An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.

First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.

Exploring return to work for patients with head and neck cancer.

BACKGROUND: The number of survivors of head and neck cancer (HNC) has steadily increased due to major advances in cancer care. However, cancer survivors who experience job loss face different challenges regarding return to work (RTW). Relatively few studies have integrated the experience encountered by patients. OBJECTIVE: This mixed-methods study aimed to explore the experience and challenges of RTW in patients with HNC. METHODS: Data were collected with structured questionnaires (n = 120) and semi-structured face-to-face interviews (n = 12). RESULTS: Relationships were found between patient's physical status, perceived stress, and social support. Patients who continued work, or not, had significant differences in reported physical function and stress. Four themes emerged from the qualitative data, including the perceived meaning of work, challenges for RTW, preparing for RTW, and social support. After diagnosis and treatment, patients perceived the meaning of work, such as personal value, responsibility, and financial need. They faced many challenges to RTW, including declining physical strength, workload, schedule rearrangement, speech difficulty, and changed appearance. In order to RTW, they prepared extensively and needed support from family and friends. CONCLUSION: This study revealed the experiences and challenges of RTW patients with HNC. The results allowed us to identify patients' concerns and ways that healthcare providers could improve the RTW process. Future studies may develop tailored approaches for RTW in healthcare and government policies.

Simulation education utilizing phantom and angle reference guide in pulmonary nodule CT localization.

Objective: The incidence of sub-centimeter pulmonary nodules has been increasing along with the use of low-dose computed tomography (LDCT) as a screening tool for early lung cancer detection. In our institution, pulmonary nodule computed tomography-guided localization (PNCL) is performed preoperatively with the laser angle guided assembly (LAGA), an angle reference device. This study aims to investigate the efficacy of postgraduate education in a phantom simulation of PNCL, with or without LAGA. Setting design: This prospective study was conducted in an academic hospital in Taiwan. Seven thoracic surgery residents and three experienced senior physicians were recruited to perform PNCL using a phantom simulation, with or without LAGA, for five nodules each and complete a questionnaire. Performance data were collected. χ2 tests, Mann-Whitney U test, univariate and multivariate linear regression were used for statistical analyses. Results: The confidence level increased from median 7[range 1, 9] to 8, range [6,9] (p = 0.001) before and after the simulation education course. The scores of enhanced PNCL ability and course satisfaction were as high as 8 [5,9], and 9 [7,9]. LAGA enabled broader puncture angles (with 27.5° [0°,80°]; without 14° [0°, 80°], p = 0.003), a lower puncture frequency (with 1 [1,4]; without 2 [1,5], p < 0.001), and a smaller angle deviation (with 3°[ 0°,8°]; without 5°[ 0°,19°], p = 0.002). Pleural depth in millimeters was associated with increased puncture frequency (0.019[0,010,0.028]) and procedure time (0.071'[ 0.018,0.123']. The PNCL-experienced physicians performed the procedure in less time (-2.854'[-4.646',1.061']. The traverse direction toward the mediastinum diminished the frequency (toward 1[ 1,3]; away 1 [1,5], p = 0.003) and time (toward 7.5'[2',18]'; away 9'[ 3',31'], p = 0.027). The learning curve did not improve procedure performance after ten PNCL simulation rounds. Conclusions: The phantom PNCL simulation education course increased the confidence level, enhanced residents' skill acquisition, and promoted learning satisfaction. The angle reference device helped improve the outcomes of the puncture frequency and reduced angle deviation.

Comparison of three-dimensional and two-dimensional thoracoscopic segmentectomy in lung cancer.

