Trigger Point Injections for Myofascial Pain in Terminal Cancer: A Randomized Trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a single trigger point injection (TPI) of a local anesthetic for the treatment of myofascial pain syndrome (MPS) in patients with incurable cancer. METHODS: This multicenter, exploratory, open-label, randomized comparative trial was conducted in five specialized palliative care departments. Hospitalized patients with incurable cancer who had been experiencing pain related to MPS were randomized to receive either a TPI of 1% lidocaine plus conventional care (TPI group) or conventional care alone (control group). The short-term efficacy and occurrence of adverse events were compared between groups. The primary endpoint was the percentage of patients who experienced a reduction in pain scores of ≥ 50%, assessed using an 11-point Numerical Rating Scale, at 3 days post-intervention. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v5.0. RESULTS: Fifty patients were enrolled, and the trial completion rate was 100%. The proportion of patients who experienced an improvement in Numerical Rating Scale pain scores of ≥ 50% was 70.8% (95% confidence interval, 52.4% to 89.2%) in the TPI group and 0.0% in the control group; the difference was statistically significant (p < 0.001). In the TPI group, one case (4.2%) of Grade 1 nausea and one case (4.2%) of Grade 1 somnolence were reported. CONCLUSION: A single TPI of a local anesthetic is safe and efficacious in inducing an immediate reduction in MPS-related pain in patients with incurable cancer.

Dimethyl Sulfoxide Attenuates Ionizing Radiation-induced Centrosome Overduplication and Multipolar Cell Division in Human Induced Pluripotent Stem Cells.

Centrosomes are important organelles for cell division and genome stability. Ionizing radiation exposure efficiently induces centrosome overduplication via the disconnection of the cell and centrosome duplication cycles. Over duplicated centrosomes cause mitotic catastrophe or chromosome aberrations, leading to cell death or tumorigenesis. Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), can differentiate into all organs. To maintain pluripotency, PSCs show specific cellular dynamics, such as a short G1 phase and silenced cell-cycle checkpoints for high cellular proliferation. However, how exogenous DNA damage affects cell cycle-dependent centrosome number regulation in PSCs remains unknown. This study used human iPSCs (hiPSCs) derived from primary skin fibroblasts as a PSC model to address this question. hiPSCs derived from somatic cells could be a useful tool for addressing the radiation response in cell lineage differentiation. After radiation exposure, the hiPSCs showed a higher frequency of centrosome overduplication and multipolar cell division than the differentiated cells. To suppress the indirect effect of radiation exposure, we used the radical scavenger dimethyl sulfoxide (DMSO). Combined treatment with radiation and DMSO efficiently suppressed DNA damage and centrosome overduplication in hiPSCs. Our results will contribute to the understanding of the dynamics of stem cells and the assessment of the risk of genome instability for regenerative medicine.

What are the barriers to medical collaboration in community-based integrated care supporting cancer patients? A qualitative analysis of healthcare and long-term care providers' perceptions.

BACKGROUND: Patients required comprehensive cancer treatment in the community based on medical collaboration between designated cancer care hospitals and community medical and nursing care facilities to help them live life on their own terms. This study aims to describe the barriers to medical collaboration in community-based integrated care from the perspectives of healthcare providers (HCPs) and long-term care providers (LCPs) supporting cancer patients. METHODS: Semi-structured interviews were conducted with 88 HCPs and LCPs supporting cancer patients. We analyzed interview data to describe barriers to medical collaboration between designated cancer care hospitals and community medical and nursing care facilities using content analysis in MAXQDA. RESULTS: Participants were mostly HCPs, with physicians accounting for the largest proportion (27.3%). Totally, 299 codes were integrated into seven barriers to medical collaboration in community-based integrated care, including lack of information provision including life perspectives and a delay in sharing cancer patients' values with HCPs to provide end-of-life care according to the patients' wishes. Furthermore, insufficient coordination of cancer and non-cancer symptom management was identified as a barrier specific to older adults with cancer. CONCLUSIONS: Barriers related to cancer treatment that integrate lifestyle perspectives, end-of-life care emphasizing patient values, and medical collaboration between cancer and non-cancer care are distinctive. They emphasize the importance of utilizing professionals to connect treatment and lifestyle information, establishing a central coordinating organization led by the DCCH, and developing a community palliative care network. Moreover, connecting cancer and non-cancer care through government and medical collaboration is crucial.

