, at the 3-month, the change scores of the HADS depression subscale increased by 4.43 (effect size, 0.71) and those of the HADS anxiety subscale increased by 4.14 (effect size, 0.61) in the passive-decision aid group than in active-decision aid group, showing moderate to large difference. CONCLUSIONS: These findings suggest that information might be ethically recommended in a format that is interactive and tailored to how much an individual wishes to be involved in the decision-making process.

Optimal timing of influenza vaccination during 3-week cytotoxic chemotherapy cycles.

BACKGROUND: Cytopenia occurs frequently during cytotoxic chemotherapy. Little is known about the optimal timing of influenza vaccination for patients receiving chemotherapy. This study compared the immunogenicity of an influenza vaccine administered concurrently with chemotherapy (day 1) and within the cytopenic period (day 11) during 3-week cytotoxic chemotherapy cycles. METHODS: Adult patients with solid cancer undergoing scheduled 3-week cytotoxic chemotherapy were randomly assigned to receive the 2014-2015 seasonal influenza vaccine on day 1 or 11 during the chemotherapy cycle. Patients were stratified by their age (<60 and ≥60 years) and previous influenza vaccination status. Antibody responses to influenza vaccine strains H1N1, H3N2, and B were measured before and 21 to 28 days after vaccination with a hemagglutination inhibition antibody assay. RESULTS: Ninety-seven patients were randomized into a day 1 group (n = 43) or a day 11 group (n = 54). Eighty-three patients were included in the final analysis. The mean age was 54 (± 11) years. Cancer types included breast (61%) and lung cancer (30%). Baseline characteristics were not significantly different between the groups. Seroprotection rates after vaccination were also not significantly different for the day 1 and 11 groups (strain H1N1, 67% vs 75% [P = .403]; strain H3N2, 77% vs 80% [P = .772]; strain B, 21% vs 27% [P = .472]). Seroconversion rates and postvaccination geometric mean titers were also similar for the groups. Vaccine-related adverse events were more common in the day 11 group (13% vs. 32%; P = .040). CONCLUSIONS: The antibody responses to influenza vaccination on days 1 and 11 during a 3-week cytotoxic chemotherapy cycle were comparable. Influenza vaccination can be performed concurrently with cytotoxic chemotherapy or during the cytopenic period. Cancer 2017;123:841-48. © 2016 American Cancer Society.

Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation.

Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL-1ß + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1ß + IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1ß+ IL-23, and IL-2 expanded ILC3s while IL-1ß+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC3s maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use.