BACKGROUND: Thoracoscopic segmentectomy is considered to be a safe and effective procedure for early lung cancer. A three-dimensional (3D) thoracoscope can provide high resolution and accurate images. We compared the outcomes from using two-dimensional (2D) and 3D video systems in thoracoscopic segmentectomy for lung cancer. METHODS: The data of consecutive patients diagnosed with lung cancer that underwent 2D or 3D thoracoscopic segmentectomy in Changhua Christian Hospital from January 2014 to December 2020 were retrospectively analyzed. Tumor characteristics and perioperative short-term outcomes (operative time, blood loss, incision numbers, length of stay and complication) were compared between 2D and 3D thoracoscopic segmentectomy. RESULTS: Among the 192 patients, 68 patients underwent segmentectomy with a 2D thoracoscopic system and 124 patients had 3D thoracoscopic surgery. Patients undergoing 3D thoracoscopic segmentectomy had a shorter operative time (174.19 ± 64.63 min vs. 207.06 ± 72.99 min, p = 0.002), less blood loss (34.40 ± 43.58 ml vs. 50.81 ± 57.61 ml, p = 0.028), fewer incisions (1.50 ± 0.716 vs. 2.19 ± .058, p < 0.001) and a shorter length of stay (5.67 ± 3.44 days vs. 8.18 ± 11.862 days, p = 0.029). The postoperative complications were similar between the two groups. Surgical mortality was not found in any patient. CONCLUSION: Our finding suggests that the incorporation of a 3D endoscopic system could facilitate thoracoscopic segmentectomy in lung cancer patients.

Relationship between Preoperative Nutritional Status and Clinical Outcomes in Patients with Head and Neck Cancer.

The nutritional status in cancer patients is related to cancer survival and surgical outcome. The objective of this study was to examine the relationship between preoperative prognostic nutritional index (PNI) and post-operative clinical outcomes in head and neck cancer (HNC) patients. A total of 1282 head and neck cancer patients receiving surgical resection in Changhua Christian Hospital between 1 January 2010 and 30 August 2021 were recruited in the final analysis after undergoing propensity score matching analysis. The logistic regression model was used to assess the association of the PNI group with overall and various complications. The patients in the high PNI group had a significant lower incidence of overall complications, medical complications, and pulmonary complications; but not significant surgical complications. The high PNI group had lower mortality risk. The results in this study revealed that PNI score was a significant independent predictor of postoperative complications in HNC patients undergoing surgical resection. We recommend preoperative testing and evaluation of HNC patients to identify low PNI and high-risk groups for postoperative surveillance.

Survival of Lung Cancer Patients by Histopathology in Taiwan from 2010 to 2016: A Nationwide Study.

OBJECTIVE: Lung cancer poses a tremendous threat to the modern world. According to Taiwan's Ministry of Health and Welfare, lung cancer took first place in total cancer deaths in 2021. This study investigated the overall lung cancer survival based on histopathology between 2010 and 2016 in Taiwan. METHOD: Data from 2010 to 2016 was collected from the Taiwan Cancer Registry (TCR). The characteristics and overall survival of 71,334 lung cancer patients were analyzed according to the tumor, node, metastasis (TNM) 7th staging system. Univariate and multivariate analyses were performed to identify differences in 1-year, 3-year, and 5-year survival between different histopathologies of lung cancer. RESULTS: The 1-year overall survival rate increased from 54.07% in 2010 to 66.14% in 2016. The 3-year overall survival rate increased from 26.57% in 2010 to 41.12% in 2016 in all patients. Among the histopathologies of lung cancer, 3-year overall survival of adenocarcinoma patients increased the most and largely contributed to the increased 3-year overall survival of all lung cancer patients. CONCLUSIONS: The introduction of target therapy has led to a tremendous increase in overall survival for lung adenocarcinoma patients. However, target therapy differs by histopathology. Choosing the right target therapy and determining the correct histopathology of lung cancer is a pivotal key in increasing the overall survival of patients. Together with immune therapy, the landscape of lung cancer treatments is changing.

Xanthohumol targets the JNK1/2 signaling pathway in apoptosis of human nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is one of the most aggressive malignant tumors of the head and neck. Xanthohumol (Xn) is a compound extracted in a high concentration from the hard resin of hops (Humulus lupulus L.), the basic raw material of beer. This study investigated the apoptotic effect and anticancer properties of Xn in human NPC cell lines. Our study demonstrated that at the concentration 40 µM, Xn significantly reduced cell viability and promoted cell cycle arrest in the G2/M phase in two cell lines. The results indicated that Xn induced apoptosis in NPC cell lines through annexin V/propidium iodide staining, chromatin condensation, and apoptosis-related pathways. Xn upregulated the expression of apoptosis-related proteins, namely DR5, cleaved RIP, caspase-3, caspase-8, caspase-9, PARP, Bim, and Bak, and it downregulated the expression of Bcl-2. Xn upregulated the c-Jun N-terminal kinase (JNK) in the mitogen-activated protein kinase (MAPK), and the inhibition of JNK clearly resulted in decreasing expression of Xn-activated cleaved caspase-3 and PARP. Our research provides sufficient evidence to confirm that Xn induces the MAPK JNK pathway to promote apoptosis of NPC and is expected to become a safe and acceptable treatment option for human NPC.