Structural study of wild-type and phospho-mimic XRCC4 dimer and multimer proteins using circular dichroism spectroscopy.

PURPOSE: To investigate the structural features of wild-type and phospho-mimicking mutated XRCC4 protein, a protein involved in DNA double-strand break repair. MATERIALS AND METHODS: XRCC4 with a HisTag were expressed by E. coli harboring plasmid DNA and purified. Phospho-mimicking mutants in which one phosphorylation site was replaced with aspartic acid were also prepared in order to reproduce the negative charge resulting from phosphorylation. The proteins were separated into dimers and multimers by gel filtration chromatography. Circular dichroism (CD) spectroscopy was performed in the region from ultraviolet to vacuum-ultraviolet. The CD spectra were analyzed with two analysis programs to evaluate the secondary structures of the wild-type and phospho-mimicked dimers and multimers. RESULT AND DISCUSSION: The proportion of ß-strand in the wild-type dimers was very low, particularly in their C-terminal region, including the five phosphorylation sites. The secondary structure of the phospho-mimic hardly changed in the dimeric form. In contrast, the ß-strand content increased and the α-helix content decreased upon multimerization of the wild-type protein. The structural change of multimers slightly depended on the phospho-mimic site. These results suggest that the ß-strand structure stabilizes the multimerization of XRCC4 and it is regulated by phosphorylation at the C-terminal site in living cells. CONCLUSION: An increase in the ß-strand content in XRCC4 is essential for stabilization of the multimeric form through C-terminal phosphorylation, allowing the formation of the large double-strand break repair machinery.

Do Types of Opioids Matter for Terminal Cancer Dyspnea? A Preliminary Multicenter Cohort Study.

CONTEXT: Dyspnea is among the most distressing symptoms in the last weeks to days of life (terminal dyspnea). While physicians frequently use parenteral opioids other than morphine for terminal dyspnea, little is known about their effects in cancer patients. OBJECTIVES: To explore the effectiveness and safety of parenteral morphine, oxycodone, and hydromorphone for cancer patients with terminal dyspnea. METHODS: This was a secondary analysis of a multicenter cohort study that consecutively enrolled advanced cancer patients with moderate/severe terminal dyspnea. Participating palliative care physicians initiated parenteral opioids (morphine/oxycodone/hydromorphone), utilizing a standardized treatment algorithm. We examined the dyspnea intensity (Integrated Palliative care Outcome Scale [IPOS]) at 24 and 48 hours. RESULTS: Of 108 patients (mean age = 72), 66 (61%), 34 (32%), and 8 (7.4%) received morphine, oxycodone, and hydromorphone, respectively. At 24 hours, mean dyspnea IPOS scores significantly decreased from 3.0 (standard error (SE) = 0.1) at the baseline to 1.6 (0.1), 2.9 (0.1) to 2.0 (0.2), and 3.5 (0.2) to 1.2 (0.4) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.011) groups, respectively. At 48 hours, the IPOS scores significantly reduced from 2.9 (0.1) at the baseline to 1.4 (0.1), 2.9 (0.1) to 1.6 (0.2), and 3.5 (0.2) to 1.2 (0.2) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.004) groups, respectively. No significant differences in mean scores were found among the three groups at 24 (P = 0.080) and 48 hours (P = 0.322). Adverse events were rare. CONCLUSION: Parenteral morphine, oxycodone, and hydromorphone may be similarly effective and safe for cancer patients with terminal dyspnea.

APTX acts in DNA double-strand break repair in a manner distinct from XRCC4.

Aprataxin (APTX), the product of the causative gene for hereditary neurogenerative syndromes Ataxia-oculomotor apraxia 1 and early onset ataxia with oculomotor apraxia and hypoalbuminemia, has an enzymatic activity of removing adenosine monophosphate from DNA 5'-end, which arises from abortive ligation by DNA ligases. It is also reported that APTX physically binds to XRCC1 and XRCC4, suggesting its involvement in DNA single-strand break repair (SSBR) and DNA double-strand break repair (DSBR) via non-homologous end joining pathway. Although the involvement of APTX in SSBR in association with XRCC1 has been established, the significance of APTX in DSBR and its interaction with XRCC4 have remained unclear. Here, we generated APTX knock-out (APTX-/-) cell from human osteosarcoma U2OS through CRISPR/Cas9-mediated genome editing system. APTX-/- cells exhibited increased sensitivity toward ionizing radiation (IR) and Camptothecin in association with retarded DSBR, as shown by increased number of retained γH2AX foci. However, the number of retained 53BP1 foci in APTX-/- cell was not discernibly different from wild-type cells, in stark contrast to XRCC4-depleted cells. The recruitment of GFP-tagged APTX (GFP-APTX) to the DNA damage sites was examined by laser micro-irradiation and live-cell imaging analysis using confocal microscope. The accumulation of GFP-APTX on the laser track was attenuated by siRNA-mediated depletion of XRCC1, but not XRCC4. Moreover, the deprivation of APTX and XRCC4 displayed additive inhibitory effects on DSBR after IR exposure and end joining of GFP reporter. These findings collectively suggest that APTX acts in DSBR in a manner distinct from XRCC4.

Protocol for a confirmatory trial of the effectiveness and safety of palliative arterial embolization for painful bone metastases.

BACKGROUND: Transcatheter arterial embolization (TAE) has long been used for hemostasis of traumatic or postoperative hemorrhage and embolization of tumors. Previous retrospective studies of TAE for painful bone metastases showed 60%-80% pain reduction with a median time to response of 1-2 days. Compared with radiotherapy and bisphosphonates, time to response appeared earlier than that of radiotherapy or bone-modifying agents. However, few prospective studies have examined TAE for this indication. Here, we describe the protocol for a confirmatory study designed to clarify the efficacy and safety profile of TAE. METHODS: This study will be a multicenter, single-arm confirmatory study (phase 2-3 design). Patients with painful bone metastases from any primary tumor are eligible for enrollment. TAE will be the main intervention. Following puncture of the femoral artery under local anesthesia and insertion of an angiographic sheath, angiography will confirm that the injected region includes tumor vasculature. Catheter position will be adjusted so that the embolization range does not include non-target tissues. Spherical embolic material will then be slowly injected into the artery to embolize it. The primary endpoint (efficacy) is the proportion of subjects with pain relief at 72 h after TAE and the secondary endpoint (safety) is the incidence of all NCI Common Terminology Criteria for Adverse Events version 5.0 Grade 4 adverse events and Grade ≥ 3 necrosis of the central nervous system. DISCUSSION: If the primary and secondary endpoints are met, TAE can be a treatment choice for painful bone metastases. Trial registry number is UMIN-CTR ID: UMIN000040794. TRIAL REGISTRATION: The study is ongoing, and patients are currently being enrolled. Enrollment started in March 2021. A total of 36 patients have participated as of Aug 2022. PROTOCOL VERSION: Ver1.4, 13/07/2022.

Implication of E3 ligase RAD18 in UV-induced mutagenesis in human induced pluripotent stem cells and neuronal progenitor cells.

Pluripotent stem cells (PSCs) have the potential to differentiate to any of the other organs. The genome DNA integrity of PSCs is maintained by a high level of transcription for a number of genes involved in DNA repair, cell cycle and apoptosis. However, it remains unclear how high the frequency of genetic mutation is and how these DNA repair factors function in PSCs. In this study, we employed Sup F assay for the measurement of mutation frequency after UV-C irradiation in induced pluripotent stem cells (iPSCs) as PSC models and neural progenitor cells (NPCs) were derived from iPSCs as differentiated cells. iPSCs and NPCs exhibited a lower mutation frequency compared with the original skin fibroblasts. In RNA-seq analysis, iPSCs and NPCs showed a high expression of RAD18, which is involved in trans-lesion synthesis (TLS) for the emergency tolerance system during the replication process of DNA. Although RAD18 is involved in both error free and error prone TLS in somatic cells, it still remains unknown the function of RAD18 in PSCs. In this study we depleted of the RAD18 by siRNA knockdown resulted in decreased frequency of mutation in iPSCs and NPCs. Our results will provide information on the genome maintenance machinery in PSCs.

The feasibility and effects of a pharmacological treatment algorithm for cancer patients with terminal dyspnea: A multicenter cohort study.