Impact of illness perception, mental adjustment, and sociodemographic characteristics on return to work in patients with head and neck cancer.

PURPOSE: To examine the effects of emotional distress, illness perception, and mental adjustment on return to work (RTW) among patients with head and neck cancer (HNC) and identify factors associated with RTW. METHODS: A cross-sectional study with convenience sampling was conducted in Taiwan. Structured questionnaires were used to collect data on RTW status and to explore possible factors related to RTW. RTW status was assessed by a single question. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, illness perception was assessed by the Brief Illness Perception Questionnaire, and mental adjustment was assessed using the Mini-mental Adjustment to Cancer Scale. Sociodemographic and disease background data were also collected and analyzed. Factors related to RTW were identified by multivariate logistic regression. RESULTS: A total of 150 patients with HNC were recruited into the study. Of them, 58 (38.7%) returned to work after treatment. Compared to those who did not RTW, patients who did RTW had lower levels of emotional distress (anxiety and depression), better illness perception (cognitive illness representations and illness comprehensibility), and better mental adjustment (hopelessness and helplessness, anxious preoccupation, avoidance, and fatalism). Multivariable analysis indicated that anxiety (OR = 0.863, p < 0.05), avoidance (OR = 1.280, p < 0.001), cognitive illness representations (OR = 0.891, p < 0.01), illness comprehensibility (OR = 1.271, p < 0.05), higher education level (OR = 3.048-3.609, p < 0.05), married status (OR = 5.220, p < 0.05), tumor site in oral cavity (OR = 5.057, p < 0.05), and no reconstruction (OR = 3.415, p < 0.05) were significantly associated with RTW. CONCLUSION: The issue of RTW among patients with HNC is related to multidimensional factors, including sociodemographic, psychological, and disease-related situations. We suggest that programs for emotional rehabilitation and occupational counseling need to be developed to assist patients with HNC to RTW at an early stage.

Modulating effect of Coronarin D in 5-fluorouracil resistance human oral cancer cell lines induced apoptosis and cell cycle arrest through JNK1/2 signaling pathway.

Coronarin D (CD) is one of the main components of Hedychium coronarium rhizome, which has therapeutic potential by reducing cell proliferation in cancer cells. However, the mechanism of CD to 5-fluorouracil (5FU) oral cancer cell remain unclearly. This study discusses the CD to 5FU chemoresistance oral squamous cell carcinoma (OSCC) biochemical mechanisms and possibly pathways to inhibit multiplication in oral cancer. The effect of CD-treated 5FU-chemoresistance human oral cancer cell lines were subjected to MTT assay, cell cycle assay, DAPI assay, annexin-V/PI double staining assay and mitochondrial membrane potential measurement. Furthermore, western blotting was performed to assess the effect of CD on the expression levels of apoptosis related protein and MAPK signaling pathway. The results of the study evidenced that CD reduced viability of 5FU cancer cells in a dose- and time-dependent manner compared with control. The cytotoxic effect of CD lead to cell cycle arrest in the G2/M phase and induced apoptosis in both internal and external pathways. CD induces apoptosis by enhancing phosphorylation of JNK, further exploring the combination of CD and SP600125 reduced the overexpression of phosphate JNK levels. The mechanism of action of CD in 5FU on human oral cancer cells is reported for the first time and can hopeful to be a potential therapeutic agent for 5FU against human oral cancer cells.

The Impact of Metronomic Adjuvant Chemotherapy in Patients with Advanced Oral Cancer.