BACKGROUND: How clinicians treat patients with terminal dyspnea widely varies, which could hamper quality care. We visualized comprehensive pharmacological treatment delivered by palliative care physicians. AIM: To examine adherence to a comprehensive pharmacological treatment algorithm for patients with terminal dyspnea, and to explore its outcomes during 48 h. DESIGN: A multicenter cohort study at five sites (February 2020 to June 2021). SETTING/PARTICIPANTS: We prospectively enrolled consecutive patients with advanced cancer, Eastern Cooperative Oncology Group performance status 3-4, and moderate/severe dyspnea. Participating palliative care physicians initiated algorithm-based treatment. The primary outcome was the proportion of adherence to the treatment algorithm over 24 h (predefined goal, 70%). We evaluated the adherence, goal achievement, and dyspnea level with a numerical rating scale (NRS), as well as adverse events over 48 h. RESULTS: All 108 patients received algorithm-based pharmacological treatment. Among 96 and 87 patients who were alive at 24 and 48 h, respectively, 96 (100%; 95% confidence interval [CI] = 96%-100%) and 82 (94%; 95%CI = 87%-98%) continued to receive the algorithm treatment, respectively, and 66 (69%; 95%CI = 59%-77%) and 64 (74%; 95%CI = 63%-82%) achieved the treatment goals, respectively. Using a complete case analysis with paired t-tests, mean dyspnea NRS scores significantly reduced from 7.3 (standard error, 0.2) at the baseline to 4.9 (0.3) at 24 h (n = 72; p < 0.001), and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h (n = 55; p < 0.001). Most adverse events were mild to moderate. CONCLUSIONS: The comprehensive pharmacological treatment algorithm was feasible, and the study data supports its preliminary efficacy and safety. The use of this algorithm may help clinicians improve care for patients with terminal dyspnea.

Influence of different air CT numbers for IVDT on the dose distribution in TomoTherapy MVCT.

This study aims to evaluate the effect of different air computed tomography (CT) numbers of the image value density table (IVDT) on the retrospective dose calculation of head-and-neck (HN) radiotherapy using TomoTherapy megavoltage CT (MVCT) images. The CT numbers of the inside and outside air and each tissue-equivalent plug of the "Cheese" phantom were obtained from TomoTherapy MVCT. Two IVDTs with different air CT numbers were created and applied to MVCT images of the HN anthropomorphic phantom and recalculated by Planned Adaptive to verify dose distribution. We defined the recalculation dose with MVCT images using both inside and outside air of the IVDT as IVDT MVCT inair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{inair}}$ and IVDT MVCT outair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{outair}}$ , respectively. Treatment planning doses calculated on kVCT images were compared with those calculated on MVCT images using two different IVDT tables, namely, IVDT MVCT inair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{inair}}$ and IVDT MVCT outair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{outair}}$ . The difference between average MVCT numbers ±1 standard deviation on inside and outside air of the calibration phantom was 65 ± 36 HU. This difference in MVCT number of air exceeded the recommendation lung tolerance for dose calculation error of 2%. The dose differences between the planning target volume (PTV): D98% , D50% , D2% and the organ at risk (OAR): Dmax , Dmean recalculated by IVDT MVCT inair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{inair}}$ and IVDT MVCT outair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{outair}}$ using MVCT images were a maximum of 0.7% and 1.2%, respectively. Recalculated doses to the PTV and OAR with MVCT showed that IVDT MVCT outair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{outair}}$ was 0.5%-0.7% closer to the kVCT treatment planning dose than IVDT MVCT inair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{inair}}$ . This study showed that IVDT MVCT outair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{outair}}$ was more accurate than IVDT MVCT inair ${\mathrm{IVDT}}_{\mathrm{MVCT}}^{\mathrm{inair}}$ in recalculating the dose HN cases of MVCT using TomoTherapy.

New aneurysm formation and regrowth associated with rebleeding of residual pediatric ruptured arteriovenous malformation: patient series.