BACKGROUND: This study evaluated the efficacy of tegafur-uracil for advanced oral cancer. METHODS: From January 2008 to December 2013, clinical data from 356 patients with stage III or IV oral squamous cell carcinoma who received curative surgical resection and postoperative concurrent chemoradiotherapy, treated with or without tegafur-uracil, were analyzed from a prospectively designed database. Tegafur-uracil was orally administered to 114 of the 356 patients. Disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) rates were studied. RESULTS: In our study, the 5-year OS (p = 0.0008), DFS (p = 0.0034), and DSS (p = 0.0029) rates were significantly better in the tegafur-uracil group than in the control group. Distant metastasis occurred in 16.28% of patients in the tegafur-uracil group and 45.28% in the control group (odds ratio 4.3). The distant metastasis rate in the tegafur-uracil group was significantly lower than the control group, indicating that administration of tegafur-uracil after curative surgical treatment and concurrent chemoradiotherapy prevented distant metastasis and improved the OS, DFS, and DSS rate. CONCLUSIONS: The result of tegafur-uracil treatment in patients with advanced oral cancer showed significant improvement in the 5-year OS, DFS, and DSS rate, while also showing a decreased distant metastasis rate. Tegafur-uracil treatment is a useful, effective, and well-tolerated anticancer treatment for advanced oral cancer.

Adenoid cystic carcinoma of head and neck: A retrospective clinical analysis of a single institution.

Objective: In this study, patients with head and neck adenoid cystic carcinoma were investigated with respect to disease characteristics, treatments, and potentially prognostic variables. Materials and Methods: Between January 1995 and December 2010, 29 patients with ACC of the head and neck treated at our institution were retrospectively reviewed. Results: The 29 patients had a mean age of 54.7 years. Of the 29 patients, 4 (13.8%) underwent surgical resection only, 21 (72.4%) underwent surgery with radiotherapy, and 4 (13.8%) received postoperative chemoradiotherapy. Of 9 patients (31.0%) who experienced a recurrence within the follow-up period, 3 (10.3%) had local recurrence and 5 (17.2%) had distant metastasis; 1 (3.4%) patient had both local recurrence and distant metastatic spread. Conclusion: ACC is a relatively rare tumor associated with long survival, even in metastatic settings. Despite aggressive therapy with surgery, radiotherapy, and chemo- therapy, a marked potential for local and distant recurrence still remains.

The effectiveness of school educating program for betel quid chewing: A pilot study in Papua New Guinea.

BACKGROUND: To investigate the effectiveness of educating program among primary and secondary school students in Papua New Guinea, where has the highest incidence of oral cancer all over the world. METHODS: A cross-sectional school based survey was arranged in primary and secondary school in Papua New Guinea in June, 2015. A self-administrated questionnaire was administered before and after education done by health experts from Taiwan. The subjects were chosen by random. The schools provided the students we educated and did the questionnaires on. RESULTS: Ninety five primary school students and 55 secondary school students in Papua New Guinea participated in the study. Before education, both groups lacked the knowledge that betel quid is harmful to health and had no motivation to quit betel quid consumption with the average score 4.580 out of the total score of 8 for primary school students, and the average score of 4.600 out of the total score of 8 for secondary school students. After education, improvements were noted in knowledge of betel quid among both groups, and reached the statistical significance for secondary school students (mean difference 0.700 ± 0.277, 95% CI 0.164-1.248, p-value = 0.018). CONCLUSION: A great achievement was gained by a short time of education. To prevent the incidence and mortality of oral cancer in Papua New Guinea, education programs should be arranged aggressively and effectively.

The iNOS/Src/FAK axis contributes to lithium chloride-mediated macrophage migration.