BACKGROUND: If complete obliteration of ruptured pediatric arteriovenous malformation (AVM) cannot be achieved, the appropriate follow-up duration and predictors of rebleeding remain unknown. OBSERVATIONS: Pediatric patients with ruptured AVMs admitted to the authors' hospital within the past 30 years were evaluated. Rebleeding was confirmed in two patients. The first patient was a 5-year-old boy who experienced right thalamic hemorrhage. AVM was found in the bilateral thalamus and treated with stereotactic radiosurgery (SRS). New aneurysm formation and residual AVM regrowth were confirmed 21 years after the SRS. Eight months later, rebleeding occurred. The second patient was a 5-year-old boy who underwent removal of a left cerebellar hemorrhage and AVM. The residual AVM was treated with SRS. Residual AVM regrowth was detected at 6 years 7 months after SRS. Five months later, new aneurysm formation was confirmed. Two additional days later, rebleeding occurred. LESSONS: New aneurysm formation and residual AVM regrowth may predict rebleeding and can occur >20 years after the initial rupture and treatment. If AVM obliteration is not achieved, long-term follow-up is needed, even in adulthood, with attention to new aneurysm formation and residual AVM regrowth. Further treatment is recommended if these findings are confirmed.

Availability of and factors related to interventional procedures for refractory pain in patients with cancer: a nationwide survey.

BACKGROUND: Cancer pain may be refractory to standard pharmacological treatment. Interventional procedures are important for quality of analgesia. The aim of the present study was to clarify the availability of four interventional procedures (celiac plexus neurolysis/splanchnic nerve neurolysis, phenol saddle block, epidural analgesia, and intrathecal analgesia), the number of procedures performed by specialists, and their associated factors. In addition, we aimed to establish how familiar home hospice physicians and oncologists are with the different interventional procedures available to manage cancer pain. METHODS: A cross-sectional survey using a self-administered questionnaire was conducted. Subjects were certified pain specialists, interventional radiologists, home hospice physicians, and clinical oncologists. RESULTS: The numbers of valid responses/mails were 545/1,112 for pain specialists, 554/1,087 for interventional radiology specialists, 144/308 for home hospice physicians, and 412/800 for oncologists. Among pain specialists, depending on intervention, 40.9-75.2% indicated that they perform each procedure by themselves, and 47.5-79.8% had not performed any of the procedures in the past 3 years. Pain specialists had performed the four procedures 4,591 times in the past 3 years. Among interventional radiology specialists, 18.1% indicated that they conduct celiac plexus neurolysis/splanchnic nerve neurolysis by themselves. Interventional radiology specialists had performed celiac plexus neurolysis/splanchnic nerve neurolysis 202 times in the past 3 years. Multivariate analysis revealed that the number of patients seen for cancer pain and the perceived difficulty in gaining experience correlated with the implementation of procedures among pain specialists. Among home hospice physicians and oncologists, depending on intervention, 3.5-27.1% responded that they were unfamiliar with each procedure. CONCLUSIONS: Although pain specialists responded that the implementation of each intervention was possible, the actual number of the interventions used was limited. As interventional procedures are well known, it is important to take measures to ensure that pain specialists and interventional radiology physicians are sufficiently utilized to manage refractory cancer pain.

THE ROLE OF DNA DOUBLE-STRAND BREAK REPAIR THROUGH NON-HOMOLOGOUS END JOINING IN THE DOSE-RATE EFFECT IN TERMS OF CLONOGENIC ABILITY.

It is generally and widely accepted that the biological effects of a given dose of ionizing radiation, especially those of low linear energy transfer radiations like X-ray and gamma ray, become smaller as the dose rate becomes lower. This phenomenon, known as 'dose-rate effect (DRE),' is considered due to the repair of sublethal damage during irradiation but the precise mechanisms for DRE have remained to be clarified. We recently showed that DRE in terms of clonogenic cell survival is diminished or even inversed in rodent cells lacking Ku, which is one of the essential factors in the repair of DNA double-strand breaks (DSBs) through non-homologous end joining (NHEJ). Here we review and discuss the involvement of NHEJ in DRE, which has potential implications in radiological protection and cancer therapeutics.

Psychological Distress among Caregivers for Patients Who Die of Cancer: A Preliminary Study in Japan.

BACKGROUND: In Japan, little is known of the severity of and factors associated with psychological distress among caregivers of patients with advanced or recurrent cancer who die. METHODS: This prospective cohort study of cancer patients at the National Cancer Center Hospital East, Japan, and their caregivers followed the participants from the initial palliative care consultation (T1) to 6 months (T2) and 13 months (T3) after the patient's death. At T1, patients and caregivers were interviewed separately. After T1, telephone interviews were conducted periodically, and a mail survey was distributed at T2 and T3. The Patient Health Questionnaire-9 (PHQ-9) was used to assess depression, and the Distress and Impact Thermometer (DIT) was used to screen for psychological distress. Items on end-of-life attitudes, including awareness, discussion, and willingness of cancer care and death, were developed. RESULTS: Thirty-one of 86 eligible pairs participated in this study. The participation rate was low (36%) and enrollment was thus halted. Data were collected up to T3 for 22 pairs (completion rate 71%). PHQ-9 scores at T2 and T3 were higher than at T1, but the difference was not significant (p = 0.07). PHQ-9 score at T3 was significantly associated with caregiver PHQ-9 and distress at T1, with patient distress and impact at T1, and with caregiver health problems at T2. CONCLUSIONS: Caregiver depression persisted up to 13 months after the patient's death, which suggests that pre-bereavement screening with the DIT might be useful. The present paired enrollment process requires improvement.

Parenting experiences of cancer patients with minor children and their conversations about the possibility of death: a cross-sectional web-based survey for an online cancer community.

PURPOSE: Many cancer patients with minor children experience difficulty talking about their illness with their children. This study aimed to investigate the parenting experiences of cancer patients with minor children and their conversations about the possibility of death. METHODS: A cross-sectional web-based survey was conducted between April and May 2019. Cancer patients with at least one child aged < 18 years were recruited from an online peer support group called "Cancer Parents." The participants were asked to complete a questionnaire about their experiences of talking about their illnesses with their children. The participants were classified into those who disclosed their cancer to their children ("disclosing group"), and those who did not disclose ("non-disclosing group"). The association between whether they talked with their children about their cancer, and whether it included conversations about the possibility of death, was examined. RESULTS: A total of 370 parents participated (with 80.8% female parents, with a median age of 43.0 years). The disclosing group (n = 274, 74.1%) wanted to know what their child felt, more than the non-disclosing group did (p < 0.001). Members of the non-disclosing group had a greater tendency than those in the disclosing group to report that they did not want their children to see their suffering (p = 0.002) and did not know how to explain their disease status (p < 0.002). Some members of both the disclosing (42.1%) and non-disclosing (6.5%) groups told their children about the possibility of death. CONCLUSION: This study showed that 74.1% of the patients with minor children disclosed their cancer to their children. The parents' feelings when thinking about interacting with their children differed significantly between the disclosing and non-disclosing groups. It is important for healthcare professionals treating patients with cancer to provide appropriate multidisciplinary support for discussing their diagnosis and prognosis with their children.

Gliosarcoma with unusual glial components: Two case reports.

Gliosarcoma is characterized by the presence of alternating lesions of glial and mesenchymal components. Although many mesenchymal components have been reported, there are few reports on glial components. We here report two cases of gliosarcoma. Case 1 was a 42-year-old woman with right hemiparesis and motor aphasia. Magnetic resonance imaging (MRI) identified a tumor in the left frontal lobe. Pathological analysis of the tumor removal specimen revealed gliosarcoma, with a glial component resembling pleomorphic xanthoastrocytoma. Postoperatively, radiotherapy and chemotherapy were conducted, and the patient was symptom-free over 12 months after surgery. Case 2 was a 67-year-old woman with a consciousness disorder and left hemiparesis. MRI revealed a tumor in the right frontal lobe. Pathological analysis of the first tumor removal specimen identified gliosarcoma, with a glial component characterized by large tumor cells. Additionally, the Ki-67 labeling index of the glial component was greater than that of the mesenchymal component, and molecular genetic analysis disclosed a mutation in the telomerase reverse transcriptase (TERT) gene (TERT). Chemotherapy and radiotherapy were performed. Four months later, MRI revealed recurrence, and the second surgery was performed. Pathological analysis revealed giant cell glioblastoma without TERT mutation. The patient died due to tumor progression 12 months after the first surgery. It is essential to continue histopathological evaluation of glial components, and further genetic evaluation on gliosarcoma is required.

Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.

Early specialized palliative care for patients with metastatic lung cancer receiving chemotherapy: a feasibility study of a nurse-led screening-triggered programme.