Lithium chloride (LiCl) has long been used as a mood stabilizer for bipolar mood depression patients. However, its biological effects on immune cells are unclear yet. In this study, we observed that upon LiCl stimulation, the motility and the content of total protein tyrosine phosphorylation in RAW264.7 macrophages and murine peritoneal macrophages (PEMs) were significantly increased. The inhibition of LiCl-induced macrophage migration by PP2 (an inhibitor for Src family kinases (SFKs)) suggested the involvement of SFKs in this process. Interestingly, LiCl induced NF-kB activation, and while Src was greatly induced, the expression of its myeloid relatives (i.e. Lyn, Fgr, Hck) was almost unaltered in RAW264.7 cells. Knockdown of Src suppressed LiCl-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by siRNA-resistant Src. Consistent with Src and migration increment was iNOS-dependent in macrophages, markedly reduced Src expression, activity and cell migration were observed in iNOS-null PEMs treated with LiCl. Moreover, FAK knockdown suppressed LiCl-stimulated macrophage motility, suggesting the involvement of FAK in this process. Remarkably, similar increment of iNOS, Src, FAK Pi-Tyr861 and migration ability could also be detected in RAW264.7 treated with other GSK3ß inhibitors (i.e. SB216763 and Kenpaullone). These results corroborate that through inhibition of GSK3ß, the iNOS/Src/FAK axis occupies a critical role in macrophage locomotion in response to LiCl.

Extra-adrenal paraganglioma presenting as acute chest pain mimicking acute myocardial infarction in a 10-year-old boy.

Extraadrenal paragangliomas are rare pediatric tumors with variable symptoms that cause difficultly in diagnosis and delayed treatment. We report the case of a 10-year-old boy who presented to the pediatric emergency department with acute chest pain and dyspnea mimicking a non-ST-segment elevation acute myocardial infarction. He was subsequently found to have an extraadrenal paraganglioma after a series of imaging and laboratory examinations. The mass was subsequently removed, and the diagnosis of extraadrenal paraganglioma was confirmed histologically. Acute coronary syndrome as the presenting feature of extraadrenal paragangliomas in pediatric population is an even rarer clinical entity.

The inducible nitric-oxide synthase (iNOS)/Src axis mediates Toll-like receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading to interferon-ß synthesis in macrophages.

Double-stranded RNA (dsRNA) induces phosphorylation of Toll-like receptor 3 (TLR3) at tyrosine 759 and subsequently triggers signaling pathways to promote interferon-ß (IFN-ß) production. In this study, we found that dsRNA stimulation induces biphasic TLR3 Tyr-759 phosphorylation in macrophages. In addition to the immediate TLR3 Tyr-759 phosphorylation, we identified a second wave of Tyr-759 phosphorylation accompanied by an increase of both Src and ifn-ß transcription in the later phase of dsRNA stimulation. Interestingly, Src phosphorylated TLR3 Tyr-759 in vitro and in vivo. However, knockdown of Src abolished the late phase of TLR3 Tyr-759 phosphorylation and decreased the nuclear accumulation of interferon regulatory factors 3 and 7 (IRF3 and -7) and IFN-ß production. Reintroduction of Src restored all of these molecular changes. Notably, via down-regulation of Src, dsRNA-elicited TLR3 Tyr-759 phosphorylation, the nuclear accumulation of IRF3/IRF7, and IFN-ß generation were inhibited in inducible nitric-oxide synthase (iNOS)-null macrophages. TLR3 knockdown destabilized Src and reduced the nuclear level of IRF3/IRF7 and IFN-ß production in macrophages exposed to LPS (a TLR4 ligand known to induce Src and IFN-ß expression). Ectopic expression of wild type TLR3, but not its 759-phenylalanine mutant, restored Src activity and ifn-ß transcription. Taken together, these results suggested an essential role of the iNOS/Src/TLR3 axis in IFN-ß production in macrophages.

Rare case of atrophic ectopic kidney with giant hydronephrosis in a 7-year-old girl.

Ectopic kidney is a rare condition. Giant hydronephrosis is also an uncommon lesion in children and is usually due to ureteropelvic junction obstruction. We report a case of 7-year-old girl presenting with abdominal fullness. The imaging characteristics of magnetic resonance urography of the lesions are reported. The findings from the radiologic investigations were suggestive of a dysplastic ectopic pelvic kidney with giant hydronephrosis. Subsequent surgery confirmed the diagnosis. An ectopic kidney with giant hydronehrosis is an extremely rare condition in children and can present as an asymptomatic abdominal mass. A careful survey for other structural anomalies is mandatory in such cases.