BACKGROUND: Strategies to implement early specialized palliative care have not yet been established. The present study investigated the feasibility of a nurse-led, screening-triggered early specialized palliative care intervention programme and obtained data to design a randomized controlled trial. METHODS: Patients with metastatic lung cancer undergoing first-line platinum-based chemotherapy were eligible. The intervention consisted of (1) a questionnaire-based screening programme and (2) advanced-level nurse counselling and care coordination with interdisciplinary team approach. The primary endpoint was the completion rate of the assessment questionnaire after the second course of first-line chemotherapy (T2). Secondary endpoints included changes in Functional Assessment of Cancer Therapy-Lung scores, depression and anxiety rates based on the Patient Health Questionnaire 9 and the Hospital Anxiety and Depression Scale, and the contents of specialized palliative care. RESULTS: A total of 50 patients were enrolled between August 2012 and March 2014. Median age was 66 years (range, 40-78 year) and 84% were male. A total of 38 patients had stage IV non-small cell lung carcinoma and 12 had extensive disease small-cell lung carcinoma. The completion rate was 70% (95% confidence interval 56.0-81.0). The median duration between baseline and T2 was 53 days. Improvement from baseline were observed at T2 in Functional Assessment of Cancer Therapy-Lung scores (86.0 ± 18.1 vs 94.9 ± 18.2, P = 0.057), depression (16.0 vs 5.7%; P = 0.26) and anxiety (32.0 vs 22.9%; P = 0.65); however, these results were not statistically significant. CONCLUSIONS: This early specialized palliative care intervention is feasible and could be useful in improving patients' quality of life. The present results justify the initiation of a randomized control trial.

Research policy in supportive care and palliative care for cancer dyspnea.

BACKGROUND: Dyspnea is a common and distressing symptom in patients with cancer. To improve its management, multicenter confirmatory studies are necessary. Research policy would be useful in conducting these studies. Here, we propose a new research policy for the management of dyspnea in patients with cancer. METHODS: The first draft was developed by a policy working group of 11 specialists in the field of supportive care or palliative care for dyspnea. Then, a provisional draft was developed after review by a research support group (the Japanese Supportive, Palliative and Psychosocial Care Study Group) and five Japanese scientific societies (Japanese Association of Supportive Care in Cancer, Japanese Society of Medical Oncology, Japanese Society of Palliative Medicine, Japanese Association of Rehabilitation Medicine and Japanese Society of Clinical Oncology), and receipt of public comments. RESULTS: The policy includes the following components of research policy on dyspnea: (i) definition of dyspnea, (ii) scale for assessment of dyspnea, (iii) reason for dyspnea or factors associated with dyspnea and (iv) treatment effectiveness outcomes/adverse events. The final policy (Ver1.0) was completed on 1 March 2021. CONCLUSIONS: This policy could help researchers plan and conduct studies on the management of cancer dyspnea.

Predictive Factors for the Development of Dyspnea Within 7 Days After Admission Among Terminally Ill Cancer Patients.

BACKGROUND: Predictive factors for the development of dyspnea have not been reported among terminally ill cancer patients. OBJECTIVE: This current study aimed to identify the predictive factors attributed to the development of dyspnea within 7 days after admission among patients with cancer. METHODS: This was a secondary analysis of a multicenter prospective observational study on the dying process among patients admitted in inpatient hospices/palliative care units. Patients were divided into 2 groups: those who developed dyspnea (development group) and those who did not (non-development group). To determine independent predictive factors, univariate and multivariate analyses using the logistic regression model were performed. RESULTS: From January 2017 to December 2017, 1159 patients were included in this analysis. Univariate analysis showed that male participants, those with primary lung cancer, ascites, and Karnofsky Performance Status score (KPS) of ≤40, smokers, and benzodiazepine users were significantly higher in the development group. Multivariate analysis revealed that primary lung cancer (odds ratio [OR]: 2.80, 95% confidence interval [95% CI]: 1.47-5.31; p = 0.002), KPS score (≤40) (OR: 1.84, 95% CI: 1.02-3.31; p = 0.044), and presence of ascites (OR: 2.34, 95% CI: 1.36-4.02; p = 0.002) were independent predictive factors for the development of dyspnea. CONCLUSIONS: Lung cancer, poor performance status, and ascites may be predictive factors for the development of dyspnea among terminally ill cancer patients. However, further studies should be performed to validate these findings.